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.