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Lack of FFAR1/GPR40 does not Protect Mice from High-Fat Diet-Induced Metabolic Disease

Departments of ¹Cardiovascular and Metabolic Diseases and
²Discovery Technologies, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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.

Key Words: FFAR1/GPR40 • insulin secretion • fatty acid • high-fat diet • metabolic homeostasis

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