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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.sup.-/-]) 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.sup.-/-] 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.sup.+/+] (wild-type) and [Ffar1.sup.-/-] (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.sup.-/-] mice, confirming that FFAR1 contributes significantly to [Ffar1.sup.+/+] acid stimulation of insulin secretion in vivo. However, [Ffar1.sup.+/+] and [Ffar1.sup.-/-] mice had similar weight, adiposity, and hyperinsulinemia on high-fat diets, and [Ffar1.sup.-/-] 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.sup.+/+] and [Ffar1.sup.-/-] mice. CONCLUSIONS--FFAR1 is required for normal insulin secretion in response to fatty acids; however, [Ffar1.sup.-/-] mice are not protected from high-fat diet-induced insulin resistance or hepatic steatosis., Fatty acids are involved in a diverse array of physiological functions in a variety of tissues. Many of the effects of fatty acids are thought to be mediated by intracellular [...]