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The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models

Zhiyong Wang1, O Jameel Shah, Tony Hunter

  • 1Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America. zwang@salk.edu

Plos One
|August 4, 2012
PubMed

Insights

The p160 coactivators, p/CIP and SRC-1, are crucial for regulating insulin signaling and glucose metabolism. Their absence enhances insulin sensitivity and glucose uptake, offering potential therapeutic targets for obesity and diabetes.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Metabolic Research

Background:

  • p160 family members p/CIP, SRC1, and TIF2 function as transcriptional coactivators.
  • Previous studies showed obesity resistance in p/CIP and SRC-1 double knockout (DKO) mice, suggesting nuclear hormone receptor involvement.
  • The precise role of these coactivators in metabolic regulation remained unclear.

Purpose of the Study:

  • To investigate the role of p/CIP and SRC-1 in insulin signaling and glucose metabolism.
  • To determine the in vitro and in vivo effects of p/CIP and SRC-1 deletion on metabolic parameters.
  • To identify the molecular mechanisms underlying the metabolic phenotypes observed in DKO mice.

Main Methods:

  • Generation and analysis of p/CIP and SRC-1 double knockout (DKO) mice.
  • In vitro studies using cell lines representing fat and muscle lineages.
  • Assessment of glucose uptake, insulin sensitivity, and energy expenditure.
  • Analysis of insulin receptor substrate 1 (IRS1) expression levels in various tissues and cell types.

Main Results:

  • Genetic deletion of p/CIP and SRC-1 enhanced insulin sensitivity and glucose uptake in DKO mice, irrespective of diet.
  • DKO mice exhibited resistance to age-related obesity and glucose intolerance.
  • Increased expression of insulin receptor substrate 1 (IRS1) was observed in fat and muscle cells and tissues of DKO mice, correlating with improved glucose metabolism.

Conclusions:

  • p/CIP and SRC-1 play a critical role in controlling insulin signaling and glucose metabolism through IRS1.
  • The p160 coactivators regulate metabolic homeostasis in a cell-autonomous manner.
  • p/CIP and SRC-1 represent potential therapeutic targets for obesity and diabetes treatment.

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