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IRIG: AMPK, HIF-1b and APPL1 in Cell Metabolism

hpguan@mac.com — 2009-05-15T09:37:39-05:00

Here are three outstanding papers in the current issue of Cell Metabolism. Click the title.

Review

AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome

B.B. Zhang, G. Zhou, and C. Li

Articles

APPL1 Potentiates Insulin‑Mediated Inhibition of Hepatic Glucose Production and Alleviates Diabetes via Akt Activation in Mice

K.K.Y. Cheng, M.A. Iglesias, K.S.L. Lam, Y. Wang, G. Sweeney, W. Zhu, P.M. Vanhoutte, E.W. Kraegen, and A. Xu

Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. This study provides evidence demonstrating that the endosomal adaptor protein APPL1 alleviates hepatic insulin resistance by potentiating insulin‑mediated suppression of glucose production in obese mice. In hepatocytes, APPL1 interacts with the protein kinase Akt and blocks the interaction of Akt with its endogenous inhibitor Tribble3, thereby facilitating Akt activation by promoting its translocation to the plasma membrane and endosomes. These findings suggest that APPL1 and Tribble3 act as a "Yin and Yang" pair that tightly controls hepatic glucose production by fine‑tuning the insulin‑evoked Akt signaling cascade.

Ablation of ARNT/HIF1β in Liver Alters Gluconeogenesis, Lipogenic Gene Expression, and Serum Ketones
X.L. Wang, R. Suzuki, K. Lee, T. Tran, J.E. Gunton, A.K. Saha, M.‑E. Patti, A. Goldfine, N.B. Ruderman, F.J. Gonzalez, and C.R. Kahn

Diabetic patients have reduced levels of the transcription factor ARNT/HIF1β in the pancreas, a reduction which is associated with impaired insulin secretion. Here, we show that ARNT is also reduced in the liver of obese individuals with type 2 diabetes. We further demonstrate that liver‑specific knockout of ARNT/HIF1β in mice affects transcriptional networks resulting in increased gluconeogenesis and dyslipidemia but also hypoketonemia, independently of alterations in expression of enzymes in fatty acid β oxidation or hepatic ketogenesis. Our results suggest that modulation of ARNT could be a therapeutic approach in treating diabetes, fatty liver, and the metabolic syndrome.

By Jianping

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Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu

Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Adiponectin and Shp2 in PNAS

hpguan@mac.com — 2009-04-27T11:00:00-05:00

Adiponectin is an adipokine whose activity is determined by
protein multimerization. There are 3 adiponectin complexes in
circulation: trimer, hexamer, and high‑molecular‑weight forms (HMW) of
18‑36 monomers. The 3 forms of adiponectin display distinct biochemical
characteristics and exert nonoverlapping biological functions. In
obesity, adiponectin expression and the molecule multimerization are
both reduced. These changes may contribute to lipid disorder and insulin
resistance. It is not clear what gene regulates the multimerization of
adiponectin. In a recent study, a gene by the name of disulfide‑bond A
oxidoreductase (DsbA) has been found to control the multimer formation.
Please see the paper and commentary at this link:
http://www.ncbi.nlm.nih.gov/pubmed/19011089?dopt=Citation

The activities of many signaling proteins are regulated by kinase
(phosphorylation) and phosphatase (dephosphorylation). A balance of the
two types of enzymes/modifications is required for precise control of
intracellular signal transduction. This is observed in the control of
insulin secretion. In a recent study, Shp2, a widely expressed protein
tyrosine phosphatase (PTP), has been found to regulate insulin secretion
in Beta‑cells. Shp2 controls signaling by receptors for growth factors,
cytokines, and hormones. Shp2 binds to tyrosine‑phosphorylated IRS
proteins and operates in insulin responsive tissue cells. B‑cell
specific knockout of Shp2 led to deficiency in insulin production.
Please see the paper at this link:
http://www.ncbi.nlm.nih.gov/pubmed/19380737?dopt=Citation

By Jianping at PBRC/LSU

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Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Brown fat in Human

hpguan@mac.com — 2009-04-20T11:18:37-05:00

Brown fat is known to produce heat for maintenance of the body
temperature in rodents. Brown adipocytes have a high density of
mitochondria thus make it "brown" in color. Mitochondria in brown
adipocytes are unique in that it oxidizes fatty acid and glucose to
generate heat, not ATP. This feature is due to expression of uncoupling
protein 1 (UCP‑1) that prevents ATP production in the mitochondria. It
has been controversial about existence and function of brown fat in
human. Now, this issue is resolved by three papers in the New England
Journal of Medicine. In these studies, it was found that human body does
have brown fat, but not every body have it. It is found in 7.5% of Women
and 3.5% of man. It produces heat in response to cold environment in
healthy man. It's mass is reduced in obese condition. See attached PDF
files of the three papers and a mini review. These papers are
recommended by Dr. Eugene Chen at the University of Michigan.

Brown fat minireview
Brown fat in healthy adults
Brown fat in healthy men
Brown fat in men and women

Regards,

By Jianping at PBRC/LSU

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu

Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Chronic inflammation in adipose tissue: How and Why?

hpguan@mac.com — 2008-12-15T09:50:13-06:00

Chronic inflammation occurs in adipose tissue in obesity. This
is observed in many excellent studies with an increase in inflammation
cytokines and macrophage infiltration. It has been a question, why does
the inflammation occurs, and how does it mean? For your reference, here
are some results from our studies. The inflammation is likely a result
of hypoxia response in adipose tissue (1), and inflammation may serves
as a signal to stimulate angiogenesis in adipose tissue (2). The hypoxia
response may promote macrophage infiltration through induction of
chemokines (MIF) (1) as well as adipocyte death (3). The hypoxia may
contribute to systemic insulin resistance by increasing FFA and
decreasing adiponectin in circulation since it inhibits storage (TAG)
and secretion functions in adipocytes (1; 3). Adipose tissue hypoxia may
explain many other malfunction in adipose tissue and insulin resistance
in obstructive sleep apnea in obesity (4). Possible cause of the adipose
tissue hypoxia is discussed in a review (4). To keep the post short, I
am sorry that related studies by other labs are not cited here. They are
in the review article (Attached PDF file).

1. Ye J, Gao Z, Yin J, He H: Hypoxia is a potential risk factor for
chronic inflammation and adiponectin reduction in adipose tissue of
ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab
293:E1118‑E1128, 2007

2. Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J: Macrophage Infiltration
into Adipose Tissue May Promote Angiogenesis for Adipose Tissue
Remodeling in Obesity. Am J Physiol Endocrinol Metab 295:E313‑E322, 2008

3. Yin J, Gao Z, He Q, Ye J: Role of hypoxia in obesity‑induced
disorders of glucose and lipid metabolism in adipose tissue. Am J
Physiol Endocrinol Metab doi:10.1152/ajpendo.90760.2008

4. Ye J: Emerging Role of Adipose Tissue Hypoxia in Obesity and Insulin
Resistance. Int J Obes DOI: Dec. 9th 2007, 2008

By Jianping at PBRC

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu

Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIR stands for "Insulin Resistance Interest Group", an electronic and
non‑profitable academic activity for promotion of basic research in
metabolic syndrome. The activity was started by me in 2003 at the
Pennington Biomedical Research Center. If you prefer to stop receiving
this type of e‑mail in the future, please let me know. I will be happy
to make a change in the e‑mail list. The previous posts can be found at:
http://c-ada.org/journalclub/journalclub.html. Your comments on the
post are welcome.

IRIG: Tissue crosstalk in "Cell" and "Science"

hpguan@mac.com — 2008-12-01T16:22:08-06:00

The pathogenesis of systemic insulin resistance involves in
crosstalk among multiple organs/tissues including fat, muscle, liver,
pancreas, gut and brain. It is well accepted that the languages in such
crosstalk are hormones and nerve signals among these organs/tissues.
However, words that are used in these languages (signal mediators)
remains to be fully identified or interpreted. This issue is addressed
by several recent reports in Cell and Science. Below is the brief
introduction.

Fat control of muscle and liver: In Cell, a new product of
adipose tissue named "lipokine" was reported to mediate fat tissue
signal in the control of metabolism in muscle and liver. This new
molecule (real name: C16:1n7‑palmitoleate) is identified with lipidomics
approach. It strongly stimulates muscle insulin action and suppresses
hepatosteatosis. The data reveal a lipid‑mediated endocrine network and
supports a new concept "lipokine" in the crosstalk. This is recommended
by Dr. Steven Smith at PBRC. See PDF file in attachment 1.

Liver control of pancreas: In Science, liver is reported to
regulate B‑cell growth in pancreas through a nerve signal. In the study,
activation of extracellular regulated kinase (ERK) in liver was found to
promote pancreatic B‑cell proliferation. This signaling pathway is
involved in obesity‑induced islet expansion in obesity. It even can
increase B‑cell mass and normalized serum glucose levels in type 1
diabetes model. The study enriches our understanding of nerve in
liver‑pancreas crosstalk. See PDF file in attachment 2.

Gut control of brain: In Cell, a new "Gut‑ Derived
Circulating Factor" is reported to inhibit food intake through the
hypothalamus in the brain. This new factor is
N‑acylphosphatidylethanolamine (NAPE). It is a relatively abundant
plasma lipid and secreted in the small intestine in response to ingested
fat. Systemic administration of NAPE, at physiologic doses, decreases
food intake in rats without causing conditioned taste aversion. The
study highlights the role of lipid in the crosstalk. See PDF file in
attachment 3.

Have a nice Thanksgiving holiday!

By Jianping at PBRC

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu

IRIR stands for "Insulin Resistance Interest Group", an electronic and
non‑profitable academic activity for promotion of basic research in
metabolic syndrome. The activity was started by me in 2003 at the
Pennington Biomedical Research Center. If you prefer to stop receiving
this type of e‑mail in the future, please let me know. I will be happy
to make a change in the e‑mail list. The previous posts can be found at:
http://c-ada.org/journalclub/journalclub.html

IRIG: Adipose Tissue - Hometown of insulin resistance

hpguan@mac.com — 2008-09-10T08:12:10-05:00

It is generally accepted that accumulation of free fatty
acids (FFA) or its derivatives (such as DAG or Ceramide) contributes to
the pathogenesis of insulin resistance. This may be the molecular basis
of hypothesis of ectopic fat deposition or lipotoxicity. Many studies
suggest that the lipid accumulation is a result of adipose tissue
failure in collection and storage of FFA or triglycerides. If adipose
tissue function is enhanced in this regard, there will be no insulin
resistance. This possibility is supported by the metabolic phenotype of
ob/ob mice with overexpression of adiponectin (see attachment 1, JCI
paper). This line of transgenic mice is more obese than ob/ob mice, but
their insulin sensitivity is as good as that in the lean mice. There is
no chronic inflammation in the adipose tissue of these mice. They are
obese, but healthy.

In contrast, if the adipose tissue function is reduced, insulin
resistance may strike much earlier. This possibility is supported by the
metabolic phenotype of db/db mice with leptin receptor reconstitution in
adipose tissue (see attachment 2, PNAS paper). This line of transgenic
db/db mice is resistant to obesity as adipose tissue can not expand as
needed. However, their insulin resistance is more severe than the native
db/db mice. They are lean, but not healthy as a result of ectopic lipid
overload. It seems that adipose tissue is the hometown of insulin
resistance (=lipids). If the hometown is peaceful and good for living,
insulin resistance will stay there quietly. If the hometown is insulted
by "hurricane" and "curfew", insulin resistance will be subject to
evacuation and make a strike. Insulin may act as a policeman to force
lipids (insulin resistance) back into adipose tissue. If adipose tissue
reaches its limit in expansion without extra room, a high dose of
insulin may have a side effect, such as heart attack. This point is in a
recent review in JAMA (attachment 3).

Have a nice day,

By Jianping at PBRC

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: UCP2/grehlin and FGF21/insulin resistance

hpguan@mac.com — 2008-08-07T13:58:16-05:00

Ghrelin, a 28‑aa gut peptide, is a hormone secreted mainly
by stomach in response to starvation. It stimulates food intake through
induction of NPY/AgRP in the hypothalami. A new study at Nature online
suggests that UCP2 (uncoupling protein 2) is required for Ghrelin action
in the stimulation of food intake (See attached paper).

FGF21 (Fibroblast growth factor 21) is a PPARa target gene
in the liver. It's activities in the protection of insulin sensitivity
and anti‑obesity have drawn a lot of attention recently. Several studies
in animal models suggest that FGF21 has "good" metabolic activities.
FGF21‑transgenic animals are resistant to diet‑induced weight gain and
fat accumulation. Administration of FGF21 improved blood glucose,
insulin, and triglycerides (TG) in diabetic mice or monkeys. Its
expression is increased in starvation. FGF21 has been described as a
novel metabolic regulator and as a master hormonal switch for liver
ketogenesis and overall metabolic adaptation to fasting. Does FGF21 act
in human? In the current "Cell Metabolism", a new study shows that FGF21
expression is induced by prolonged fasting and PPARa activator in human.
Please find the details in attached paper.

By Jianping at PBRC/LSU

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Leptin in Nature Medicine and FFA receptor review in JBC

hpguan@mac.com — 2008-06-16T07:02:25-05:00

The central activity of leptin is well established for the
control of food intake. This activity was believed to control adipose
tissue mass through inhibition of appetite. It was not clear if the
central leptin signal can be passed to adipose tissue directly through
nerves. Now, this possibility is supported by a recent study in Nature
Medicine. The paper suggests that leptin activates PI3K signaling
pathway in the brain, and generates a nerve signal, which is delivered
to the adipose tissue by the sympathetic nerves. In this mechanism,
leptin inhibits white adipose tissue mass through suppression of
lipogenesis. Interestingly, leptin finishes the job without activation
of the classical STAT3 signaling pathway in the brain, which is required
for inhibition of appetite by leptin. See details in attached PDF file.
This paper is recommended by Dr. Hans‑Rudolf Berthoud at PBRC.

Receptors for free fatty acids (FFA) have drawn a lot of
attention in research for the FFA signaling pathways. Many cell membrane
receptors have been proposed to mediate FFA signal into the cells. These
included TLR4, CD36, FATP, and G‑protein related receptors. Recently,
the G‑protein related receptors have gained more territory in the fields
of metabolism, obesity and diabetes. For example, GPR40 is a G‑protein
receptor for FFA. It specifically mediates FFA signal in pancreatic
B‑cells. Knockout of GPR40 was shown to prevent insulin resistance
without influencing adiposity. If you like to know more about this group
of receptors, see attached review article from JBC.

Have a nice weekend,

Jianping at PBRC/LSU

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center (PBRC)
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

IRIR stands for "Insulin Resistance Interest Group", an electronic and
non‑profitable activity for promotion of basic research in metabolic
syndrome. The activity was started by me in 2003 at the Pennington
Biomedical Research Center. If you prefer to stop receiving this type of
e‑mail in the future, please let me know. I will be happy to make a
change in the e‑mail list.

IRIG: Gut-brain-liver axis controls liver glucose production

hpguan@mac.com — 2008-04-24T09:45:06-05:00

Liver is a primary organ in glucose production in fasting condition. This liver activity is regulated by Insulin/Glucagon system. In fasting, glucagon from pancreatic A cells stimulates the glucose production. In response to food intake, insulin from pancreatic B cells inhibits the glucose production. It was controversial about the role of neural signal in the regulation of glucose production. The data from dog model suggests that a nerve signal is not involved in the control of liver function. In the current "Nature", this question is addressed in a rat study through vagotomy or gut vagal deafferentation. The study shows that there is neural connection between the gut and the brain. The connection is able to sense lipids in the gut and pass the signal to liver to inhibit glucose production. This is an excellent study about endocrine‑independent mechanism in the control of glucose homeostasis.
See attached PDF file.

The neuropeptide Y (NYP) is a neurotransmitter with well‑known function in the stimulation of food intake in the brain. In ob/ob mice, an increase in NPY contributes to hyperphagia, and obesity. Its expression in response to emotional stress may explain increased food intake or stress‑related obesity. In "Nature", it is found that a single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro, and seems to account for more than half of the variation in expression in vivo. This polymorphism predicts brain responses to emotional and stress challenges. See attached PDF file.

By Jianping at PBRC

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: TORC2 and PGC-1 in Science and EMBO

hpguan@mac.com — 2008-04-17T15:59:32-05:00

TORC2 and PGC‑1 are two nuclear coactivators in the control of glucose metabolism. TORC2 that was highlighted in IRIG several times promotes gluconeogenesis in liver through CREB, a transcription factor that activates PEPCK and G6Pase expression for glucose production. TORC2 activity is regulated by serine phosphorylation. In the Science, TORC2 (also named as CRTC2) was found to promote hepatic gluconeogenesis in response to glucose or related analogs (mannose, fructose, or galactose). The mechanism is modification of TORC2 by O‑glycosylation, which is triggered by glucose or its analogs. The importance of signaling protein modification by glycosylation is demonstrated again in the regulation of glucose metabolism. Modification of IRS‑1 by glycosylation was highlighted in IRIG earlier.

PGC‑1 is a downstream target of TORC2, which promotes PGC‑1a expression through CREB. Activity of PGC‑1a is regulated by expression, phosphorylation, and acetylation. Deacetylation of PGC‑1a by SIRT1 is involved in induction of hepatic gluconeogenesis. PGC‑1a also stimulates mitochondrial function through gene transcription. In EMBO, PGC‑1a is shown to enhance fatty acid oxidation in muscle through induction of mitochondrial function. The study suggests that in response to fasting, PGC‑1a is activated in muscle by SIRT1‑medaited deacetylation. This paper is recommended by Dr. Eric Ravussin at PBRC.

These two studies provide new evidence that epigenetic signaling pathways are important in the regulation of glucose metabolism. Attached are PDF files of the two papers. Previous posts in IRIG can be found at: http://c-ada.org

By Jianping at PBRC

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center (PBRC)
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763‑3163
E‑mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: O-GlcNAc and PGC-1 in Nature

hpguan@mac.com — 2008-03-09T20:20:17-05:00

           The negative-feedback loop in the insulin signaling pathway is a framework for the concept of post-receptor signaling defect theory, which represents the mainstream views of insulin resistance. In the school, inhibition of insulin receptor substrates (IRSs) by serine/threonine kinases is the core. Many molecular hypotheses for insulin resistance, such as inflammation, ER stress, mitochondrial dysfunction, oxidative stress, hyperinsulinemia, and hypoadiponectinemia, are built on the core. A new study in Nature enriched the theory by demonstration that insulin may promote IRS-1 inhibition by increasing glycocylation of IRS-1. The enzyme O-GlcNAc transferase (OGT) mediates this activity of insulin. This paper is recommended by Dr. Marina Bouché at the University of Rome, Italy. (See PDF file attached).

            PGC-1a is another “star” molecule like SIRT1. PGC-1a is a transcription coactivator originally identified in the study of PPARg. PGC-1a is involved in glucose homeostasis, mitochondrial biogenesis, circadian rhythm, and energy expenditure. A new study in Nature shows that PGC-1a is involved in protection of microcirculation from ischemia damage by promoting angiogenesis. The mechanism is induction of VEGF expression by PGC-1a. (See PDF file attached).

            By the way, the “Insight” section of Nature is focused on Cardiovascular disease in this issue. It contains eight excellent reviews about different aspects of CVDs. Here is the link: http://www.nature.com/nature/index.html


By Jianping at PBRC

-----------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Studies in Nature, Science and Cell

hpguan@mac.com — 2008-03-09T20:19:22-05:00

            The product of longevity gene SIRT1 has been a “Star” molecular in the past five years. Most of papers about SIRT1 are published in the top journals. This reflects the strong desire of the scientific community for understanding molecular mechanism of ageing. Now, SIRT1 is known to regulate carcinogenesis, energy metabolism and embryo development. All of these activities are “good” for longevity. The precise control of SIRT1 activity is of interesting. In Nature, two recent studies suggest that SIRT1 activity is controlled by breast cancer-related gene. DBC1 (deleted in breast cancer 1) is shown to be a native inhibitor of SIRT1 in human cells. See attached PDF. These papers are recommended by Dr. Eric Ravussin at PBRC.

Control of blood glucose is a major work in the treatment of diabetes. However, the degree of reducing blood glucose is controversial. To clarify the issue, the best way is clinical trial though it is very expensive. Now, a report in Science suggests that reducing blood glucose to the normal level is bad in long term as the diabetes patients died at a higher rate in the clinical trial. See PDF attached. This is recommended by Dr. Zhong Yun at the Yale University.

            Hyperglycemia leads to insulin resistance. The molecular mechanism is related to oxidative stress. In Cell, a study shows that glucose may induce insulin resistance in muscle by reducing diacylglycerol (DAG) kinase. This leads to an increase in DAG and PKC activity for insulin resistance. Though it is well known that glucose increases DAG level, people believe that it is a result of enhanced DAG production. This study suggests that a reduction in DAG metabolism contributes to the increase. See PDF attached.

            An interesting paper about Ghrelin at: http://www.sciencedirect.com/science/article/B6WSN-4RSJ9JW-C/2/d1fb4471d9bd18c50fc64043372e929c

By Jianping at PBRC

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu

IRIG: Insulin secretion, PPARg and inflammation of ageing in "Nature Medicine"

hpguan@mac.com — 2008-02-10T08:26:22-06:00

Following are three papers in the current issue of “Nature Medicine”. These papers are related to insulin secretion, PPARg and inflammation of ageing.

Dual role of proapoptotic BAD in insulin secretion and beta cell survival       pp144 - 153
Nika N Danial et al.
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ei2a0SohGc0HjT0Bm7x0Eh
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ei2a0SohGc0HjT0Bm7y0Ei

Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-[gamma] phosphorylation            pp188 - 193
Tetsuya Hosooka et al.
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ei2a0SohGc0HjT0Bm8B0Eo
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ei2a0SohGc0HjT0Bm8C0Ep

Oxidative damage-induced inflammation initiates age-related macular degeneration pp194 - 198
Joe G Hollyfield et al.
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ei2a0SohGc0HjT0Bm8D0Eq
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ei2a0SohGc0HjT0Bm8E0Er

By Jianping at PBRC

---------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Autophagy in Metabolic Syndrome

hpguan@mac.com — 2008-01-13T08:38:22-06:00

In the current issue of “Cell”, there is a very nice review article on “Autophagy”. The role of autophagy in metabolic syndrome, longevity, and various diseases are covered in the review. What is “Autophagy”? In the introduction, it states that “One of the most evolutionarily conserved cellular responses to organismal fasting is the activation of the lysosomal degradation pathway of autophagy, a process in which the cell self-digests its own components. This self-digestion not only provides nutrients to maintain vital cellular functions during fasting but also can rid the cell of superfluous or damaged organelles, misfolded proteins, and invading microorganisms. Interestingly, self-digestion by autophagy—a process that is potently triggered by fasting—is now emerging as a central biological pathway that functions to promote health and longevity.” Attached is the PDF file.

By Jianping

----------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Lipotoxicity = Mitochondria + ROS

hpguan@mac.com — 2008-01-13T08:29:47-06:00

Two studies in recent issues of “Cell Metabolism” and “Cell ” suggest that overloading of mitochondria with fatty acids drives oxidative phosphorylation out of control in mitochondria, leading to incomplete metabolism of fatty acids and overproduction of ROS (reactive oxygen species). Prevention of lipid abuse of oxidative phosphorylation by gene knockout protected the mice from insulin resistance in dietary obese mice. The two studies suggest that lipotoxicity is a result of ROS production from lipid overloading in mitochondria.
In the first study, fatty acid oxidation in mitochondrial was found to be increased in skeletal muscle of dietary obese mice. However, the increase did not bring in benefit, but incomplete oxidation of fatty acids. The abused mitochondria produced large amount of ROS in oxidation of overloaded fatty acids. It is proposed that ROS leads to insulin resistance in cells loaded with fatty acids. These conclusions are supported by data from metabolomic analysis of tricarboxylic acid cycle products in mitochondria. This paper is recommended by Dr. Eric Ravussin at Pennington (See attachment 1).
In the second study in “Cell”, mitochondrial oxidative phosphorylation is reduced by deletion of AIF (apoptosis inducing factor) gene. Tissue-specific deletion of AIF in muscle or liver generated mitochondrial deficiency in oxidative phosphorylation in the two organs. This engineered mitochondrial “dysfunction” did not produce extra ROS in the presence of lipid overloading. The knockout mice gained weight at normal rate on high fat diet, but did not develop insulin resistance (See attachment 2). This study provides a nice support to the first study about role of mitochondrial ROS in lipid-induced insulin resistance.

By Jianping

---------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Why TZD increases rate of bone fractures in diabetic individuals ?

hpguan@mac.com — 2008-01-13T08:23:54-06:00

TZD is a well-established insulin sensitizer that is widely used in clinics for the treatment of type 2 diabetes. Among the major side effects of TZD, increased rate for bone fractures has been known together with the side effects of TZD on CDV system. The molecular mechanism underlying the TZD-associated fracture is not clear. One possibility is that activation of PPARg by TZD inhibits the differentiation of osteoblasts that are required for bone formation. PPARg is known to inhibit differentiation of stem cells into osteoblasts and at meantime promotes differentiation of the stem cells into adipocytes. In response to PPARg activation, loss of esteoblasts will lead to less formation of bone materials, and thus bone fracture. However, this possibility is challenged by a study in “Nature Medicine”, in which an increase in bone absorption was found to be the reason for TZD-associated fracture. This point is demonstrated using tissue-specific PPARg knockout mice in which PPARg is removed in both endothelial cells and osteoclasts. Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. The PPARg-KO made the bone density much higher in the transgenic mice as bone-resorbtion was inhibited in the bone. This is a result of loss of osteoclasts. The study reveals that PPARg is required for osteoclast differentiation from the bone marrow cells. With normal PPARg expression in osteoblasts, the KO mice does not loss bone mass in response to TZD. Attached is the PDF file of this paper.

Merry Christmas!

By Jianping at PBRC

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Reviews about obesity and Mitochondria

hpguan@mac.com — 2007-11-05T20:56:30-06:00

Attached are three papers listed below.

1. Gesta S, Tseng YH, Kahn CR: Developmental origin of fat: tracking obesity to its source. Cell 131:242-256, 2007

2. Jager S, Handschin C, St-Pierre J, Spiegelman BM: AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104:12017-12022, 2007

3. Detmer SA, Chan DC: Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870-879, 2007

By Jianping

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Obesity without insulin resistance and AMPK crystal

hpguan@mac.com — 2007-10-15T15:41:22-05:00

There are many hypotheses for insulin resistance under lipotoxicity. These include inflammation, liver steatosis, ER stress, oxidative stress, PKC/Ceramide and hyperinsulinemia. These concepts are generated to explain pathogenesis of insulin resistance in obesity. In the current issue of Nature Medicine, a report suggests that the length of fatty acid chain is critical for the lipotoxicity. If synthesis of 18C fatty acid is abolished in the body, the gene knockout mice will develop obesity on high fat diet as the wild type mice do. However, insulin sensitivity will not be severely damaged by the obesity. The gene is called Elovl6 that catalyze biosynthesis of 18C fatty acid from 16C fatty acid. The study suggests that fatty acid with a chain longer than 16C is “Toxic” (See attachment 1 and 2). Elovl6 is similar to SCD1, but SCD1 KO mice are not obese on HFD. This paper is recommended by Dr. Eric Ravussin at Pennington.

        AMPK is an intracellular sensor of energy (ATP) supply. Activation of MAPK leads to an increase in fat and glucose oxidation in mitochondria in liver and muscle, promotes insulin sensitivity in peripheral tissues, and regulate food intake through the hypothalamus. In “Nature”, the crystal structure of AMPK is reported. The study suggests that in normal condition, AMPK binds to ATP for inactivation (See attachment 3).

