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

PLoS One. 2012;7(7):e36961. doi: 10.1371/journal.pone.0036961. Epub 2012 Jul 31.

Abstract

Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / blood
  • Adipose Tissue, White / metabolism
  • Animals
  • Blood Glucose
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Gene Expression
  • Gene Knockdown Techniques
  • Glucose Tolerance Test
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Resistance*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • NIH 3T3 Cells
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / metabolism
  • Nuclear Receptor Coactivator 1 / physiology*
  • Nuclear Receptor Coactivator 3 / genetics
  • Nuclear Receptor Coactivator 3 / metabolism
  • Nuclear Receptor Coactivator 3 / physiology*
  • Obesity / blood
  • Obesity / etiology
  • Obesity / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction

Substances

  • Adiponectin
  • Blood Glucose
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • RNA, Small Interfering
  • Ncoa1 protein, mouse
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 3