Lack of FFAR1/GPR40 Does Not Protect Mice From High-Fat Diet–Induced Metabolic Disease

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 (Ffar1−/−) mice were resistant to high-fat diet–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 β3 adrenergic receptor agonist, to acutely elevate blood free fatty acids and to study its effect on insulin secretion in vivo. Ffar1+/+ (wild-type) and Ffar1−/− (knockout) mice were placed on two distinct high-fat diets 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 high-fat diets, and Ffar1−/− mice showed no improvement in glucose or insulin tolerance tests. In addition, high-fat diet 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 high-fat diet–induced insulin resistance or hepatic steatosis.