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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1167-78
Number of pages12
JournalDiabetologia
Volume55
Issue number4
DOIs
Publication statusPublished - 2012 Apr
Externally publishedYes

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Free 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

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