(P21-007-25) Intermittent Fasting Enhances Leptin Sensitivity via Epigenetic Modification of Hypothalamic Leptin Receptor in Mice

Objectives: Leptin regulates energy balance by suppressing appetite and promoting energy expenditure. Its therapeutic potential for obesity is limited by leptin resistance, where the hypothalamus becomes unresponsive to leptin. This research aimed to investigate the effects of intermittent fasting (IF) on leptin sensitivity in a diet-induced obesity mouse model.

Methods: Male C57BL/6J mice were fed a high fat diet (HFD) for 8 weeks to induce obesity. The mice were then randomly divided into two groups: an ad libitum (AL) feeding group and an IF group, subjected to every-other-day fasting. After 5 cycles of IF, leptin sensitivity was assessed in live mice by evaluating body weight reductions and food intake suppressions following an intraperitoneal injection of exogenous leptin (0.5 mg/kg body weight) for 1 hour.

Results: Leptin sensitivity was assessed after 5 cycles of IF, during which body weights of the AL and IF groups remained comparable to minimize potential secondary effects from differing body weights. Following leptin administration, IF mice exhibited significantly greater reductions in body weight and food intake suppression compared to AL mice. The IF group displayed enhanced leptin activation markers, including increased hypothalamic phosphorylated STAT3 and upregulated expression of leptin-responsive genes (Socs3, Bcl3, and Atf3), suggesting that IF led to enhanced leptin signaling. Mechanistically, IF mice showed significantly higher hypothalamic expression of the leptin receptor (LepRb), compared to AL mice, thereby potentiating downstream leptin signaling. This IF-mediated upregulation of LepRb was attributed to significantly lower H3K27 methylation at the LepRb promoter region, an epigenetic modification that activates gene expression.

Conclusions: This study demonstrates that IF enhances leptin sensitivity in obesity by elevating hypothalamic LepRb expression via an epigenetic mechanism. These findings suggest that IF may serve as an effective dietary intervention to mitigate leptin resistance and improve metabolic health in obesity.

Funding Sources: This research project was supported by NIH R01DK139038 and startup funding from the College of Health Solutions at Arizona State University.