By Jianping at PBRC

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: TORC2 and aP2 in "Nature"

hpguan@mac.com — 2007-09-11T22:32:23-05:00

       In last IRIG post, insulin is shown to inhibit hepatic gluconeogenesis through the Akt2-PGC1 pathway in a Nature paper. Now, the story is extended by another paper online in Nature. In this new study, TORC2, a coactivator of transcription factor CREB, is identified as a downstream molecule for Akt. In response to insulin, Akt inhibits TORC2 function through ubiquitination-mediated TORC2 degradation (See attachment 1). This event leads to inactivation of the transcriptional activity of CREB, which is required for expression of key enzymes (PEPCK and G6Pase) in hepatic gluconeogenesis. Both TORC2 and PGC-1 are coactivators for CREB, but they act at different steps in the transcription initiation mechanism of CREB. The two papers suggest that in response to insulin, Akt may target more than one transcription coactivator for suppression of gluconeogenesis in liver.

       aP2 (also known as fatty acid binding protein 4, FABP4) is a small cytoplasmic protein expressed in adipocytes and macrophages. The function of aP2 is related to lipolysis in adipocytes and inflammation response in macrophages. In the absence of aP2, lipolysis is reduced and fat accumulation is increased in adipocytes, inflammation cytokine expression is reduced in macrophages. In aP2 KO mice, adiposity is increased, but insulin sensitivity is not decreased. These findings suggest aP2 as a therapeutic target for treatment of obesity-associated insulin resistance. This possibility was tested in a study published in Nature. A small molecule designed to inhibit aP2 function specifically was used in mouse and cell models. The inhibitor decreased inflammation response in macrophages, improved insulin sensitivity, and reduced atherosclerosis and more. Please find details in attachment 2. This paper is recommended by Dr. Michael Roden (the Karl-Landsteiner Institute for Endocrinology and Metabolism, Vienna) who has a comment on this paper in Cell Metabolism (Aug. issue).

Have a nice weekend!

-----------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: PGC-1/Akt interaction in "Nature" and PPARg regulator in "Cell"

hpguan@mac.com — 2007-08-25T22:27:20-05:00

Liver produces glucose from amino acids through gluconeogenesis. If glucose is too much to be consumed by the peripheral tissues (muscle or fat), liver will covert the carbohydrate into fatty acids or triglycerides through hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride and a reduction in plasma high-density lipoprotein. This is demonstrated in human in a new study in PNAS (See attachment 1). The hepatic gluconeogenesis and lipogenesis is regulated by insulin, which inhibits the two processes through the PI3K/Akt signaling pathway. In a “Nature” paper, a new event at downstream Akt is identified for the insulin-mediated inhibition. Akt2 was found to phosphorylate PGC-1 resulting in inhibition of PGC-1 function (See attachment 2). This event leads to shutdown of gene expression in the programs for gluconeogenesis and lipogenesis in the liver. PGC-1 is a coactivator of PPARg. In a “Cell” paper, a small molecule (Harmine) from a botanical product was found to increase insulin sensitivity by inducing PPARg gene expression. Harmine acts by inhibition of the Wnt signaling pathway (See attachment 3, 2MB in size).

The paper in attachment 1 is recommended by Dr. Zhenqi Liu (University of Virginia School of medicine), and paper in attachment 3 is recommended by Dr. Eugene Chen (University of Michigan Medical Center).

Have a nice weekend.

By Jianping at PBRC

------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

RIG: Akt review in Cell

hpguan@mac.com — 2007-08-04T15:03:41-05:00

Akt (PKB) is a serine kinase in the signaling pathway of insulin receptor. In the metabolic branch of the signaling pathway, Akt mediates insulin signal for GLUT4 translocation, glycogen synthesis (Through GSK-3) and protein synthesis (through mTOR/S6K). However, this is only a part of biological activities of Akt in cells. A recent review in Cell gives a nice update on molecules at up- and down-stream of Akt. By the way, a figure in "Cell Signaling" website is helpful to get a full picture of Akt activities. See attached PDF files.

        In the current issue of "Molecular Cell", a new study made a progress in the signaling pathway of FFA. It is known that FFA may induce insulin resistance by targeting IRS-1 in the insulin receptor pathway. This activity is dependent on activation of PKC-JNK kinase axis by FFA. However, the molecules linking PKC to JNK are not completely identified in the FFA pathway. This study shows that a kinase by name of MLK (mixed lineage kinase) mediates PKC signal for JNK activation. Knockout of MLK may reduce Ser307 phosphorylation in IRS-1. See attached PDF file.

by Jianping at PBRC

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Longevity in "Science" and Lipid-ER interaction in "Nature"

hpguan@mac.com — 2007-08-04T14:54:55-05:00

Insulin resistance in obesity increases risk for type 2 diabetes and cardiovascular diseases. These diseases usually accelerate aging and reduce lifespan. However, a study in the current issue of Science suggests that insulin resistance from IRS-2 knockout increased lifespan together with body weight. The abstract states that "In mice, less insulin receptor substrate–2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%." The study suggests that the role of insulin resistance in aging and longevity of obese subjects is not that simple. See attached paper that is recommended by Dr. Dixit at PBRC.

         ER stress in obesity has been used to explain insulin resistance. Oversupply of lipid may cause ER stress. However, it is not clear how lipid induces ER stress in obese condition. In the current issue of Nature, an article presents a hypothesis for the regulation of ER function by lipid. See attached paper.

By Jianping at PBRC

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Incretin Safety in JAMA

hpguan@mac.com — 2007-07-20T06:34:37-05:00

Incretin are defined as a hormone produced in the gastrointestinal tract in response to food (especialy carbohydrates) intake, and stimulating insulin secretion in the presence of glucose. Presently, there are are two such hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Since incretin is able to reduce blood glucose and increase insulin sensitivity, GLP-1 has been a pharmalogical target in the control of glucose in clinics. Safety of GLP-1 analogues and GLP-1 enhancer (Dipeptidyl peptidase 4 inhibitors) has been a concern. In the current issue of JAMA, this issue is addressed in a review article. The conclusion is that "Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0-4.2] for nausea and 3.2 [95% CI, 2.5-4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection". See detail in attached paper.

By Jianping at PBRC

---------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: NYP jumps out of brain, article in Nature Medicine

hpguan@mac.com — 2007-07-11T02:19:54-05:00

Neuropeptide Y (NPY) is a neurotransmitter with well-known function in the stimulation of food intake in the brain. In ob/ob mice, expression of NPY is increased in the brain and this increase contributes to hyperphagia, which leads to obesity in ob/ob mice on a regular diet. It is generally believed that NPY is expressed in the brain, and acts locally in the brain. In the current issue of Nature Medicine, a new study suggests that NPY is able to act in the adipose tissue for development of central obesity in stress condition, such as cold or aggression. This peripheral activity of NPY includes stimulation of proliferation and differentiation of preadipocytes, promotion of angiogenesis and inhibition of lipolysis in adipose tissue. NYP is found to be released from sympathetic nerves in response to the stress. The study suggests a novel function of NPY. Attached is the paper and commentary.

This paper is also recommended by Drs. Eric Ravussin and Vishwa Dixit at PBRC.

By Jianping at PBRC

--------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Macrophage as TZD target for insulin sensitization in Natureand JCI

hpguan@mac.com — 2007-07-11T02:16:14-05:00

TZD is a powerful medicine for improvement of insulin sensitivity in both human and animals. Adipocytes are generally believed as the primary target of TZD, which activates the nuclear receptor PPARg. PPARg expression is highest in adipocytes and adipocyte differentiation is induced by TZD. However, this concept is challenged by new studies published in Nature and JCI in June. Both studies consistently suggest that PPARg in macrophages is required for maintenance of insulin sensitivity and energy balance. When PPARg is specifically knocked out in macrophages, mice developed metabolic syndrom and lost response to TZD. See details in attached PDF files.

Akt is a serine kinase in insulin signaling pathway. The up- and down-stream molecules of Akt are actively studied in several fields, including endocrinology, immunology and cancer biology. The reason is that Akt is also involved in signaling transduction of other growth factors. Attached include a review for Akt in this issue of Cell.

By Jianping at PBRC/LSU

----------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Vitamin A and aP2 inhibitor in Nature and Nature medicine

hpguan@mac.com — 2007-06-09T19:47:19-05:00

Association of vitamin A (or its products) with glucose metabolism is indicated by the finding of RBP4 (retinol binding protein 4) in the regulation of insulin sensitivity. In 2005, RBP4 was reported as an insulin resistance protein secreted by adipocytes of GLUT4 knockout mice. The study suggests a possible role of vitamin A or its derivatives such as ratinoic acids in the regulation of insulin sensitivity. This possibility is confirmed in a new study in Nature Medicine, in which vitamin A product, Retinaldehyde, is shown to enhance insulin sensitivity in mice. An increase in Retinaldehyde led to resistance to dietary obesity and prevention of insulin resistance. The mechanism is about inhibition of adipocyte differentiation. In this report, retinaldehyde is claimed to bind to RBP4, but the biological consequence of the binding was not clearly discussed. See attached PDF file of the paper.

aP2 (fatty acid binding protein 4) was thought to be expressed in adipocytes only. Therefore, aP2 gene promoter has been used as a adipocyte-specific promoter in transgenic studies to control fat-specific gene expression. Although it is known now that aP2 is also expressed in macrophages, the aP2 promoter is still widely used for the fat-specific gene expression in the absence of substitute promoter. Knockout of aP2 gene was shown to prevent obesity and insulin resistance in transgenic mice. Then, does aP2 inhibitor work in the same way? This question is answered by a new study in Nature advanced online publication, in which an orally active small-molecule inhibitor of aP2 is shown to be an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. See attached PDF files.

Have a nice weekend.

By Jianping at PBRC/LSU

------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Muscle insulin resistance

hpguan@mac.com — 2007-05-22T06:58:33-05:00

Accumulation of triglycerides in skeletal muscle was taken as an indicator of muscle insulin resistance. However, this idea was challenged by a reverse association of TG and insulin resistance in the trained athlete muscle. Increasing evidence suggests that not TG, but intermediates of FFAs (DAG and ceramide), are the problem in muscle for insulin resistance. This concept is re-enforced by two new studies in JCI as following.

In last e-mail, I provided a PDF file of my review that is not printable. Now, the printable file is attached. Thanks a lot for your interest in the printable file.

Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance
Simon Schenk and Jeffrey F. Horowitz
published 17 May 2007, 10.1172/JCI30566 [Abstract] [PDF]

Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance Li Liu, Yiying Zhang, Nancy Chen, Xiaojing Shi, Bonny Tsang, and Yi-Hao Yu published 17 May 2007, 10.1172/JCI30565 [Abstract] [PDF]
by Jianping at PBRC
-----------------------------------
Jianping Ye, MD Professor of Molecular Biology Pennington Biomedical Research Center Louisiana State University System 6400 Perkins Road Baton Rouge, LA 70808 Phone: (225) 763-3163 Fax: (225) 763-2525 E-mail: yej@pbrc.edu

IRIG: Obesity in "Cell" and "Science"

hpguan@mac.com — 2007-05-20T21:18:49-05:00

In the current issue of Cell, a very nice review article summarizes recent advance in hormone control of food intake, a central topic in the study of obesity. Hormones or peptides produced by fat cells, the gastrointestinal tract, and the pancreas are discussed in the regulation of appetite. The molecular pathway is proposed for each hormones.

        In the current issue of Science, a new gene by the name of FTO (fat mass and obesity associated gene) is reported as a genetic factor predisposing to obesity. This gene is identified through a genowise screening of human genes. Mutation of this gene is associated with an increase in body weight or BMI.

       In obesity, hyperinsulinemia and insulin resistance stays together. Their relationship represents a question of chicken and egg. Although most people believe that insulin resistance happens before hyperinsulinemia in obesity, the concept remains to be tested. With an interest into this question, I reviewed literature and wrote an article to support hyperinsulinemia for insulin resistance. I have received many requests for it through e-mail. Here, I wish to share it with you. Comments are welcome.

Attached are the PDF files of three papers mentioned above.

By Jianping at PBRC

—-----------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: PGC-1a in Nature and Metformin in JCI

hpguan@mac.com — 2007-05-09T21:30:00-05:00

PGC-1a (PPARg coactivator 1a) is a transcription coactivator for many transcription factors that are involved in the regulation of glucose and fat metabolism. PGC-1a has been a model to demonstrate the role of nuclear cofactor in the control of metabolism. PGC-1a stimulates gluconeogenesis through induction of key enzymes PEPCK and G6Pase, promotes fatty acid oxidation and heat production through mitochondrial biosynthysis and UCP1 expression. In a recent issue of "Nature", PGC-1a is reported to link biological clock to energy metabolism in mice (See attached PDF file). The study further supports the role of PGC-1a in the regulation of energy (glucose and fat) metabolism.

Metformin is a popular medicine in the control of blood glucose in patients with metabolic syndrom. The action mechanism of metformin is related to stimulation of glycolysis for glucose consumption. This activity is dependent on uptake of metformin by cells. In a recent issue of JCI, it is reported that cellular uptake of metformin is determined by a transmembrane protein by the name of organic cation transporter 1 (OCT1). In the absence of OCT1, metformin failed to exhibit its therapeutic activity in the OCT1 knockout mice. Given the high degree polymorphism of OCT1 gene in human, this study provides molecular basis for personalized medicine. Attached is the PDF file of the paper and the editorial.

By Jianping at PBRC

—----------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Regulation of fat inflammation by STAMP (Cell paper)

hpguan@mac.com — 2007-05-09T21:28:33-05:00

Inflammation contributes to insulin resistance in obesity. However, it is not clear what molecular pathway is involved in initiation of the chronic inflammation (such as TNFa, IL-6 expression and macrophage infiltration) in adipose tissue under obesity. Although FFA and ER stress have been shown to contribute to the inflammatory response, the whole story seems far from completed. The search for new molecule or mechanism is undergoing in adipose tissue. In this respect, a new study published in the current issue of "Cell" demonstrates that a transmembrane protein "STAMP2" is a new molecule for the story. STAMP2 belongs to the STAMP or STEAP family of six transmembrane domain proteins. Members of this family are metalloreductases that are important for the cellular import of iron and copper. Loss of STAMP2 in mice leads to increased inflammatory response in adipose tissue. See full text of the paper in attached PDF file.

