MON-679 Study on the improvement of hypothalamic leptin resistance by SGLT2 inhibitors

Disclosure: J. Kim: None. D. Kim: None. S. Kim: None. J. Bae: None. M. Lee: None. Y. Kang: None. D. Yi: None. Background and Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) manage type 2 diabetes through an insulin-independent pathway by blocking glucose reabsorption in the kidney, promoting urinary glucose excretion. Recent studies suggest that SGLT2 interacts with hypothalamic neuropeptides involved in energy metabolism, potentially influencing leptin signaling and metabolic diseases. This study investigates how SGLT2i affects leptin resistance and related pathways in hypothalamic regulation. Materials and Methods: We examined the effects of SGLT2i on body weight, mRNA expression of energy-regulating neuropeptides, and leptin receptor expression in two animal models: one with direct intracerebroventricular (i.c.v.) injection of SGLT2i, and another induced with a high-fat diet (HFD) for 16 weeks, followed by 21 days of SGLT2i treatment. Leptin resistance was assessed by administering leptin to HFD-induced obese mice and measuring food intake. Additionally, leptin signaling was evaluated by analyzing STAT3 phosphorylation and SOCS3 mRNA expression in hypothalamic cell lines using immunoblot analysis and qRT-PCR. Results: Both direct and indirect SGLT2i administration led to significant weight reduction and increased POMC mRNA expression in the hypothalamus. In the leptin resistance model induced by HFD, leptin failed to suppress appetite in the control group but reduced food intake in the SGLT2i-treated group, indicating improved leptin sensitivity. Furthermore, SGLT2i treatment increased STAT3 phosphorylation and decreased SOCS3 mRNA expression in hypothalamic cell lines, suggesting modulation of leptin signaling. Conclusion: Our findings suggest that SGLT2i modulates leptin signaling through changes in STAT3 and SOCS3 expression in the hypothalamus, providing insights into potential therapeutic strategies for metabolic disorders linked to leptin resistance. Presentation: Monday, July 14, 2025