Skip to Main content Skip to Navigation
Journal articles

Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J mice.

Abstract : Chronic low grade inflammation is closely linked to obesity-associated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6 β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HS+INDO-fed mice remained insulin-sensitive. However, mice fed HF/HS+INDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.
Document type :
Journal articles
Complete list of metadatas

Cited literature [1 references]  Display  Hide  Download

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01074835
Contributor : Marie Lecoupe-Grainville <>
Submitted on : Monday, November 3, 2014 - 4:26:37 PM
Last modification on : Monday, January 20, 2020 - 2:44:11 PM
Long-term archiving on: : Wednesday, February 4, 2015 - 10:05:49 AM

File

JBC-2013-525220v2-Kristiansen-...
Files produced by the author(s)

Authors accepted peer-reviewed manuscript may be posted on an institutional repository : Author's Post-print: subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) : 12 months embargo

Identifiers

Citation

Even Fjære, Ulrike L Aune, Kristin Røen, Alison H Keenan, Tao Ma, et al.. Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J mice.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2014, 289 (23), pp.16032-45. ⟨10.1074/jbc.M113.525220⟩. ⟨hal-01074835⟩

Share

Metrics

Record views

355

Files downloads

229