By Jianping at PBRC

—-----------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Ceramide in insulin resistance in "Cell Metabolism"

hpguan@mac.com — 2007-03-15T23:27:01-05:00

Although it is generally accepted that FFA is a risk factor for insulin resistance, it is quite controversial about the signaling molecules for FFA-induced insulin resistance. Ceramide and DAG are two derivatives of FFA. It has been confusing about which of the two FFA derivatives is the "dominant player" in the translation of FFA signal into insulin resistance. Each molecule is supported by multiple published studies of many labs. In the current issue of "Cell Metabolism", a study using transgenic and pharmacological approaches demonstrated that ceramide is the "dominant player". Inhibition of ceramide led to blocking of insulin resistance in three models: glucocorticoid, FFA and obesity. In these conditions, DAG level was not changed by ceramide inhibition. See attache PDF file.

     Regarding adiponectin receptor knockout mice, there are two additional studies published in "Diabetes" and Endocrinology" this month along with the one in "Nature Medicine". It seems that the metabolic phenotypes are not consistent among the three independent studies. Attached are the PDF files from Diabetes and Endocrinology. These two papers are recommended by Drs. Lu Cai at the University of Louisville, and Jianhua Shao at the University of Kentucky.

by Jianping at PBRC

—-----------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Adiponectin receptor knockout in "Nature Medicine"

hpguan@mac.com — 2007-03-07T20:27:04-06:00

The metabolic activities of adiponectin have been well known for some times. However, its nature of hormone or cytokine is challenged by its high protein concentration (mg level) in the blood. Cloning of its receptor and identification of the receptor signaling pathways support the hormone/cytokine nature of adiponectin. Now, this consensus is enforced by a knockout study of the adiponectin receptor in the current issue of Nature Medicine. This issue also has another exciting study to provide evidence that TZD (PPARg) acts on Beta-cells through ABCA1. Following are links to these papers.

Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions pp332 - 339
Toshimasa Yamauchi et al.
10.1038/nm1557
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ecoP0SohGc0HjT0BNem0EP
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ecoP0SohGc0HjT0BNen0EQ

[beta]-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment pp340 - 347
Liam R Brunham et al.
10.1038/nm1546
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ecoP0SohGc0HjT0BNeo0ER
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ecoP0SohGc0HjT0BNep0ES

The ABCs of [beta]-cell dysfunction in type 2 diabetes pp241 - 242
Cholesterol toxicity may damage pancreatic [beta]-cells, leading to decreased insulin secretion and impaired glucose tolerance (pages 340-347).
Manu V Chakravarthy and Clay F Semenkovich
10.1038/nm0307-241
http://ealerts.nature.com/cgi-bin24/DM/y/ecoP0SohGc0HjT0BNd50ES

By Jianping at PBRC

—-------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: New diabetes genes and models for GKS-3b in Nature

hpguan@mac.com — 2007-02-16T01:03:43-06:00

There are two interesting papers published online in Nature. The first one is about identification of new genes for type 2 diabetes through genome-wide analysis of gene polymorphism. A couple of beta-cell specific genes were found to associate with risk of type 2 diabetes. The second study describes a new model for analysis of GSK-3b function in transgenic mice. GSK-3b is quickly degraded after tagged with a short amino acid sequence by the name of FRB (FKBP/rapamycin binding). The degradation leads to inactivation of GSK-3b in the transgenic mice. Rapamycin is able to block the degradation in vivo through specific binding to the tag domain in the fusion protein of GSK-3b. Following are the links to these two papers.

ADVANCE ONLINE PUBLICATION
------------------------------
11 February 2007
Article
A genome-wide association study identifies novel risk loci for type 2 diabetes
Robert Sladek et al.
doi:10.1038/nature05616
http://ealerts.nature.com/cgi-bin24/DM/y/ecWf0SohGc0HjB0BL4G0Ea
See also: News and Views by Freimer & Sabatti
http://ealerts.nature.com/cgi-bin24/DM/y/ecWf0SohGc0HjB0BL4H0Eb

Letters
Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice
Karen J. Liu et al.
doi:10.1038/nature05557
http://ealerts.nature.com/cgi-bin24/DM/y/ecWf0SohGc0HjB0BL4I0Ec

by Jianping at PBRC

—-------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Obestatin in "Science" and S6K in JCI IRIG: Obestatin in "Science" and S6K in JCI IRIG: Obestatin in "Science" and S6K in JCI IRIG: Obestatin in "Science" and S6K in JCI IRIG: Obestatin in "Science" and S6K in JCI

hpguan@mac.com — 2007-02-09T07:26:11-06:00

Obestatin, a peptide derived from the ghrelin precursor, has an activity opposite to ghrelin for appetite. In the action mechanism, obestatin was reported to activate the orphan G protein–coupled receptor GPR39. This activity of obestatin is under debate in two technical comments in the current issue of Science. Below is the titles and links.

Comment on "Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake"
N. Chartrel, R. Alvear-Perez, J. Leprince, X. Iturrioz, A. Reaux-Le Goazigo, V. Audinot, P. Chomarat, F. Coge, O. Nosjean, M. Rodriguez, J. P. Galizzi, J. A. Boutin, H. Vaudry, and C. Llorens-Cortes

http://www.sciencemag.org/cgi/content/abstract/315/5813/766c?etoc
p. 766

Response to Comment on "Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake"
Jian V. Zhang, Cynthia Klein, Pei-Gen Ren, Stefan Kass, Luc Ver Donck, Dieder Moechars, and Aaron J. W. Hsueh

http://www.sciencemag.org/cgi/content/abstract/315/5813/766d?etoc
p. 766

S6K is a signaling enzyme in the insulin receptor pathway. S6K has been shown to induce IRS-1 serine phosphorylation (at Ser307 in mouse or Ser312 in human) for insulin resistance. S6K knockout mice are resistant to obesity and insulin resistance. In the current JCI, mice with increased S6K activity have "Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2". Below are titles and links of the paper and relative comment in JCI.

Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2 Olivier Le Bacquer, Emmanuel Petroulakis, Sabina Paglialunga, Francis Poulin, Denis Richard, Katherine Cianflone, and Nahum Sonenberg J. Clin. Invest. 2007; 117:387-396. [Abstract] [Full Text] [PDF]
A link between protein translation and body weight Liangyou Rui J. Clin. Invest. 2007; 117:310-313. [Abstract] [Full Text] [PDF]

By Jianping at PBRC
—--------------------------------------------------
Jianping Ye, MD Professor of Molecular Biology Pennington Biomedical Research Center Louisiana State University System 6400 Perkins Road Baton Rouge, LA 70808 Phone: (225) 763-3163 Fax: (225) 763-2525 E-mail: yej@pbrc.edu

IRIG: PKC regulation of mitochondria in Science

hpguan@mac.com — 2007-02-07T08:52:20-06:00

Protein kinase C (PKC) may have dual activities in the regulation of glucose and fatty acid metabolism. When it is over-activated by DAG (Diaglyceride), PKC may induce insulin resistance by increasing serine phosphorylation of insulin receptor as well as insulin receptor substrate 1 (IRS-1). This happens when DAG level is increased in cells under obesity or lipid infusion. Oxidative stress from hyperglycemia also induces PKC over-activation.

       On the other side, inactivation of PKC in mice may lead to reduction in energy expenditure promoting obesity and insulin resistance on high fat diet. The molecular basis of this activity remains unknown for PKC. A study in the current issue of Science may provide a possible mechanism. In the investigation of aging-related protein p66Shr, PKC was shown to activate this protein through phosphorylation, leading to production of free radicals in the mitochondria. This activity of PKC was demonstrated in an extreme condition where the cells were treated with H2O2 for apoptosis. Although regulation of the mitochondrial function by PKC was used to explain apoptosis in the study, the linkage of PKC to p66Shr suggests that in the physiological condition, PKC may use this channel to stimulate metabolism of glucose and fatty acids in the mitochondria. Mitochondrial production of free radicals is associated with metabolism of glucose or fatty acids. In obesity, PKC may use this linkage to induce mitochondrial dysfunction. These possibilities are not discussed in the paper, but it is worth to read it. Attached is PDF file of this paper.

        In the current issue of Nature Medicine, there are several interesting papers related to molecular physiology related to metabolic syndrom. Below is the list.

Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins pp171 - 180
Tony K T Lam et al.
10.1038/nm1540
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ecOm0SohGc0HjT0BLcW0Eu
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ecOm0SohGc0HjT0BLcX0Ev

Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity pp189 - 197
Jane A Leopold et al.
10.1038/nm1545
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ecOm0SohGc0HjT0BLca0E5
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ecOm0SohGc0HjT0BLcb0E6

Angiotensin II type 1 receptor blockade attenuates TGF-[beta]-induced failure of muscle regeneration in multiple myopathic states pp204 - 210
Ronald D Cohn et al.
10.1038/nm1536
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ecOm0SohGc0HjT0BLce0EA
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ecOm0SohGc0HjT0BLcf0EB

by Jianping at PBRC

—---------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Interesting papers in JCI and JBC

hpguan@mac.com — 2007-01-25T00:14:49-06:00

Neuronal SH2B1 is essential for controlling energy and glucose homeostasis
Decheng Ren, Yingjiang Zhou, David Morris, Minghua Li, Zhiqin Li, and Liangyou Rui
published 18 January 2007, 10.1172/JCI29417 [Abstract] [PDF]

MAP4K4 gene silencing in human skeletal muscle prevents TNF-a-induced insulin resistance
Karim Bouzakri and Juleen R. Zierath
published 16 January 2007, 10.1074/jbc.M608602200 [Abstract] [PDF]

Protein Kinase Cd Plays a Non-redundant Role in Insulin Secretion in Pancreatic B Cells Toyoyoshi Uchida, Noseki Iwashita, Mica Ohara-Imaizumi, Takeshi Ogihara, Shintaro Nagai, Jong Bock Choi, Yoshifumi Tamura, Norihiro Tada, Ryuzo Kawamori, Keiichi I. Nakayama, Shinya Nagamatsu, and Hirotaka Watada J. Biol. Chem. 2007; 282:2707-2716. [Abstract] [Full Text] [PDF]
Glucose Stimulates Ca2+ Influx and Insulin Secretion in 2-Week-old B-Cells Lacking ATP-sensitive K+ Channels Andras Szollosi, Myriam Nenquin, Lydia Aguilar-Bryan, Joseph Bryan, and Jean-Claude Henquin J. Biol. Chem. 2007; 282:1747-1756. [Abstract] [Full Text] [PDF]
The luminal Vps10p domain of sortilin plays the predominant role in targeting to insulin-responsive Glut4-containing vesicles Jun Shi and Konstantin V. Kandror published 12 January 2007, 10.1074/jbc.M608971200 [Abstract] [PDF]
Skp2 Controls Adipocyte Proliferation during the Development of Obesity Tamon Sakai, Hiroshi Sakaue, Takehiro Nakamura, Mitsuru Okada, Yasushi Matsuki, Eijiro Watanabe, Ryuji Hiramatsu, Keiko Nakayama, Keiichi I. Nakayama, and Masato Kasuga J. Biol. Chem. 2007; 282:2038-2046. [Abstract] [Full Text] [PDF]
Calcineurin Regulates Skeletal Muscle Metabolism via Coordinated Changes in Gene Expression Yun Chau Long, Stephan Glund, Pablo M. Garcia-Roves, and Juleen R. Zierath J. Biol. Chem. 2007; 282:1607-1614. [Abstract] [Full Text] [PDF]
Glucose Induces MafA Expression in Pancreatic Beta Cell Lines via the Hexosamine Biosynthetic Pathway Nathan L. Vanderford, Sreenath S. Andrali, and Sabire Özcan J. Biol. Chem. 2007; 282:1577-1584. [Abstract] [Full Text] [PDF]
Regulation of S6 kinase 1 activation by phosphorylation at Ser411 Zhibo Hou, Lisheng He, and Robert Z. Qi published 12 January 2007, 10.1074/jbc.M607836200 [Abstract] [PDF]
By Jianping at PBRC
—----------------------------------
Jianping Ye, MD Professor of Molecular Biology Pennington Biomedical Research Center Louisiana State University System 6400 Perkins Road Baton Rouge, LA 70808 Phone: (225) 763-3163 Fax: (225) 763-2525 E-mail: yej@pbrc.edu

IRIG: Controversy on obesity gene in Science

hpguan@mac.com — 2007-01-16T22:01:36-06:00

It was reported in Science (Reports, 14 April 2006, p. 279) about an association between the INSIG2 gene variant rs7566605 and obesity in four sample populations, under a recessive model. The controversy about the association is reported in the current issue of Science. Data from a couple of labs does not support the association. See below.

In Science Magazine

TECHNICAL COMMENTS
Comment on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity"
Christian Dina, David Meyre, Chantal Samson, Jean Tichet, Michel Marre, Beatrice Jouret, Marie Aline Charles, Beverley Balkau, and Philippe Froguel (12 January 2007)
Science 315 (5809), 187b. [DOI: 10.1126/science.1129402]
| Abstract » | Full Text » | PDF »

TECHNICAL COMMENTS
Comment on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity"
Ruth J. F. Loos, Inês Barroso, Stephen O'Rahilly, and Nicholas J. Wareham (12 January 2007)
Science 315 (5809), 187c. [DOI: 10.1126/science.1130012]
| Abstract » | Full Text » | PDF »

TECHNICAL COMMENTS
Comment on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity"
Dieter Rosskopf, Alexa Bornhorst, Christian Rimmbach, Christian Schwahn, Alexander Kayser, Anne Krüger, Grietje Tessmann, Ingrid Geissler, Heyo K. Kroemer, and Henry Völzke (12 January 2007)
Science 315 (5809), 187d. [DOI: 10.1126/science.1130571]
| Abstract » | Full Text » | PDF »

REPORTS
A Common Genetic Variant Is Associated with Adult and Childhood Obesity
Alan Herbert, Norman P. Gerry, Matthew B. McQueen, Iris M. Heid, Arne Pfeufer, Thomas Illig, H.-Erich Wichmann, Thomas Meitinger, David Hunter, Frank B. Hu, Graham Colditz, Anke Hinney, Johannes Hebebrand, Kerstin Koberwitz, Xiaofeng Zhu, Richard Cooper, Kristin Ardlie, Helen Lyon, Joel N. Hirschhorn, Nan M. Laird, Marc E. Lenburg, Christoph Lange, and Michael F. Christman (14 April 2006)
Science 312 (5771), 279. [DOI: 10.1126/science.1124779]
| Abstract » | Full Text » | PDF » | Supporting Online Material »

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Controversy about Leptin CRP interaction

hpguan@mac.com — 2007-01-11T04:18:55-06:00

In last year, Nature Medicine reported that leptin interacts with CRP (C-reactive peptide), and the interaction may account for leptin resistance in obesity. This concept is challenged by results from three independent groups using different experiment systems. The argument is published in the current issue of Nature Medicine (see links below). This is also recommended by Dr. Vishwa Dixit at PBRC.

