3074-LB: Inhibition of VDAC1 Oligomerization Regulates Energy Balance through Hypothalamic STAT3 Activation in Mice

Introduction and Objective: Vdac1 oligomerization forms large pores in the outer mitochondrial membrane, promoting the release of pro-apoptotic factors and inflammation. Although inhibition of Vdac1 oligomerization has been explored in cancer and neurodegeneration, its role in hypothalamic regulation of energy homeostasis remains unclear. We investigated whether inhibition of Vdac1 oligomerization modulates energy balance via hypothalamic Stat3 signaling. Methods: High-fat diet (HFD)-induced obese mice were orally treated with an inhibitor of Vdac1 oligomerization (IVO; a modified form of oteseconazole). A loading dose (3 mg/kg) was followed by a maintenance dose (1.2 mg/kg) three times weekly for 7 weeks. Body weight and food intake were monitored twice weekly. Mouse hypothalamic cells were treated with IVO (1-10 μM). Neuropeptide expression was measured by qPCR, and Stat3 activity and Socs3 expression were analyzed by Western blot. Synergistic effects with leptin were assessed using subthreshold IVO (0.5 μM) and leptin (5 ng/mL). Results: IVO-treated HFD mice showed reduced body weight gain without changes in food intake. IVO increased Pomc mRNA expression, while Npy and Agrp were unchanged. IVO enhanced Stat3 phosphorylation in hypothalamic cells. Notably, combined subthreshold IVO and leptin treatment significantly increased Stat3 activation and reduced Socs3 expression compared with control. Conclusion: Inhibition of Vdac1 oligomerization regulates energy balance independently of food intake, potentially through enhanced hypothalamic Stat3 signaling and Pomc induction. These findings identify Vdac1 as a novel regulator of central energy homeostasis. Future studies will determine its effects on glucose metabolism and insulin sensitivity and evaluate its translational potential as a therapeutic target for obesity and type 2 diabetes. Disclosure M. Song: None.