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This version published online on June 27, 2006
Molecular Endocrinology, doi:10.1210/me.2006-0224
A more recent version of this article appeared on November 1, 2006
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Submitted on May 24, 2006
Accepted on June 23, 2006

Orphan receptor SHP is an important mediator of glucose homeostasis

Li Wang*, Jiansheng Huang, Pradip Saha, Rohit N. Kulkarni, Min Hu, Yong Deuk Kim, Keun Gyu Park, Lawrence Chan, Arun S. Rajan, Inkyu Lee, and David D. Moore

Departments of Medicine & Pharmacology, University of Kansas Medical Center, KS 66160; Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030; Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; Department of Internal Medicine, Keimyung University School of Medicine, Daegu 700-712, Korea

* To whom correspondence should be addressed. E-mail: lwang2{at}kumc.edu.

The orphan receptor Small Heterodimer Partner (SHP, NROB2) is a transcriptional repressor that inhibits nuclear receptor signaling in diverse metabolic pathways. Here we report that SHP-/- mice exhibited hypoinsulinemia with age that was associated with increased peripheral insulin sensitivity, increased response of isolated islets to glucose stimulation, yet maintain normal levels of blood glucose. Deficiency in SHP function resulted in up-regulation of Glut4 mRNA and glucose uptake in muscles, and overexpression of SHP in C2C12 cells inhibited both basal and PGC-1{alpha} stimulated Glut4 expression and glucose uptake. SHP-/- hepatocytes showed markedly decreased basal glucose production in cultures, and SHP-/- livers had increased glycogen stores and were more sensitive to insulin inhibition of glucose output, which were concomitant with decreased expression for PPAR{gamma}1, CD36, G6P and PEPCK and increased mRNAs for GK and PK. In white fat, SHP-deficiency resulted in up-regulation of genes involved in insulin sensitizing, including PPAR{gamma}2 and adiponectin. We show that at the transcriptional level, SHP directly represses adiponectin promoter activity by PPAR{gamma}/LRH-1. The results suggest that the increases in insulin sensitivity though multiple signaling pathways in muscle, liver and fat, with an increase in islet secretory function, represent the complex mechanism whereby SHP-deficiency leads to improvement in insulin sensitivity, secretion and diabetes.
Key words: nuclear receptor • SHP • glucose homeostasis

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  PPARγ  |  LRH-1



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