Abstract

Objective— FFAR1/GPR40 is a G protein-coupled receptor expressed predominantly in pancreatic islets mediating free fatty acid-induced insulin secretion. However, the physiological role of FFAR1 remains controversial. It was previously reported that FFAR1 knockout (KO or Ffar1^-/-) mice were resistant to high-fat diet (HFD)-induced hyperinuslinemia, hyperglycemia, hypertriglyceridemia and hepatic steatosis. A more recent report suggested that although FFAR1 was necessary for fatty acid-induced insulin secretion in vivo, deletion of FFAR1 did not protect pancreatic islets against fatty acid-induced islet dysfunction. This study is designed to investigate FFAR1 function in vivo using a third line of independently generated Ffar1^-/- mice in the C57BL/6 background.

Research Design and Methods— We used CL-316,243, a β-3 adrenergic receptor agonist, to acutely elevate blood free fatty acids and study its effect on insulin secretion in vivo. Ffar1^+/+ (WT) and Ffar1^-/- (KO) mice were placed on two distinct HFDs in order to study their response to diet-induced obesity.

Results— Insulin secretion was reduced by ∼50% in Ffar1^-/- mice, confirming that FFAR1 contributes significantly to fatty acid stimulation of insulin secretion in vivo. However, Ffar1^+/+ and Ffar1^-/- mice had similar weight, adiposity, and hyperinsulinemia on HFDs, and Ffar1^-/- mice showed no improvement in glucose or insulin tolerance tests. In addition, HFD-induced comparable levels of lipid accumulation in livers of Ffar1^+/+ and Ffar1^-/- mice.

Conclusions— FFAR1 is required for normal insulin secretion in response to fatty acids, however, Ffar1^-/- mice are not protected from HFD-induced insulin resistance or hepatic steatosis.