Aims/hypothesis We assessed the contribution of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) signalling to thermogenesis induced by high-fat diet (HFD) consumption. Furthermore, we determined whether brown adipose tissue (BAT) activity contributes to weight loss induced by chronic subcutaneous treatment with the GLP-1R agonist, liraglutide, in a model of diet-induced obesity. Methods Metabolic phenotyping was performed using indirect calorimetry in wild-type (WT) and Glp1r-knockout (KO) mice during chow and HFD feeding at room temperature and at thermoneutrality. In a separate study, we investigated the contribution of BAT thermogenic capacity to the weight lowering effect induced by GLP-1 mimetics by administering liraglutide (10 or 30 nmol kg−1 day−1 s.c.) to diet-induced obese (DIO) mice for 6 or 4 weeks, respectively. In both studies, animals were subjected to a noradrenaline (norepinephrine)-stimulated oxygen consumption (V̇O2) test. Results At thermoneutrality, HFD-fed Glp1r-KO mice had similar energy expenditure (EE) compared with HFD-fed WT controls. However, HFD-fed Glp1r-KO mice exhibited relatively less EE when housed at a cooler standard room temperature, and had relatively lower V̇O2 in response to a noradrenaline challenge, which is consistent with impaired BAT thermogenic capacity. In contrast to the loss of function model, chronic peripheral liraglutide treatment did not increase BAT activity as determined by noradrenaline-stimulated V̇O2 and BAT gene expression. Conclusions/interpretation These data suggest that although endogenous GLP-1R signalling contributes to increased BAT thermogenesis, this mechanism does not play a significant role in the food intake-independent body weight lowering effect of the GLP-1 mimetic liraglutide in DIO mice.

Perfusion of ionophore A23187 (10 muM) in the isolated dog pancreas resulted in a monophasic release of insulin. Ionophore A23187 (10 muM) failed, however, to elicit insulin secretion when added to calcium deficient (0.1 mmoles/L) perfusate. Simultaneous reintroduction of calcium (1.27 mmoles/L) and discontinuance of ionophore A23187 following calcium deficient periods caused a monophasic secretion of insulin which was quantitatively very similar (41,400 +/- 13,800 muU) to that stimulated by ionophore during normocalcemic perfusion. With reference to the current literature, these results suggest that ionophore A23187 elicits insulin secretion in the perfused dog pancreas preparation by increasing the level of free intracellular calcium, a process which is dependent upon a normal extracellular ionic calcium concentration.