The Fatty-Acid Receptor GPR40 Plays a Role in Insulin Secretion In Vivo After High-Fat Feeding

Melkam Kebede,Thierry Alquier,Martin G Latour,Meriem Semache,Vincent Poitout

doi:10.1016/s1499-2671(08)24147-x

Abstract

The G protein-coupled receptor GPR40 is expressed in pancreatic β-cells and is activated by long-chain fatty acids (FAs). Gene deletion studies have shown that GPR40 mediates, at least in part, FA-amplification of glucose-induced insulin secretion (GSIS) but is not implicated in GSIS itself. However, the role of GPR40 in the long-term effects of FAs on insulin secretion remains controversial. This study was aimed to test the hypothesis that GPR40 plays a role in insulin secretion after high-fat feeding. GPR40 knock-out (KO) mice on a C57BL/6 background and their wild-type (WT) littermates were fed a high-fat diet (HFD) for 11 weeks. Glucose tolerance, insulin tolerance, and insulin secretion in response to glucose and Intralipid were assessed during the course of the diet period. GPR40 KO mice had fasting hyperglycemia. They became as obese, as glucose intolerant and as insulin resistant as their WT littermates under HFD, and developed a similar degree of liver steatosis. Their fasting blood glucose increased earlier than those of control mice during the course of the HFD. The remarkable increase in insulin secretory responses to intravenous glucose and Intralipid seen in WT mice after HFD was of much lower magnitude in GPR40 KO mice. In conclusion, GPR40 plays a role not only in fatty-acid modulation of insulin secretion, but also in GSIS after high-fat feeding. These observations raise doubts on the validity of a therapeutic approach based on GPR40 antagonism for the treatment of type 2 diabetes.

Highlights

The remarkable increase in insulin secretory responses to intravenous glucose and Intralipid seen in WT mice after high-fat diet (HFD) was of much lower magnitude in GPR40 KO mice
The discovery of GPR40 as a G-protein– coupled receptor highly expressed in pancreatic ␤-cells and activated by long-chain fatty acids [1,2,3,4] has enabled the identification of a novel mechanism of action of fatty acids on insulin secretion
C57BL/6 background, deletion of GPR40 leads to fasting hyperglycemia despite normal glucose and insulin tolerance, suggesting that GPR40 contributes to the maintenance of blood glucose levels during fasting

Summary

Introduction

We sought to examine whether GPR40 KO mice are more susceptible to HFD-induced hyperglycemia and, if so, whether this is due to changes in insulin secretion in vivo or associated with changes in the expression of genes controlling fatty acid metabolism in islets. Fat pad weight (white and brown adipose tissue), and food intake increased to similar levels in GPR40 KO and WT mice under HFD (Table 1).

Results

Conclusion