Is leptin an important physiological regulator of CRP?
I Sadaf Farooqi and Stephen O'Rahilly
10.1038/nm0107-16
http://ealerts.nature.com/cgi-bin24/DM/y/ebtw0SohGc0HjT0BJAQ0Ey

Is leptin an important physiological regulator of CRP?
Winston L Hutchinson et al.
10.1038/nm0107-17
http://ealerts.nature.com/cgi-bin24/DM/y/ebtw0SohGc0HjT0BJAR0Ez

Is leptin an important physiological regulator of CRP?
Arieh Gertler, Leonora Niv-Spector and Shay Reicher
10.1038/nm0107-18
http://ealerts.nature.com/cgi-bin24/DM/y/ebtw0SohGc0HjT0BJAS0E1

Is leptin an important physiological regulator of CRP?
Allan Zhao
10.1038/nm0107-19
http://ealerts.nature.com/cgi-bin24/DM/y/ebtw0SohGc0HjT0BJAT0E2

by Jianping at PBRC

—--------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Glucose is a ligand of nuclear receptor LXR in Nature

hpguan@mac.com — 2007-01-04T07:20:50-06:00

LXR (liver X receptor) is a nuclear receptor with alpha and beta isoforms. LXR function is well established in the control of lipid metabolism in liver. When it is activated by ligands such as oxysterols and 6a-hydroxy bile acids, it stimulates tryglicerides synthesis in liver, and induces cholestreol efflux in macrophages. This function is mediated through expression of transcription factor SREBP, a target gene of LXR. In Nature online publication, a study suggests that glucose is a physiological ligand for LXR. Glucose is shown to activate the transcriptional activity of LXR through direct binding to LXR. LXR is claimed as a sensor for glucose. The study provides a new mechanism by which glucose controls lipid synthesis. See attached PDF file.

by Jianping at PBRC

—-----------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Interesting papers in Cell Metabolism and JCI

hpguan@mac.com — 2007-01-04T07:17:35-06:00

A Central Thermogenic-like Mechanism in Feeding Regulation: An Interplay between Arcuate Nucleus T3 and UCP2
A. Coppola, Z.-W. Liu, Z.B. Andrews, E. Paradis, M.-C. Roy, J.M. Friedman, D. Ricquier, D. Richard, T.L. Horvath, X.-B. Gao, and S. Diano. Cell Metabolism, Vol 5, 21-33, January 2007

The Transcriptional Coactivator PGC-1ß Drives the Formation of Oxidative Type IIX Fibers in Skeletal Muscle
Z. Arany, N. Lebrasseur, C. Morris, E. Smith, W. Yang, Y. Ma, S. Chin, and B.M. Spiegelman. Cell Metabolism, Vol 5, 21-33, January 2007

Glucokinase and IRS-2 are required for compensatory ß cell hyperplasia in response to high-fat diet–induced insulin resistance Yasuo Terauchi, Iseki Takamoto, Naoto Kubota, Junji Matsui, Ryo Suzuki, Kajuro Komeda, Akemi Hara, Yukiyasu Toyoda, Ichitomo Miwa, Shinichi Aizawa, Shuichi Tsutsumi, Yoshiharu Tsubamoto, Shinji Hashimoto, Kazuhiro Eto, Akinobu Nakamura, Mitsuhiko Noda, Kazuyuki Tobe, Hiroyuki Aburatani, Ryozo Nagai, and Takashi Kadowaki J. Clin. Invest. 2007; 117:246-257. [Abstract] [Full Text] [PDF]

A dominant role for glucose in ß cell compensation of insulin resistance Gordon C. Weir and Susan Bonner-Weir J. Clin. Invest. 2007; 117:81-83. [Abstract] [Full Text] [PDF]

Obesity induces a phenotypic switch in adipose tissue macrophage polarization Carey N. Lumeng, Jennifer L. Bodzin, and Alan R. Saltiel J. Clin. Invest. 2007; 117:175-184. [Abstract] [Full Text] [PDF]

Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure Tanya Hansotia, Adriano Maida, Grace Flock, Yuichiro Yamada, Katsushi Tsukiyama, Yutaka Seino, and Daniel. J. Drucker J. Clin. Invest. 2007; 117:143-152. [Abstract] [Full Text] [PDF]

The first two papers in "Cell Metabolism" are recommended by Dr. Eric Revussin at the Pennington Biomedical Research Center.
-----------------------------------------
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Hot topic in "Nature" - Obesity and Type 2 diabetes

hpguan@mac.com — 2006-12-15T08:00:08-06:00

In the current issue of Nature, several review articles are published around obesity and type 2 diabetes to provide an update in the field of metabolic syndrom research. Additionally, two original studies are reported for identification of a new molecular mechanism controlling insulin signaling. Following is the related content of this issue.

By Jianping at PBRC
—-----------------------------------------
INSIGHT OF NATURE
----------------------
INTRODUCTION
Obesity and diabetes
Deepa Nath, Marie-Therese Heemels and Lesley Anson
10.1038/444839a
http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHwz0EB

REVIEW ARTICLE
Mechanisms linking obesity to insulin resistance and type 2 diabetes
Steven E. Kahn, Rebecca L. Hull and Kristina M. Utzschneider
10.1038/nature05482
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw10Ew
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw20Ex

Adipocytes as regulators of energy balance and glucose homeostasis
Evan D. Rosen and Bruce M. Spiegelman
10.1038/nature05483
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw30Ey
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw40Ez

Gut hormones and the regulation of energy homeostasis
Kevin G. Murphy and Stephen R. Bloom
10.1038/nature05484
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw50E1
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw60E2

Inflammation and metabolic disorders
Gokhan S. Hotamisligil
10.1038/nature05485
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw70E3
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHw80E4

Sirtuins as potential targets for metabolic syndrome
Leonard Guarente
10.1038/nature05486
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxA0EF
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxB0EG

Mechanisms linking obesity with cardiovascular disease
Luc F. Van Gaal, Ilse L. Mertens and Christophe E. De Block
10.1038/nature05487
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxC0EH
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxD0EI

Abdominal obesity and metabolic syndrome
Jean-Pierre Despres and Isabelle Lemieux
10.1038/nature05488
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxE0EJ
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxF0EK
Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance
An inhibitor of SecinH3 is identified, and shows that treatment of mice with
this molecule induces hepatic insulin resistance, an early step in the
development of type 2 diabetes.
Markus Hafner et al.
10.1038/nature05415
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxe0Ep
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxf0Eq

The cytohesin Steppke is essential for insulin signalling in Drosophila
A complementary study to that of Famulock et al. shows that feeding SecinH3 to
flies inhibits steppke, a cytohesin, leading to growth defects and a block in
insulin signalling.
Bernhard Fuss, Thomas Becker, Ingo Zinke and Michael Hoch
10.1038/nature05412
Abstract: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxg0Er
Article: http://ealerts.nature.com/cgi-bin24/DM/y/ebgD0SohGc0HjB0BHxh0Es

------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm

IRIG: Botanicals and Adipogenesis

hpguan@mac.com — 2006-11-28T07:36:51-06:00

Botanical products are widely used in folk medicines in the treatment of metabolic or endocrine diseases. The National Center for Complementary and Alternative Medicines (NCCAM/NIH) are supporting research in botanicals. Now, single botanical compound with known chemical structure are attracting more attention in the basic research of metabolic syndrom. In this regard, we highlighted a "Nature" paper about Resveratrol (in variety of fruits, such as grape skin) in insulin sensitization and longevity in the last IRIG post. Here, two more examples published in "Cell Metabolism" are included.

       The first is Genipin that was reported to inhibit UCP-2 (uncoupling protein 2) in beta-cells, and protect beta-cell function in type 2 diabetes. The second is Chloroquine, a medicine for treatment of malaria. Chloroquine is reported to activate ATM (Ataxia Telangiectasia Mutated) kinase and reduce risk of cardivescular diseases in apoE-/- deficient mice (recommended by Dr. Frank Greenway at PBRC). Both Genipin and Chloroquine are single compounds from the Chinese Herbal Medicines. See attached PDF files.

      Mechanisms of adipogenesis is of interest in basic research of obesity. In the current issue of "Nature Reviews Molecular Cell Biology", there is a review about adipogenesis, which should include new insights in the molecular network controlling adipogenesis. See attached PDF file (provided by Dr. Feng Liu at UTHSC, San Antonio).

by Jianping

—----------------------------------



Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525

IRIG: Longevity and Immunity in "Nature"

hpguan@mac.com — 2006-11-02T20:09:37-06:00

SIRT1 is a longevity protein whose activity is positively associated with longevity. The chemical nature of SIRT1 is histone deacetylase. In yeast, SIRT1 is called Sir2. The function of SIRT1/Sir2 is increased by caloric restriction. In the nucleus, SIRT1 regulates gene transcription through modification of chromatin structure. SIRT1 in known to regulate the transcriptional activities of several nuclear factors including p53, NF-kB, PPARg, and PGC-1. It was speculated that a chemical activator of SIRT1 should be able to extend life span in mammalians. Resveratrol, an extract from botanicals especially skin of grapes, is one of the chemical activators of SIRT1. Resveratrol has been well known for its anti-cancer activities. In Nature online, it is reported that resveratrol is able to extend the life span of obese mice, and the mechanism is associated with insulin sensitization by resverarol. See attached PDF file.
          The endocrine function of adipose tissues is well known in obesity field. Leptin and adiponectin are two unique cytokines in the adipose tissue. Many other adipokines (such as TNF-a, IL-6, and MCP1) are also produced by immune cells. A possible interaction between adipose tissue and immune system has been in speculation for some times. However, there is not many good review articles to address the interaction in detail. In the current "Nature Reviews Immunology", such a review is available now. See attached PDF file.

By Jianping at PBRC

—---------------------------------


Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Insulin, PGC-1, GSK-3 in "Nature" and "Cell"

hpguan@mac.com — 2006-10-30T07:16:59-06:00

In the current "Nature Reviews: Molecular Cell Biology", there is a nice review article about signaling pathway of insulin. It introduces current understanding of the pathway and also summarizes major events in the history on study of the pathway. Attached is the PDF file (provided by Feng Liu at UTHSCS).

        In the current "Cell", a study demonstrates that PGC-1a is an important nuclear protein in the inhibition of reactive oxygen species (ROS). In the absence of PGC-1a, ROS production is increased from the respiratory chain reaction in the mitochondria. The ROS leads to degeration of neuron in cell culture and in PGC-1a KO mice. See attached PFD file.

       In the current "Molecular Cell", a study suggests that mTOR/S6K is able to regulate GSK-3 activity through Akt. See attached PDF file.

       In the current JCI, a study supports that free fatty acids induce inflammation in adipocytes and macrophages through activation of the Toll like receptor 4 (TLR4). In the TLR4 knockout female mice, inflammation was reduced and insulin sensitivity was preserved on high fat diet although the body weight was even higher. See attached PDF file.

By Jianping at PBRC
—-------------------------------------------


Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Papers in Nature about PGC-1 and Food intake

hpguan@mac.com — 2006-10-18T21:18:32-05:00

PGC-1 (PPARg coactivator 1) was identified as a transcriptional coactivator for nuclear receptor PPARg. Now, PGC-1 is known to interact with many transcription factors in the regulation of gene expression in addition to PPARg. The biological activities of PGC-1 are well-established in the promotion of hepatic gluconeogenesis and mitochondrial biosynthesis. In the regulation of gluconeogenesis in the liver, PGC-1 has been shown to promote transcription of the rate-limiting enzyme (G6Pase and PEPCK) through an interaction with transcription factors including HNF4, FOXO1 and CREB. In a recent issue of Nature, it is reported that PGC-1 does not directly interact with FOXO1 in G6Pase gene promoter, and is not required for the FOXO1 function. The PGC-1/HNF4 interaction is confirmed for their function in G6Pase expression. Attached is the PDF file.

         Regulation of food intake is a focus in obesity research with an expectation that the research will lead to identification of a target for drug intervention of food intake, which will be useful in prevention and treatment of obesity. However, the current understanding of the mechanism of food intake has not been able to provide an effective drug target for such a purpose. As a result, the research in this field has drawn a great deal of attention. This is reflected by the increasing number of review articles in the high profile journals in recent years. In Nature, a review about food intake is published recently (see attached PDF file). This paper is recommended by Dr. Roy Martin at Pennington.

