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 language | English |
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Pages (from-to) | 1167-78 |
Number of pages | 12 |
Journal | Diabetologia |
Volume | 55 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2012 Apr |
Externally published | Yes |
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