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

Maris, M ; Overbergh, L ; Gysemans, C ; Waget, A ; Cardozo, A K ; Verdrengh, E ; Cunha, J P M LU orcid ; Gotoh, T ; Cnop, M and Eizirik, D L , et al. (2012) In Diabetologia 55(4). p.78-1167
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
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
in
Diabetologia
volume
55
issue
4
pages
12 pages
publisher
Springer
external identifiers
  • pmid:22237685
  • scopus:84862577245
ISSN
1432-0428
DOI
10.1007/s00125-011-2427-7
language
English
LU publication?
no
id
5b6f70ab-9305-4320-ace6-cce8487b13ec
date added to LUP
2019-02-14 09:55:41
date last changed
2024-06-12 07:53:12
@article{5b6f70ab-9305-4320-ace6-cce8487b13ec,
  abstract     = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Maris, M and Overbergh, L and Gysemans, C and Waget, A and Cardozo, A K and Verdrengh, E and Cunha, J P M and Gotoh, T and Cnop, M and Eizirik, D L and Burcelin, R and Mathieu, C}},
  issn         = {{1432-0428}},
  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}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{78--1167}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance}},
  url          = {{http://dx.doi.org/10.1007/s00125-011-2427-7}},
  doi          = {{10.1007/s00125-011-2427-7}},
  volume       = {{55}},
  year         = {{2012}},
}