By Jianping at PBRC
—---------------------------------------------


Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Interesting papers in JAMA and JBC

hpguan@mac.com — 2006-10-18T07:35:31-05:00

Following are some interesting papers in JAMA and recent issues of JBC.
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Insulin Effects Weigh Heavy on the Brain M. J. Friedrich JAMA. 2006; 296:1717-1718. [Extract] [Full Text] [PDF]

Oncostatin M inhibits adipogenesis through the Ras/ERK and STAT5 signaling pathways Yuichiro Miyaoka, Minoru Tanaka, Takahiro Naiki, and Atsushi Miyajima published 6 October 2006, 10.1074/jbc.M606089200 [Abstract] [PDF]

Transcription Factor Activating Enhancer-binding Protein-2: A NEGATIVE REGULATOR OF ADIPONECTIN GENE EXPRESSION Kazuhiro Ikeda, Hiroshi Maegawa, Satoshi Ugi, Yukari Tao, Yoshihiko Nishio, Shuichi Tsukada, Shiro Maeda, and Atsunori Kashiwagi J. Biol. Chem. 2006; 281:31245-31253. [Abstract] [Full Text] [PDF]

Negative Modulation of RXR Transcriptional Activity by Small Ubiquitin-related Modifier (SUMO) Modification and Its Reversal by SUMO-specific Protease SUSP1 Soo Joon Choi, Sung Soo Chung, Eun Jung Rho, Hyung Woo Lee, Moon Hee Lee, Hueng-Sik Choi, Jae Hong Seol, Sung Hee Baek, Ok Sun Bang, and Chin Ha Chung J. Biol. Chem. 2006; 281:30669-30677. [Abstract] [Full Text] [PDF]

A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion Sarah M. Ronnebaum, Olga Ilkayeva, Shawn C. Burgess, Jamie W. Joseph, Danhong Lu, Robert D. Stevens, Thomas C. Becker, A. Dean Sherry, Christopher B. Newgard, and Mette V. Jensen J. Biol. Chem. 2006; 281:30593-30602. [Abstract] [Full Text] [PDF]

Underexpressed Coactivators PGC1 AND SRC1 Impair Hepatocyte Nuclear Factor 4 Function and Promote Dedifferentiation in Human Hepatoma Cells Celia P. Martínez-Jiménez, M. José Gómez-Lechón, José V. Castell, and Ramiro Jover J. Biol. Chem. 2006; 281:29840-29849. [Abstract] [Full Text] [PDF]

Effect of TRB3 on Insulin and Nutrient-stimulated Hepatic p70 S6 Kinase Activity Rie Matsushima, Nagakatsu Harada, Nicholas J. G. Webster, Yasuo M. Tsutsumi, and Yutaka Nakaya J. Biol. Chem. 2006; 281:29719-29729. [Abstract] [Full Text] [PDF]

Osmotic Stress Activates the TAK1-JNK Pathway While Blocking TAK1-mediated NF-B Activation: TAO2 REGULATES TAK1 PATHWAYS Wei-Chun HuangFu, Emily Omori, Shizuo Akira, Kunihiro Matsumoto, and Jun Ninomiya-Tsuji J. Biol. Chem. 2006; 281:28802-28810. [Abstract] [Full Text] [PDF]

Insulin Regulation of Cholesterol 7-Hydroxylase Expression in Human Hepatocytes: ROLES OF FORKHEAD BOX O1 AND STEROL REGULATORY ELEMENT-BINDING PROTEIN 1c Tiangang Li, Xiaoying Kong, Erika Owsley, Ewa Ellis, Stephen Strom, and John Y. L. Chiang J. Biol. Chem. 2006; 281:28745-28754. [Abstract] [Full Text] [PDF]

Destruction of Pancreatic -Cells by Transgenic Induction of Prostaglandin E2 in the Islets Hiroko Oshima, Makoto Mark Taketo, and Masanobu Oshima J. Biol. Chem. 2006; 281:29330-29336. [Abstract] [Full Text] [PDF]

The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion Jamie W. Joseph, Mette V. Jensen, Olga Ilkayeva, Ferdinando Palmieri, Cristina Alarcon, Christopher J. Rhodes, and Christopher B. Newgard published 25 September 2006, 10.1074/jbc.M602606200 [Abstract] [PDF]

by Jianping at PBRC
-----------------------------—-
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Leptin action in "Neuron"

hpguan@mac.com — 2006-10-04T07:46:18-05:00

Following are some interesting papers in the current issue of Neuron (Neuron, Vol. 51, Iss. 6, 2006).

Leptin in Energy Balance and Reward: Two Faces of the Same Coin?
Pages 678-680
Daniela Cota, Jason G. Barrera and Randy J. Seeley

Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding
Pages 801-810
Jonathan D. Hommel, Richard Trinko, Robert M. Sears, Dan Georgescu, Zong-Wu Liu, Xiao-Bing Gao, Jeremy J. Thurmon, Michela Marinelli and Ralph J. DiLeone

Leptin Regulation of the Mesoaccumbens Dopamine Pathway
Pages 811-822
Stephanie Fulton, Pavlos Pissios, Ramon Pinol Manchon, Linsey Stiles, Lauren Frank, Emmanuel N. Pothos, Eleftheria Maratos-Flier and Jeffrey S. Flier

Thoughts for Food: Brain Mechanisms and Peripheral Energy Balance
Pages 691-702
Alfonso Abizaid, Qian Gao and Tamas L. Horvath

By Jianping at PBRC/LSU
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Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Gluconeogenesis and insulin receptor in "Nature"

hpguan@mac.com — 2006-10-04T07:45:25-05:00

Hepatic gluconeogenesis is critical to glucose homeostasis. It contributes to hyperglycemia in type 2 diabetes when the function is too strong. It causes hypoglycemia in fasting condition if the function is too weak. Regulation of hepatic gluconeogenesis is an hot area and many transcription factors and cofactors have been identified in the mechanism study, such as FOXO1, GR, CREB, HNF4, PGC-1, and SIRT1. In the current issue of Nature Medicine, a new study suggests that ligand-independent nuclear receptors (Nur77, Nurr1 and NOR1) are involved in hepatic gluconeogenesis in the response to glucogan-cAMP pathway. Expression of these receptors are induced by cAMP-CREB axis. Attached is the PDF file of the paper.

Insulin receptor contains two alpha subunits and two beta subunits. The alpha subunits bind to insulin and the beta units catalyze tyrosine phosphorylation of itself and the IRS proteins. It was not clear how the receptor forms the binding site for insulin. In the current issue of Nature, this question is addressed by a study using protein crystal structure. See attached paper.

Gluconeogenesis and NR4A

Structure of insulin receptor

by Jianping at PBRC/LSU
*---------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: JBC papers

hpguan@mac.com — 2006-10-04T07:45:04-05:00

Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance
Nozomu Kamei, Kazuyuki Tobe, Ryo Suzuki, Mitsuru Ohsugi, Taku Watanabe, Naoto Kubota, Norie Ohtsuka-Kowatari, Katsuyoshi Kumagai, Kentaro Sakamoto, Masatoshi Kobayashi, Toshimasa Yamauchi, Kohjiro Ueki, Yumiko Oishi, Satoshi Nishimura, Ichiro Manabe, Haruo Hashimoto, Yasuyuki Ohnishi, Hitomi Ogata, Kumpei Tokuyama, Masaki Tsunoda, Tomohiro Ide, Koji Murakami, Ryozo Nagai, and Takashi Kadowaki
J. Biol. Chem. 2006; 281:26602-26614. [Abstract] [Full Text] [PDF]

ERK5 activation inhibits inflammatory responses via peroxisome proliferators-activated receptor (PPAR) stimulation
Chang-Hoon Woo, Michael P. Massett, Tetsuro Shishido, Seigo Itoh, Bo Ding, Carolyn McClain, Wenyi Che, Sreesatya Raju Vulapalli, Chen Yan, and Jun-ichi Abe
published 30 August 2006, 10.1074/jbc.M602369200 [Abstract] [PDF]

AS160 regulates insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle
Henning F. Kramer, Carol A. Witczak, Eric B. Taylor, Nobuharu Fujii, Michael F. Hirshman, and Laurie J. Goodyear
published 25 August 2006, 10.1074/jbc.M605461200 [Abstract] [PDF]

5-Aminoimidazole-4-carboxamide-1--D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes
Mandeep Pinky Gaidhu, Sergiu Fediuc, and Rolando Bacis Ceddia
J. Biol. Chem. 2006; 281:25956-25964. [Abstract] [Full Text] [PDF]

Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor , and the Coactivator Peroxisome Proliferator-activated Receptor Coactivator-1
Xunshan Ding, Kristin Lichti, Insook Kim, Frank J. Gonzalez, and Jeff L. Staudinger
J. Biol. Chem. 2006; 281:26540-26551. [Abstract] [Full Text] [PDF]

AKT2 regulates cardiac metabolism and cardiomyocyte survival
Brian J. DeBosch, Nandakumar Sambandam, Carla S. Weinheimer, Michael Courtois, and Anthony J. Muslin
published 31 August 2006, 10.1074/jbc.M513087200 [Abstract]

By Jianping at PBRC

—-------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Improve insulin sensitivity by ER stress inhibitors(Science paper)

hpguan@mac.com — 2006-10-04T07:44:06-05:00

Inhibition of IRS-1 function by serine phosphorylation represents a mechanism of post-receptor insulin resistance. It is well known that activation of serine kinase JNK (JUN N-terminal Kinase) leads to insulin resistance through this mechanism. In study of obese-related JNK activation, ER stress was found to be a risk factor for JNK activation in obese mice. The study was published in Science in 2004. If this hypothesis is right, chemical inhibitors for ER stress should be able to improve insulin sensitivity in obese mice. This possibility receives support from a new study published in the current issue of Science. This new study is from the same research group. Instead of adipose tissue in the earlier study, the liver is the focus in this new study for improvement of insulin sensitivity by the ER stress inhibitors. Attached are the PDF files of both studies.

ER stress in IR in 2004

ER stress inhibitor in 2006

By Jianping at PBRC
*---------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Papers in JBC

hpguan@mac.com — 2006-10-04T07:43:33-05:00

RIP140 expression is stimulated by ERR during adipogenesis
Donna Nichol, Mark Christian, Jennifer H. Steel, Roger White, and Malcolm G. Parker
published 21 August 2006, 10.1074/jbc.M604803200 [Abstract] [PDF]
Pyrrolidine dithiocarbamate inhibits interleukin-6 signaling through impaired STAT3 activation and association with transcriptional coactivators in hepatocytes
Hua-Jun He, Tie-Nian Zhu, Yi Xie, Jinshui Fan, Sutapa Kole, Satya Saxena, and Michel Bernier
published 22 August 2006, 10.1074/jbc.M603762200 [Abstract] [PDF]
The Circadian Clock within the Cardiomyocyte Is Essential for Responsiveness of the Heart to Fatty Acids
David J. Durgan, Nowice A. Trexler, Oluwaseun Egbejimi, Tracy A. McElfresh, Hee Yun Suk, Lauren E. Petterson, Chad A. Shaw, Paul E. Hardin, Molly S. Bray, Margaret P. Chandler, Chi-Wing Chow, and Martin E. Young
J. Biol. Chem. 2006; 281:24254-24269. [Abstract] [Full Text] [PDF]
The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells
Jaroslava Lieskovska, Yan Ling, Jane Badley-Clarke, and David R. Clemmons
J. Biol. Chem. 2006; 281:25041-25053. [Abstract] [Full Text] [PDF]
Peroxisome Proliferator-activated Receptor Promotes Epithelial to Mesenchymal Transformation by Rho GTPase-dependent Activation of ERK1/2
Lu Chen, Brian M. Necela, Weidong Su, Masahiro Yanagisawa, Panos Z. Anastasiadis, Alan P. Fields, and E. Aubrey Thompson
J. Biol. Chem. 2006; 281:24575-24587. [Abstract] [Full Text] [PDF]
Activation of Mammalian Target of Rapamycin (mTOR) by Insulin Is Associated with Stimulation of 4EBP1 Binding to Dimeric mTOR Complex 1
Lifu Wang, Christopher J. Rhodes, and John C. Lawrence, Jr.
J. Biol. Chem. 2006; 281:24293-24303. [Abstract] [Full Text] [PDF]
Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappa B activation, inducible nitric oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages
Xueyuan Zhou, Wenxiu Yang, and Junying Li
published 21 August 2006, 10.1074/jbc.M602739200 [Abstract] [PDF]
Toward the Active Conformation of Insulin: STEREOSPECIFIC MODULATION OF A STRUCTURAL SWITCH IN THE B CHAIN
Qing-xin Hua, Satoe Nakagawa, Shi-Quan Hu, Wenhua Jia, Shuhua Wang, and Michael A. Weiss
J. Biol. Chem. 2006; 281:24900-24909. [Abstract] [Full Text] [PDF]
----------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Papers in JCI and JBC

hpguan@mac.com — 2006-10-04T07:43:12-05:00

Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism
Michihiro Matsumoto, Seongah Han, Tadahiro Kitamura, and Domenico Accili
published 10 August 2006, 10.1172/JCI27047 [Abstract] [PDF]
Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated NF-B activation: TAO2 regulates TAK1 pathways
Wei-Chun HuangFu, Emily Omori, Shizuo Akira, Kunihiro Matsumoto, and Jun Ninomiya-Tsuji
published 7 August 2006, 10.1074/jbc.M603627200 [Abstract] [PDF]
Dual Regulation of Rho and Rac by p120 Catenin Controls Adipocyte Plasma Membrane Trafficking
June C. Hou, Satoshi Shigematsu, Howard C. Crawford, Panos Z. Anastasiadis, and Jeffrey E. Pessin
J. Biol. Chem. 2006; 281:23307-23312. [Abstract] [Full Text] [PDF]
Identification of novel glycogen synthase kinase-3 substrate interacting residues suggests a common mechanism for substrate recognition
Ronit Ilouz, Noga Kowalsman, Miriam Eisenstein, and Hagit Eldar-Finkelman
published 7 August 2006, 10.1074/jbc.M604633200 [Abstract] [PDF]
Under-expressed coactivators PGC1 and SRC1 impair HNF4 function and promote dedifferentiation in human hepatoma cells
Celia P. Martinez-Jimenez, Marin José Gomez-Lechon, Jose V. Castell, and Ramiro Jover
published 4 August 2006, 10.1074/jbc.M604046200 [Abstract] [PDF]
PP2A Regulates BCL-2 Phosphorylation and Proteasome-mediated Degradation at the Endoplasmic Reticulum
Stephen S. Lin, Michael C. Bassik, Heikyung Suh, Mari Nishino, Jason D. Arroyo, William C. Hahn, Stanley J. Korsmeyer, and Thomas M. Roberts
J. Biol. Chem. 2006; 281:23003-23012. [Abstract] [Full Text] [PDF]
Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet -cells. VOLUME 281 (2006) PAGES 15884-15892
Melissa K. Lingohr, Isabelle Briaud, Lorna M. Dickson, Jill F. McCuaig, Cristina Alarcón, Barton L. Wicksteed, and Christopher J. Rhodes
J. Biol. Chem. 2006; 281:23296-a. [Full Text] [PDF]
The Essential Role of the Death Domain Kinase Receptor-interacting Protein in Insulin Growth Factor-I-induced c-Jun N-terminal Kinase Activation
Yong Lin, Qingfeng Yang, Xia Wang, and Zheng-gang Liu
J. Biol. Chem. 2006; 281:23525-23532. [Abstract] [Full Text] [PDF]
Peroxisome Proliferator-activated Receptor -regulated ABCG2 Expression Confers Cytoprotection to Human Dendritic Cells
Istvan Szatmari, György Vámosi, Peter Brazda, Balint L. Balint, Szilvia Benko, Lajos Széles, Viktoria Jeney, Csilla Özvegy-Laczka, Attila Szántó, Endre Barta, József Balla, Balazs Sarkadi, and Laszlo Nagy
J. Biol. Chem. 2006; 281:23812-23823. [Abstract] [Full Text] [PDF]
A dominant function of IKK/NF-kB signaling in global LPS-induced gene expression
Nathalie Carayol, Ji Chen, Fan Yang, Taocong Jin, Lijian Jin, David States, and Cun-Yu Wang
published 16 August 2006, 10.1074/jbc.M603417200 [Abstract] [PDF]
Peroxisome Proliferator-activated Receptor Promotes Epithelial to Mesenchymal Transformation by Rho GTPase-dependent Activation of ERK1/2
Lu Chen, Brian M. Necela, Weidong Su, Masahiro Yanagisawa, Panos Z. Anastasiadis, Alan P. Fields, and E. Aubrey Thompson
J. Biol. Chem. 2006; 281:24575-24587. [Abstract] [Full Text] [PDF]
Dual Regulation of Rho and Rac by p120 Catenin Controls Adipocyte Plasma Membrane Trafficking
June C. Hou, Satoshi Shigematsu, Howard C. Crawford, Panos Z. Anastasiadis, and Jeffrey E. Pessin
J. Biol. Chem. 2006; 281:23307-23312. [Abstract] [Full Text] [PDF]
Activation of Mammalian Target of Rapamycin (mTOR) by Insulin Is Associated with Stimulation of 4EBP1 Binding to Dimeric mTOR Complex 1
Lifu Wang, Christopher J. Rhodes, and John C. Lawrence, Jr.
J. Biol. Chem. 2006; 281:24293-24303. [Abstract] [Full Text] [PDF]
A Conserved Histidine in Insulin Is Required for the Foldability of Human Proinsulin: STRUCTURE AND FUNCTION OF AN ALAB5 ANALOG
Qing-xin Hua, Ming Liu, Shi-Quan Hu, Wenhua Jia, Peter Arvan, and Michael A. Weiss
J. Biol. Chem. 2006; 281:24889-24899. [Abstract] [Full Text] [PDF]
A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion
Sarah M. Ronnebaum, Olga Ilkayeva, Shawn C. Burgess, Jamie W. Joseph, Danhong Lu, Robert D. Stevens, Thomas C. Becker, A. Dean Sherry, Christopher B. Newgard, and Mette V. Jensen
published 15 August 2006, 10.1074/jbc.M511908200 [Abstract] [PDF]
Role of the Activation Loop Tyrosines in Regulation of the Insulin-like Growth Factor I Receptor-tyrosine Kinase
Wanqing Li and W. Todd Miller
J. Biol. Chem. 2006; 281:23785-23791. [Abstract] [Full Text] [PDF]
If you would like to have your friends or colleagues to be a member of IRIG and receiving IRIG e-mail in the future, please feel free to contact me.
By Jianping at PBRC
-----------------------------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: ATGL in Science and PTP1B in Nature Medicine

hpguan@mac.com — 2006-10-04T07:41:58-05:00

Adipose triglyceride lipase (ATGL), highly expressed in adipose tissue, is associated with lipid droplets inside cells. The function of ATGL is to specifically hydrolyze triacylglycerol (TG) into free fatty acids. ATGL is the second TG lipase next to the hormone sensitive lipase (HSL) in adipose tissue for hydrolysis of TG. In a recent issue of Science, the phenotype of ATGL knockout mice was published. The knockout leads to an increase in adipose mass and triacylglycerol deposition in multiple tissues including heart, causing cardiac dysfunction and premature death. The mice had increased glucose utilization, increased glucose tolerance, and increased insulin sensitivity. Like CD36 KO mice, this is another example that less utilization of FFA may lead to insulin sensitization. Attached is the PDF file of the paper.

PTP1B is a tyrosine phosphatase that was shown to inhibit signaling activities of leptin and insulin receptors. Mice with global inactivation of PTP1B exhibit higher sensitivity to leptin and do not develop diet-induced obesity. However, the organ/tissue responsible for the metabolic phenotype of TP1B inactivation is not known. In Nature Medicine online publications, a new study using tissue-specific KO mice of PTP1B demonstrates that the brain is the organ. See attached PDF file.

ATGL paper in Science

PTP1B paper in Nature Medicine

By Jianping at PBRC
*----------------------------------------------------
ATGL is Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: p53-glycolysis in "Cell"

hpguan@mac.com — 2006-10-04T07:40:40-05:00

On June 22th, a paper in "Science" was highlighted in our IRIG communication. This paper suggests that the transcription factor p53, a tumor suppressor gene product, is able to inhibit glycolysis in normal cells by induction of SCO2 (Synthesis of Cytochrome c Oxidase 2). When p53 function is absent in tumor cells, such as in cancer patient with p53 mutation, SCO2 expression is down and thus glycolysis activity is up. This switch may contribute to the malignancy of tumor cells since they can grow under low level of oxygen. In the current issue of "Cell", this function of p53 is reenforced by another study. This cell paper shows that p53 inhibits glycolysis through regulation of gene transcription. However, p53 was shown to act through a new target gene "Tigar" (TP53-induced glycolysis and apoptosis regulator). This study was highlighted in a preview in the same issue of "Cell". Attached are PDF files of those papers.
The two studies in "Science" and "Cell" consistently suggests that glucose metabolism influences risk of cancer. If your gene background gives you a strong p53 function, you may have a low risk of cancer. However, the glycolysis activity might be low in your body. This may increase the risk of insulin resistance, type 2 diabetes, and cardiovascular diseases. This view is supported by the fact that metaformin is able to promote longevity and this drug stimulates glycolysis leading to insulin sensitization. The correlation may provide a clue for the molecular mechanism of aging.

P53 and tigar by Bensaad.

P53 and tigar previewed by Green.

P53 regulates mitochondrial respiration.

by Jianping at PBRC
*------------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Interesting papers in JBC

hpguan@mac.com — 2006-10-04T07:40:15-05:00

Diminished Hepatic Gluconeogenesis via Defects in Tricarboxylic Acid Cycle Flux in Peroxisome Proliferator-activated Receptor Coactivator-1 (PGC-1)-deficient Mice
Shawn C. Burgess, Teresa C. Leone, Adam R. Wende, Michelle A. Croce, Zhouji Chen, A. Dean Sherry, Craig R. Malloy, and Brian N. Finck J. Biol. Chem. 2006; 281:19000-19008. [Abstract] [Full Text] [PDF]

Aicar-induced AMPK phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes
Mandeep Pinky Gaidhu, Sergiu Fediuc, and Rolando Bacis Ceddia published 1 July 2006, 10.1074/jbc.M602992200 [Abstract] [PDF]

The role of Src kinase in insulin-like growth factor dependent mitogenic signaling in vascular smooth muscle cells
Jaroslava Lieskovska, Yan Ling, Jane Badley-Clarke, and David R. Clemmons published 5 July 2006, 10.1074/jbc.M602866200 [Abstract] [PDF]

Endoplasmic Reticulum Stress Induction of Insulin-like Growth Factor-binding Protein-1 Involves ATF4
Alexandre Marchand, Céline Tomkiewicz, Laurent Magne, Robert Barouki, and Michèle Garlatti J. Biol. Chem. 2006; 281:19124-19133. [Abstract] [Full Text] [PDF]

Caveolin-1 Functions as a Novel Cdc42 Guanine Nucleotide Dissociation Inhibitor in Pancreatic -Cells
Angela K. Nevins and Debbie C. Thurmond J. Biol. Chem. 2006; 281:18961-18972. [Abstract] [Full Text] [PDF]

Regulation of constitutive androstane receptor and its target genes by fasting, cyclic AMP, HNF-4 and the coactivator PGC-1
Xunshan Ding, Kristin Lichti, Insook Kim, Frank J. Gonzalez, and Jeff L. Staudinger published 5 July 2006, 10.1074/jbc.M600931200 [Abstract] [PDF]

Diet-induced Obesity Alters AMP Kinase Activity in Hypothalamus and Skeletal Muscle
Tonya L. Martin, Thierry Alquier, Kenji Asakura, Noboru Furukawa, Frederic Preitner, and Barbara B. Kahn J. Biol. Chem. 2006; 281:18933-18941. [Abstract] [Full Text] [PDF]

The Alternative Stimulatory G Protein -Subunit XLs Is a Critical Regulator of Energy and Glucose Metabolism and Sympathetic Nerve Activity in Adult Mice
Tao Xie, Antonius Plagge, Oksana Gavrilova, Stephanie Pack, William Jou, Edwin W. Lai, Marga Frontera, Gavin Kelsey, and Lee S. Weinstein J. Biol. Chem. 2006; 281:18989-18999. [Abstract] [Full Text] [PDF]

By Jianping at PBRC
-----------------—-
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Outstanding reviews in JCI

hpguan@mac.com — 2006-10-04T07:36:49-05:00

In the current issue of JCI (Journal of Clinical Investigation), a series of review articles are published to address the hot areas in metabolic syndrome. Following is a highlight of the reviews.

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Insulin resistance and atherosclerosis
Clay F. Semenkovich
J. Clin. Invest. 2006; 116:1813-1822. [Abstract] [Full Text] [PDF]

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome
Takashi Kadowaki, Toshimasa Yamauchi, Naoto Kubota, Kazuo Hara, Kohjiro Ueki, and Kazuyuki Tobe
J. Clin. Invest. 2006; 116:1784-1792. [Abstract] [Full Text] [PDF]

Inflammation and insulin resistance
Steven E. Shoelson, Jongsoon Lee, and Allison B. Goldfine
J. Clin. Invest. 2006; 116:1793-1801. [Abstract] [Full Text] [PDF]

Islet ß cell failure in type 2 diabetes
Marc Prentki and Christopher J. Nolan
J. Clin. Invest. 2006; 116:1802-1812. [Abstract] [Full Text] [PDF]

Central insulin action in energy and glucose homeostasis
Leona Plum, Bengt F. Belgardt, and Jens C. Brüning
J. Clin. Invest. 2006; 116:1761-1766. [Abstract] [Full Text] [PDF]

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
Leona Plum, Xiaosong Ma, Brigitte Hampel, Nina Balthasar, Roberto Coppari, Heike Münzberg, Marya Shanabrough, Denis Burdakov, Eva Rother, Ruth Janoschek, Jens Alber, Bengt F. Belgardt, Linda Koch, Jost Seibler, Frieder Schwenk, Csaba Fekete, Akira Suzuki, Tak W. Mak, Wilhelm Krone, Tamas L. Horvath, Frances M. Ashcroft, and Jens C. Brüning
J. Clin. Invest. 2006; 116:1886-1901. [Abstract] [Full Text] [PDF]

Insulin resistance and pancreatic ß cell failure
Masato Kasuga
J. Clin. Invest. 2006; 116:1756-1760. [Abstract] [Full Text] [PDF]

Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony
Mark A. Herman and Barbara B. Kahn
J. Clin. Invest. 2006; 116:1767-1775. [Abstract] [Full Text] [PDF]

by Jianping at PBRC

—------------------------------

Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: MicroRNA and Knockout mice in "Nature Genetics" and"Science"

hpguan@mac.com — 2006-10-04T07:26:04-05:00

MicroRNA is a natural RNA product with 19-22 nucleotides in length. It works as a RNAi in the regulation of gene expression. However, it is not made by man. It is made from genomic DNA and involved in gene regulation cross species. MicroRNA represents a new layer of post-transcriptional regulation in the body. "Nature Genetics" published a supplement issue to address microRNA-related questions, such as what is microRNA? How to study it? Following is the link to this free issue of Nature Genetics - microRNA supplement.

Click here to access:
http://info.nature.com/cgi-bin24/DM/y/eYp70BiDI60Ct027U0E5

Genomic DNA has been completely sequenced for human and mouse. The next qeustion is the functions of genes. To address this issue in a big way, Europe, Canada, USA and China have made huge plans to generate 60,000 knockout mice together. This is reported in the current issue of "Science" at following link:
http://www.sciencemag.org/cgi/content/summary/312/5782/1862?etoc. Hopefully, in the future, lab scientists can buy KO mice easily.

By Jianping at PBRC
—-----------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Papers in "Science"

hpguan@mac.com — 2006-10-04T07:21:02-05:00

Activation of PPARg in the adipose tissue is associated with the insulin sensitizing activity of TZDs. Activation of PPARg in the liver has been associated with the side effects of TZDs as liver toxicity is a major problem of TZDs. In the current issue of "Science", this concept is challenged by a study that hepatic PPARg may stimulate energy expenditure in the peripheral adipose tissue through a new pathway: liver-nerve-fat. The activity of this pathway in peripheral energy expenditure is promoted by TZDs. See details in attached PDF file. This paper is recommended by Dr. Jianhua Shao at the Graduate Center for Nutritional Sciences, University of Kentucky, Lexington.

