GPR40 is a member of a subfamily of homologous G protein-coupled receptors that include GPR41 and GPR43 and that have no current function or ligand ascribed. Ligand fishing experiments in HEK293 cells expressing human GPR40 revealed that a range of saturated and unsaturated carboxylic acids with carbon chain lengths greater than six were able to induce an elevation of [Ca 2؉ ] i , measured using a fluorometric imaging plate reader. 5,8,11-Eicosatriynoic acid was the most potent fatty acid tested, with a pEC 50 of 5.7. G protein coupling of GPR40 was examined in Chinese hamster ovary cells expressing the G␣ q/i -responsive Gal4-Elk1 reporter system. Expression of human GPR40 led to a constitutive induction of luciferase activity, which was further increased by exposure of the cells to eicosatriynoic acid. Neither the constitutive nor ligandmediated luciferase induction was inhibited by pertussis toxin treatment, suggesting that GPR40 was coupled to G␣ q/11. Expression analysis by quantitative reverse transcription-PCR showed that GPR40 was specifically expressed in brain and pancreas, with expression in rodent pancreas being localized to insulin-producing ␤-cells. These data suggest that some of the physiological effects of fatty acids in pancreatic islets and brain may be mediated through a cell-surface receptor.

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1 The blood glucose-lowering ecacy of rosiglitazone (RSG) and the mechanisms of associated weight gain were determined in dietary obese rats (DIOs). DIO and chow-fed rats received RSG 0.3 ± 30 mg kg 71 daily for 21 days. 2 In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg 71, respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg 71 . Neither glucose nor insulin levels were aected by treatment in chow-fed rats. 3 RSG 0.3 mg kg 71 lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg 71 . By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg 71 . Thus, the therapeutic index for RSG in DIOs was 43 and 410. 4 Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg 71) and chow-fed rats (by 25% and 35 g, at 30 mg kg 71 ). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg 71 ) and insulin (43% lower at 30 mg kg 71 ). By contrast, in chow-fed rats, weight gain and hyperphagia occurred without changes in either leptin or insulin. However, reductions in FFAs below 0.4 ± 0.3 mM were associated with hyperphagia and weight gain in DIO and chow-fed rats. 5 We conclude that increased energy intake and body weight did not attenuate the improved metabolism evoked by RSG in DIO rats, and that insulin action was enhanced at a dose 43 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats.

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