1706-P: Harnessing Lipid Metabolism in Macrophages by Lysosomal-Mitochondrial Coupling to Treat Obesity

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Introduction and Objective: Obesity-related metabolic disorders, such as insulin resistance and type 2 diabetes, are associated with lipid-mediated immune cell activation, particularly macrophages. However, inflammatory signaling alone cannot fully explain the complex relationship between immune cell recruitment and disease pathogenesis. Recent studies show that macrophages in adipose tissue adopt a lysosomal lipid metabolism program in diet-induced obesity, suggesting a potential compensatory role in managing lipid overload. This study investigates whether enhancing macrophage lipid hydrolysis and metabolism via TFEB, a regulator of lysosomal, lipid metabolic, and mitochondrial genes, can improve metabolic outcomes. Methods: We generated macrophage-specific TFEB-transgenic mice (mΦ-TFEB-tg) to induce TFEB expression in adipose tissue macrophages (ATMs). Using cultured macrophages, we examined lysosomal and mitochondrial lipid metabolic gene expression, lipid handling capacity, and mitochondrial respiration. The systemic metabolic effects were assessed in mΦ-TFEB-tg mice challenged with an HFD. Results: Overexpressing TFEB in ATMs significantly upregulated lysosomal and mitochondrial lipid metabolic genes, promoting the metabolism of fatty acids and lipid-rich exosomes and increasing mitochondrial respiration. HFD-fed mΦ-TFEB-tg mice exhibited reduced spillover of exosomes and free fatty acids in the circulation, decreased adipose tissue mass, resistance to diet-induced obesity, and improved glucose tolerance and insulin sensitivity. Conclusion: These findings demonstrate that coupling lysosomal lipid hydrolysis with mitochondrial lipid metabolism in ATMs via TFEB enhances cell-intrinsic lipid metabolism and systemic metabolic parameters. This approach could serve as a potential therapeutic strategy for treating obesity and associated metabolic dysfunctions. Disclosure J. Huang: None. Y. Yeh: None. X. Zhang: None. B. Razani: None. Funding NIH (R01 HL159461)

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