title: 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.
  
  
  METHODS
  We used CL-316,243, a beta3 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 approximately 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.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, New Jersey, USA. hong.lan@spcorp.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lan
authors.forename: Lizbeth M
authors.initials: LM
authors.lastname: Hoos
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Glen
authors.initials: G
authors.lastname: Tetzloff
authors.forename: Weiwen
authors.initials: W
authors.lastname: Hu
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Abbondanzo
authors.forename: Galya
authors.initials: G
authors.lastname: Vassileva
authors.forename: Eric L
authors.initials: EL
authors.lastname: Gustafson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hedrick
authors.forename: Harry R
authors.initials: HR
authors.lastname: Davis
mesh_terms: D050154:Adiposity; D000818:Animals; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage*; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D008659:Metabolic Diseases / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*
chemical_list: D004041:Dietary Fats; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled