Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

Research output: Contribution to journalArticle

Abstract

AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance.

METHODS: Metabolic studies were performed in Chop ( -/- ) and wild-type C57Bl/6 mice, and included euglycaemic-hyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR.

RESULTS: Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop ( -/- ) mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver.

CONCLUSIONS/INTERPRETATION: These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance.

Details

Authors
  • M Maris
  • L Overbergh
  • C Gysemans
  • A Waget
  • A K Cardozo
  • E Verdrengh
  • J P M Cunha
  • T Gotoh
  • M Cnop
  • D L Eizirik
  • R Burcelin
  • C Mathieu
External organisations
  • Catholic University of Leuven
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • Adipose Tissue/metabolism, Animals, Fatty Liver/genetics, Glucose Intolerance/genetics, Inflammation/genetics, Insulin/metabolism, Insulin Resistance/physiology, Insulin-Secreting Cells/metabolism, Liver/metabolism, Mice, Mice, Knockout, Obesity/genetics, Transcription Factor CHOP/genetics
Original languageEnglish
Pages (from-to)1167-78
Number of pages12
JournalDiabetologia
Volume55
Issue number4
Publication statusPublished - 2012 Apr
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes