Abstract Body: Introduction
Obesity-associated metabolic disorders are characterized by chronic, low-grade inflammation caused by the activation of immune cells, particularly macrophages. However, inflammatory signaling alone does not fully explain immune cell driven metabolic dysfunction. Recent evidence indicates that adipose tissue macrophages (ATMs) adopt a lysosomal lipid metabolism program in diet-induced obesity, suggesting a compensatory role in managing lipid overload. TFEB is a master regulator of lysosomal biogenesis and lipid metabolism, while its role in coordinating macrophage lipid handling and systemic metabolic health remains unclear.
Hypothesis
We hypothesize that TFEB-mediated activation of lysosomal and mitochondrial lipid metabolism in ATMs enhances macrophage lipid handling, limits lipid spillover, and improves whole-body metabolic outcomes in obesity.
Methods
Macrophage-specific TFEB-transgenic (MΦ-TFEB-Tg) mice were generated to induce TFEB expression in ATMs. In cultured macrophages, lipid handling capacity, lysosomal and lipid metabolic gene expression, and mitochondrial respiration were assessed by BODIPY staining, mRNA expression and Seahorse assay, respectively. Systemic metabolic effects were evaluated in MΦ-TFEB-Tg mice challenged with a high-fat diet (HFD). Ongoing studies assess whether the metabolic benefits of TFEB overexpression depend on key enzymes involved in lysosomal lipolysis and mitochondrial fatty acid oxidation.
Results
Our data suggests that macrophages actively participate in lipid handling within adipose tissue. TFEB overexpression significantly enhanced lipid handing capacity, upregulated lysosomal and mitochondrial lipid metabolic gene expression, and increased the mitochondrial respiration. In addition, TEFB 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 controls.
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 obesity-associated cardiometabolic disease.