3076-LB: Coupling Lysosomal and Mitochondrial Lipid Metabolism in Adipose Tissue Macrophages as a Therapeutic Strategy in Obesity

Introduction and Objective: Obesity-associated metabolic disorders are characterized by chronic low-grade inflammation driven by immune cells, particularly macrophages. However, inflammatory signaling alone does not fully explain immune cell-mediated metabolic dysfunction. Emerging evidence suggests that adipose tissue macrophages (ATMs) adopt a lysosomal lipid metabolism program in diet-induced obesity that may help manage lipid overload. TFEB is a master regulator of lysosomal biogenesis and lipid metabolism, yet its role in macrophage lipid handling and systemic metabolic health remains unclear. This study investigates whether TFEB-mediated activation of lysosomal and mitochondrial lipid metabolism in ATMs enhances macrophage lipid handling, limits lipid spillover, and improves systemic metabolic outcomes in obesity. Methods: Macrophage-specific TFEB transgenic (MΦ-TFEB-Tg) mice were generated to induce TFEB expression in macrophages. In cultured macrophages, lipid handling capacity were assessed using BODIPY staining and Seahorse assays. Systemic metabolic effects were evaluated in MΦ-TFEB-Tg mice challenged with a high-fat diet (HFD). Ongoing studies examine whether the metabolic benefits of TFEB overexpression depend on key enzymes involved in lysosomal lipolysis and mitochondrial fatty acid oxidation. Results: TFEB overexpression enhanced macrophage lipid handling capacity. TFEB activation also promoted metabolism of fatty acids and lipid-rich exosomes. In vivo, HFD-fed MΦ-TFEB-Tg mice exhibited reduced circulating free fatty acids and exosomes, decreased adipose tissue mass, and improved metabolic parameters compared with control mice. Conclusion: These findings identify TFEB as a key regulator coupling lysosomal and mitochondrial lipid metabolism in ATMs. Enhancing macrophage lipid metabolic capacity improves systemic metabolic health and represents a promising therapeutic strategy for obesity and cardiometabolic disease. Disclosure J. Huang: None. Y. Yeh: None. M. Khan: None. X. Zhang: None. B. Razani: None. Funding American Diabetes Association (1-26-PDF-0946)