Lack of FFAR1/GPR40 does not protect mice from high-fat diet-induced metabolic disease.
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.
Lan
Hong
H
Department of Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, New Jersey, USA. hong.lan@spcorp.com
Hoos
Lizbeth M
LM
Liu
Li
L
Tetzloff
Glen
G
Hu
Weiwen
W
Abbondanzo
Susan J
SJ
Vassileva
Galya
G
Gustafson
Eric L
EL
Hedrick
Joseph A
JA
Davis
Harry R
HR
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*
D004041:Dietary Fats; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled