186-OR: Brain-Angiogenesis Inhibitor-3 Ablation Enhances Brown Adipose Tissue Thermogenesis and Protects against Obesity

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Introduction and Objective: Obesity, a primary cause of cardiometabolic diseases and type 2 diabetes, is associated with impaired brown adipose tissue (BAT) function. Activating Gs-protein-coupled receptors (GPCRs) in BAT is central for promoting thermogenesis and energy expenditure (EE), which play a key role in regulating body weight (BW). However, a complete understanding of altered GPCR signaling in BAT on obesity remains elusive. Methods: In our study, using a mouse model, we identified the adhesion Gi-GPCR brain angiogenesis inhibitor 3 (BAI3) as a negative regulator of EE. BAI3, expressed in BAT, was found to inhibit BAT function. Results: Excitingly, the deletion of BAI3 enhanced EE, reduced fat mass, and decreased adipocyte size, resulting in lower BW without affecting lean mass or food intake in mice on low- and high-fat diets. Importantly, BAI3-deficient mice displayed elevated glucose clearance and internal body temperature during cold exposure, while no EE enhancement occurred at thermoneutrality, indicating BAI3’s role in adaptive thermogenesis. Mechanistically, BAI3 loss enhanced lipogenesis, fatty acid oxidation, fatty acid uptake, mitochondrial function, and thermogenesis in BAT, improving glucose and fatty acid utilization. These changes improved the metabolic profile: glucose clearance, insulin sensitivity, circulating triglycerides, and non-esterified fatty acids. Conclusion: Our findings highlight that BAI3 inhibits BAT function and adaptive thermogenesis. BAI3 ablation protects against diet-induced obesity by enhancing BAT-mediated metabolic activity and EE. Targeting BAI3 signaling represents a promising therapeutic approach to treating obesity and related metabolic disorders through BAT activation. Disclosure H. Alsharif: None. K. Perez: None. D. Tummala: None. J.B. Alexander: None. G. Ren: None. M. Rahman: None. M. Young: None. S. Bhatnagar: None.

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