2539-P: PLIN2 Deficiency Promotes White Adipose Tissue Thermogenesis and Ameliorates Metabolic Disorders in Obesity by Remodeling Lipid Droplet–Mitochondria Interactions

Introduction and Objective: White adipose tissue (WAT) thermogenesis is a critical metabolic pathway for combating obesity, yet the role of the lipid droplet protein PLIN2 in regulating this process and inter-organelle communication remains incompletely understood. Here, we investigated whether PLIN2 governs thermogenesis by modulating lipid droplet (LD)-mitochondria (MT) contact sites through its interaction with VDAC2. Methods: Adipose-specific Plin2 knockout mice on a high-fat diet underwent metabolic phenotyping, including body weight, energy expenditure, glucose and insulin tolerance. In 3T3-L1 and primary white adipocytes, PLIN2 was knocked down or overexpressed. Assays measured thermogenic genes, LD morphology, mitochondrial respiration, and LD-MT colocalization. The PLIN2-VDAC2 interaction was validated by Immunoprecipitation (IP) -Mass Spectrometry and Co-IP, with rescue experiments confirming its mechanistic role. Results: Adipose-specific Plin2 knockout in mice reduced adiposity, improved systemic glucose and lipid homeostasis, and elevated energy expenditure, indicating enhanced thermogenesis. In vitro, PLIN2 deficiency promoted a thermogenic program (e.g., increased UCP1) and reduced LD size while enhancing LD-MT contacts; whereas PLIN2 overexpression exerted opposite effects. Mechanistically, PLIN2 interacts with VDAC2, and its loss stabilizes VDAC2 and promotes its localization at contact sites. Crucially, VDAC2 knockdown abolished both the enhanced LD-MT interactions and the metabolic improvements from PLIN2 deficiency, establishing VDAC2 as a key downstream effector. Conclusion: PLIN2 interacts with VDAC2 to stabilize LD-MT contacts, thereby regulates WAT thermogenesis and lipolysis. Targeting the PLIN2-VDAC2 axis promotes energy expenditure and improves metabolic homeostasis, offering a novel therapeutic strategy for obesity. Disclosure D. Xie: None. Y. Peng: None. J. Sun: None. Funding National Natural Science Foundation of China (82571042), National Natural Science Foundation of China (82270941), Guangdong Basic and Applied Basic Research Foundation (2024A1515013160)