Mitochondrial function is associated with oxygen-dependent ATP production. In tumor cells, this ATP production pathway is usually replaced by glycolysis. Does this switch involve in tumor suppresser gene? The answer is yes. In "Science", a study shows that p53 mutation promotes such a switch through a protein by the name of Synthesis of Cytochrome c Oxidase 2 (SCO2). Expression of this protein prevents the switch. p53 function is required for the expression of this protein. See attached PDF file.

by Jianping at PBRC
*----------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Some interesting papers in JBC

hpguan@mac.com — 2006-10-03T22:42:15-05:00

Increased CUG triplet repeat binding protein-1 predisposes to impaired adipogenesis with aging Iordanes Karagiannides, Thomas Thomou, Tamara Tchkonia, Tamar Pirtskhalava, Kyriakos E. Kypreos, Andrew Cartwright, Georgia Dalagiorgou, Timothy L. Lash, Stephen R. Farmer, Nikolai A. Timchenko,
and James L. Kirkland published 5 June 2006, 10.1074/jbc.M513187200 [Abstract] [PDF]

Dual regulation of Rho and Rac by p120 catenin controls adipocyte plasma membrane trafficking June Chunqiu Hou, Satoshi Shigematsu, Howard C. Crawford, Panos Z. Anastasiadis, and Jeffrey E. Pessin published 5 June 2006, 10.1074/jbc.M603127200 [Abstract] [PDF]

Glucose acutely decreases pH of secretory granules in mouse pancreatic islets: mechanisms and influence on insulin secretion
Patrick Stiernet, Yves Guiot, Patrick Gilon, and Jean-Claude Henquin published 7 June 2006, 10.1074/jbc.M513224200 [Abstract] [PDF]

Akt Regulates Basal and Induced Processing of NF-B2 (p100) to p52 Jason A. Gustin, Chandrashekhar K. Korgaonkar, Roxana Pincheira, Qiutang Li, and David B. Donner J. Biol. Chem. 2006; 281:16473-16481. [Abstract] [Full Text] [PDF]

Nuclear Export of Retinoid X Receptor in Response to Interleukin-1-mediated Cell Signaling: ROLES FOR JNK AND SER260
Tracy L. Zimmerman, Sundararajah Thevananther, Romi Ghose, Alan R. Burns, and Saul J. Karpen
J. Biol. Chem. 2006; 281:15434-15440. [Abstract] [Full Text] [PDF]

Heparin synergistically enhances interleukin-11 signaling through upregulation of the MAP kinase pathway
Raghav Rajgopal, Martin Butcher, Jeffrey I. Weitz, and Stephen G. Shaughnessy
published 23 May 2006, 10.1074/jbc.M600169200 [Abstract] [PDF]

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: IL-18 and RNAi in "Nature"

hpguan@mac.com — 2006-10-03T22:33:55-05:00

Interleukin 18 (IL-18) is a pro-inflammatory cytokine which participates in host defense against a variety of infections, chronic inflammation and autoimmune diseases. In "Nature Medicine", a report provide evidence that in the IL-18 knockout mice, obesity is resulted from hyperphagia, and a defect in STAT3 signaling is attributed to the hyperphagia. STAT3 deficiency is due to lack of phopshorylation. The hyperphagia-obesity leads to insulin resistance in the KO mice. This is a new model that immune system may regulate energy balance (See attached PDF file). The existing models include IL-6 KO mice that have a similar metabolic phenotype to this IL-18 KO mice.

RNA interference (RNAi) is a common tool in the analysis of gene function in vitro. In vivo application of RNAi was believed to hold promise for treatment of diseases. However, non-specific activity of RNAi has drawn more and more attention. This is especially important for in vivo study. In "Nature", a report shows that over-expression of RNAi in liver may cause death in mice. This toxic effect was observed in 36 out of 49 RNAi expression systems that were made using adenovirus delivery system. This study suggests that consistent high-level expression of RNAi in transgenic mice may induce non-specific or toxic effect in vivo. For details, see attached PDF file. This paper is recommended by Dr. Bing Sun at the Otsuka Maryland Medicinal Laboratories.

IL-18 obesity and insulin resistance

RNAi and fatality

By Jianping at PBRC
*-------------------------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Protein tyrosine phosphatase in "Nature" and "Cell Metabolism"

hpguan@mac.com — 2006-10-03T22:23:11-05:00

Tyrosine phosphorylation of IRS-1/2 (insulin receptor substrate 1 or 2) is an activation signal in the signal transduction pathway of insulin receptor. The phosphorylation is catalyzed by the beta-subunits of insulin receptor that is formed by two alpha and two beta subunits. The beta subunits are auto-phosphorylated on tyrosine residues and thus become activated upon insulin engagement with the alpha subunit. Tyrosine phopshorylation of IRS-1/2 leads to activation of down-stream signaling molecule PI3K by recruiting the regulatory subunit p85. Tyrosine phosphorylation in IRS and IR is require for insulin action and subject to regulation by tyrosine de-phosphorylation. Several tyrosine phosphatases have been identified for inhibition of these tyrosine phosphorylation-mediated events, such as PTP-1B whose activity contributes to insulin resistance. In Nature and Cell Metabolism, two more protein tyrosine phosphatases were reported to regulate insulin action especially in the liver: one is SHP-1 and the other is PTP-MEG2. See attached PDF files.

HP-1 and insulin signaling by Dubois 2006.pdf (417541 bytes)
PTP-MEG2 and insulin signaling by Cho 2006.pdf (570369 bytes)

By Jianping at PBRC
*-----------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Papers in Science and Nature Genetics

hpguan@mac.com — 2006-10-03T22:15:06-05:00

Glucose and fatty acids are the major fuels in the body. A decrease in one consumption leads to an increase in consumption of the other one. Although this principal is not new, the mechanism for such balance is quit interesting. Previous study suggests that a reduction in fatty acid uptake by cells leads to an increase in glucose utilization and insulin sensitization. This was demonstrated in CD36 (fatty acid transporter) knockout mice. Now, a new study in "Science" suggests that a reduction in triglyceride hydrolysis also give such a phenotype in transgenic mice. This was demonstrated using the knockout mice for ATGL (adipocyte triglyceride lipase), an enzyme highly expressed in adipocytes to catalyze hydrolysis of triglycerides (TG). See attached PDF file.
PI3K/Akt signaling pathway is used by insulin and IGF-1 to stimulate cell growth in many type of tissues including muscle, fat and liver. In Nature Genetics, two studies using different approaches consistently demonstrate that this signaling pathway is required for beta-cell proliferation and islet mass. Knockout of insulin receptor plus IGF-1 receptor, or PDK1 (a PI3K downstream kinase) alone leads to islet atrophy and diabetes. The studies provide new support that insulin resistance in beta cells may contribute to beta-cell dysfunction in type 2 diabetes. Attached are PDF of the two papers.

By Jianping at PBRC
*--------------------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: Science paper: Amino acid sensing in Brain

hpguan@mac.com — 2006-10-03T22:12:46-05:00

A study published in the current issue of Science" suggests a mechanism by which amino acids regulate food intake. Amino acid leucine was shown to inhibit food intake through activation of mTOR (Mammalian Target Of Rapamycin), a serine kinase in the insulin signaling pathway. Leptin may also use this mechanism in the regulation of food intake. This study is highlighted in Today's "The Scientist" at following link: Attached (1) is the PDF file of this Science paper.

In addition, a study in JCI provides more support about MCP-1 (Monocyte Chemoattractant Protein 1) in macrophage infiltration in adipose tissue in obesity. Fat-specific over-expression of MCP-1 led to an increase in macrophage infiltration in fat, systemic insulin resistance and TG accumulation in liver. Global knockout of MCP-1 reduced the infiltration in mice. The conclusion is consistent with the phenotype of MCP-1 receptor (CCR2) KO mice published last year in JCI. Attached (2) is the PDF file of this paper.

By Jianping at PBRC
*------------------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: CRP, Adiponectin, STAT5 in "Nature" and "Nature Cell Biology"

hpguan@mac.com — 2006-10-03T22:10:50-05:00

In the current issue of "Nature", a study suggests that a chemical inhibitor of CRP (C-reactive protein) is able to protect
cardiovascular system, and treat cardiovascular diseases (CVDs). This study reports a novel CRP inhibitor and provides a strong support that CRP contributes the pathogenesis of CVDs. CRP was shown to cause leptin resistance recently in a study in Nature Medicine (IRIG post on 4/6/06).

In the "Nature Cell Biology", there are two interesting papers. The first study reports a new signaling molecule for adiponectin receptor. This is an adaptor protein by the name of APPL1 that interacts with adiponectin receptor and mediates signals of the receptor. Adiponectin induces recruitment of APPL1 to the receptor, and inhibitionof APPL1 blocks the signaling pathway of adiponnectin.

The second study reports that the transcription factor STAT5 is involved in insulin secretion in beta-cells. The study provides moecular connection for synergy between glucose and growth hormone in theregulation of insulin secretion. STAT5 mediates growth hormone signals.

Attached are PDF files of the these papers above.

By Jianping at PBRC
--------------------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: ROS in Insulin Resistance (Nature)

hpguan@mac.com — 2006-10-03T22:09:21-05:00

Reactive oxygen species (ROS or free radicals) are signal mediators in physiological condition. Over production of ROS is able to induce many side effects such as cell apoptosis, inflammation, and gene mutation, which has been well documented in cancer, immunology and aging fields. A role of ROS in the pathogenesis of insulin resistance has been speculated for some times. However, there was no direct evidence to support this possibility. This condition is changed by a new study in the current issue of Nature. The report suggests that ROS is required for development of insulin resistance in response to TNF-alpha or glucocortcoide hormone. Attached is the paper that is recommended by Dr. Hong-Ping Guan at UT Southwestern Medical Center. (Attachment 1)

ROS is able to activate signaling molecules such as JNK, and NF-kB, which are known to contribute to insulin resistance. In Nature Medicine, a study shows that ROS is able to activate MAP kinase p38 to reduce life span of hemopoietic stem cells (Attachment 2).

By Jianping at PBRC
-------------------------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

IRIG: More interesting papers in Nature Medicine

hpguan@mac.com — 2006-10-03T22:08:15-05:00

In the last post, the new study of leptin resistance in Nature Medicine was highlighted with PDF file. Here, we list three more
metabolism related papers published online in Nature Medicine. These studies provide new insight in the mechanisms of central control of food intake and AMPK activation in muscle. Following is the list.
By Jianping at PBRC and Feng at the Health Science Center at San Antonio, UT.

Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake
Tadahiro Kitamura, Yun Feng, Yukari Ido Kitamura, Streamson C Chua Jr, Allison W Xu, Gregory S Barsh, Luciano Rossetti & Domenico Accili
Published online: 09 April 2006 | doi:10.1038/nm1392
Abstract | Full text | PDF (490K) | Supplementary Information

Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior
Guoqing Sheng, Guo-qing Chang, John Y Lin, Zhao-Xue Yu, Zhi-Hui Fang, Juan Rong, Stuart A Lipton, Shi-Hua Li, Gang Tong, Sarah F Leibowitz & Xiao-Jiang Li
Published online: 09 April 2006 | doi:10.1038/nm1382
Abstract | Full text | PDF (676K) | Supplementary Information

CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK
Matthew J Watt, Nicolas Dzamko, Walter G Thomas, Stefan Rose-John, Matthias Ernst, David Carling, Bruce E Kemp, Mark A Febbraio & Gregory R Steinberg
Published online: 09 April 2006 | doi:10.1038/nm1383
Abstract | Full text | PDF (280K) | Supplementary Information

_________________________
Feng Liu, Ph.D.
Professor
Department of Pharmacology
Univ of Texas Health Science Center
7703 Floyd Curl Drive
San Antonio, TX 78229

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu

Hepatic STAT3 in brain-insulin action on hepatic glucose production

hpguan@mac.com — 2006-10-03T22:06:59-05:00

This paper published on "Cell Metabolism" titled " Role of hepatic STAT3 in brain-insulin action on hepatic glucose production" demonstrated a possible signaling target of insulin in brain which relays the suppression of gluconeogenesis onto liver. When STAT3 is knocked down in liver, the suppression of i.c.v. insulin on gluconeogenesis in liver is ameliorated. This suggests that the communication between brain and liver might target on STAT3 pathway.

Here is the link of the paper Cell Metabolism

IRIG: Papers in JAMA and JCI

hpguan@mac.com — 2006-10-03T22:04:22-05:00

Following are interesting papers in JAMA and JCI for glucose and fat metabolism.

By Jianping at PBRC
-------------------------------------------------
Effect of 6-Month Calorie Restriction on Biomarkers of Longevity, Metabolic Adaptation, and Oxidative Stress in Overweight Individuals: A Randomized Controlled Trial

Leonie K. Heilbronn, Lilian de Jonge, Madlyn I. Frisard, James P. DeLany, D. Enette Larson-Meyer, Jennifer Rood, Tuong Nguyen, Corby K. Martin, Julia Volaufova, Marlene M. Most, Frank L. Greenway, Steven R. Smith, Walter A. Deutsch, Donald A. Williamson, Eric Ravussin for the Pennington CALERIE Team
JAMA. 2006; 295:1539-1548. [Abstract]

Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation
Xueliang Du, Diane Edelstein, Silvana Obici, Ninon Higham, Ming-Hui Zou, and Michael Brownlee
J. Clin. Invest. 2006; 116:1071-1080. [Abstract]

Farnesoid X receptor is essential for normal glucose homeostasis

Ke Ma, Pradip K. Saha, Lawrence Chan, and David D. Moore
J. Clin. Invest. 2006; 116:1102-1109. [Abstract]

Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats
Alessandro Pocai, Tony K.T. Lam, Silvana Obici, Roger Gutierrez-Juarez, Evan D. Muse, Arduino Arduini, and Luciano Rossetti
J. Clin. Invest. 2006; 116:1081-1091. [Abstract]

IRIG: Leptin resistance in "Nature Medicine"

hpguan@mac.com — 2006-10-03T21:32:44-05:00

Leptin resistance is believed to contribute to obesity and insulin resistance. It was not clear why leptin resistance happens in the body. In the current issue of Nature Medicine, a study suggests that c-reactive protein binds to leptin, and blocks leptin interaction with its receptor. This was demonstrated in transgenic mice overexpressing c-reactive protein. This study provides a new mechanism for leptin resistance. Attached is the PDF file of this paper. Mitochondrial dysfunction is believed to contribute to pathogenesis of insulin resistance and type 2 diabetes. A news report was published in Nature weeks ago about the current status in this field. PDF file of this report is also attached.

http://www.nature.com/nm/journal/v12/n4/abs/nm1372.html

http://www.nature.com/nature/journal/v440/n7084/full/440600a.html

By Jianping at PBRC
---------------------------------------------------

Jianping Ye, MD
Associate Professor
Pennington Biomedical Research Center
Louisiana State University
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225) 763-3163
Fax: (225) 763-2525
E-mail: yej@pbrc.edu