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

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.

• 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
• Journal: Diabetologia (Diabetologia) Vol. 55 Issue 4 Pg. 1167-78 (Apr 2012) ISSN: 1432-0428 [Electronic] Germany
• PMID: 22237685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ddit3 protein, mouse
• Insulin
• Transcription Factor CHOP

Topics

• Adipose Tissue (metabolism)
• Animals
• Fatty Liver (genetics, metabolism)
• Glucose Intolerance (genetics, metabolism)
• Inflammation (genetics, metabolism)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Insulin-Secreting Cells (metabolism)
• Liver (metabolism)
• Mice
• Mice, Knockout
• Obesity (genetics, metabolism)
• Transcription Factor CHOP (genetics, metabolism)