Sep 2007
IRIG: TORC2 and aP2 in "Nature"
09/11/2007 22:32
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
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
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