2583-P: Adipose-Specific Gαq Activation Synergizes with Gαs Signaling to Increase Energy Expenditure and Fat Loss in Diet-Induced Obesity

Introduction and Objective: Pharmacologic approaches to obesity emphasize caloric restriction, exemplified by GLP-1 receptor agonists, which reduce appetite and adiposity through central and peripheral Gαs-mediated signaling. However, these therapies do not directly address reduced total daily energy expenditure (TDEE), a key contributor to obesity, and higher doses may lead to adverse effects including gastroparesis and lean mass loss. Data from our lab suggests that activation of adipose-specific Gαq signaling can potentiate Gαs-driven lipolysis and energy expenditure. We hypothesized that dual activation of Gαs/Gαq pathways in adipose tissue would synergistically enhance energy expenditure and promote fat loss. Methods: Mice expressing the hM3Dq DREADD receptor selectively in adipose tissue were fed a high-fat diet for 10 weeks to induce obesity. Gαq signaling was activated via deschloroclozapine (DCZ), while Gαs signaling was stimulated using the β3-adrenergic agonist CL 316,243. Mice received daily injections of vehicle, DCZ, CL, or CL+DCZ. Energy expenditure, food intake, and locomotor activity were assessed using metabolic cages. Body composition was measured by MRI before and after treatment. Results: CL treatment increased total and resting energy expenditure compared to control, while DCZ alone had no significant effect. Combined CL+DCZ treatment produced the greatest increase in both total and resting energy expenditure, indicating a synergistic effect of Gαq and Gαs activation. CL-treated mice exhibited significant fat mass loss with lean mass preservation, and CL+DCZ treatment resulted in the greatest fat loss while maintaining lean mass comparable to all other groups. Conclusion: Gαq activation potentiates Gαs-mediated increases in energy expenditure, promoting selective fat loss while preserving lean mass. These findings identify adipose GPCR signaling synergy as a potential therapeutic strategy to augment energy expenditure beyond current appetite-focused obesity treatments. Disclosure A. Kondilis: None. Y. Liu: None.