Increased Glucose Uptake in Brown Fat Promotes Energy Expenditure

Brown and beige fat dissipate energy as heat in response to β3-adrenergic receptor (β3AR) stimulation. Strategies to facilitate this response may be employed to promote weight loss and improve health in patients with metabolic disease. Previously, we discovered that GTPase RalA and its GAP complex RalGAP regulate exocytosis of glucose transporter GLUT4. We demonstrated in vivo, that adipose-tissue specific knockout of RalGAP subunit RalGAPB activates RalA and increases glucose uptake 7 times in brown fat (BAT), leading to improved glucose handling on high fat diet (HFD). Here we seek to test the effect of increased glucose uptake in BAT on energy expenditure (EE), using mice with BAT-specific knockout of RalGAPB (the KO mice). After 8 weeks on 45% HFD, the KO mice and control littermates (Ctr) were injected with β3AR agonist CL-316,243 (CL) or PBS for 8 days. Mice assigned to CL were placed in metabolic cages. Respiratory quotient was increased in the KO mice, indicating increased glucose oxidation (likely by BAT, due to increased glucose uptake). EE at room temperature was elevated in the KO mice. This was compensated by increased food uptake, explaining similar body weights between the KO and Ctr mice. CL injections, as expected, induced spikes in EE. Acute response to CL (arbitrarily defined as EE during 2 hours after CL injection) was consistent between daily CL injections in Ctr mice, and was increased twice in the KO mice compared to Ctr. In Ctr mice, 1st CL injection increased average day and night EE; this response gradually declined with consecutive CL injections. In the KO mice, 1st CL injection elicited similar to Ctr mice increase in average day and night EE; and the response to consecutive CL injections was preserved. As anticipated, CL reduced adiposity in Ctr mice, which was further augmented in the KO mice, consistent with finding on EE. We will further test the role of increased glucose uptake by BAT in EE of the KO mice, and will determine the mechanism of sustained CL responsiveness in the KO mice. Disclosure F.Rezayat: None. J.A.Resnick: None. I.M.Farah: None. Y.Skorobogatko: None. A.Saltiel: Board Member; Elgia Therapeutics. Funding National Institutes of Health (P30DK063491)