GPR40 is partially required for insulin secretion following activation of beta3-adrenergic receptors.
The free fatty acid (FFA) receptor GPR40, expressed by pancreatic beta-cells, may be responsible for insulin release following beta(3) adrenoceptor (Adrb3) activation. To test this hypothesis, we first studied the effects of Adrb3 agonists SR58611A and CL316,243 in GPR40 knockout (GPR40(-/-)) mice. Both drugs increased blood FFA levels in wild-type (GPR40(+/+)) and GPR40(-/-) mice, indicating that lipolysis is not GPR40-dependent. However, the magnitude of the insulin response after agonist treatment was decreased by approximately 50% in GPR40(-/-) mice. Analysis of the time-course revealed that the change in FFAs (5-10 min post-treatment) in response to SR58611A preceded insulin secretion (10-15 min post-treatment). While reduced by agonist treatment, glucose levels in GPR40(-/-) mice remained significantly higher than in GPR40(+/+) mice. Energy expenditure, food intake, or body weight was not affected in GPR40(-/-) mice, whereas SR58611A increased energy metabolism. Furthermore, CL316,243 did not potentiate glucose-stimulated insulin secretion in isolated mouse islets or activate a cAMP reporter in transgenic mice. Our data indicate that insulin secretion, a secondary event following stimulation of Adrb3 receptors, is partially mediated by GPR40 and suggest that GPR40 is integral to the anti-diabetes effects of Adrb3 agonists.
Pang
Zhen
Z
Department of Biological Sciences, sanofi-aventis, 1041 Route 202-206, Bridgewater, NJ 08807, USA. zhen.pang@sanofi-aventis.com
Wu
Nancy
N
Zhang
Xin
X
Avallone
Roberta
R
Croci
Tiziano
T
Dressler
Holly
H
Palejwala
Vaseem
V
Ferrara
Pascual
P
Tocci
Michael J
MJ
Polites
H Gregory
HG
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D004149:Dioxoles; C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D022702:Receptors, Adrenergic, beta-3; D043562:Receptors, G-Protein-Coupled; D013764:Tetrahydronaphthalenes; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C076252:amibegron