Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance
(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.
(Less)
- author
- publishing date
- 2012-04
- 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
-
- scopus:84862577245
- pmid:22237685
- 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
- 2024-10-15 18:56:55
@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}}, }