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

作者：Maris M; Overbergh L^*; Gysemans C; Waget A; Cardozo A K; Verdrengh E; Cunha J P M; Gotoh T; Cnop M; Eizirik D L; Burcelin R; Mathieu C

来源：Diabetologia, 2012, 55(4): 1167-1178.

DOI：10.1007/s00125-011-2427-7

• CHOP
• Endoplasmic reticulum
• Inflammation
• Obesity
• Steatosis
• Type 2 diabetes

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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2012-4