Objective: Leptin resistance, particularly in the ventromedial hypothalamus, is a critical driver of obesity, yet its epigenetic regulation remains poorly understood. This study investigated whether the histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates leptin sensitivity and signaling in the ventromedial hypothalamus (VMH) and influences susceptibility to high-fat diet (HFD)-induced obesity, thereby offering a novel approach to tackle obesity from an epigenetic perspective. Hypothesis: We hypothesized that diet-induced obesity suppresses JMJD3 in the VMH, contributing to leptin resistance. Restoring JMJD3 expression in the VMH enhances leptin receptor (LepRb) signaling and sensitivity, thus attenuating obesity. Methods: Male C57BL/6J mice were fed a normal chow or HFD (60% Kcal from fat) for 10 weeks. Using stereotaxic surgery, mice received VMH-specific lentiviral vectors expressing wild-type JMJD3, an epigenetically inactive JMJD3 mutant, or green fluorescent protein (GFP) control. Outcome measures included body weight, adiposity (fat mass), food intake, VMH LepR expression, leptin signaling assessed by phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and H3K27me3 enrichments by ChIP-qPCR at the LepRb promoter (n = 8 per group). Result: In HFD-fed mice, VMH JMJD3 expression and LepR expression were reduced compared with chow-fed controls (p< 0.05). JMJD3 overexpression in the VMH decreased body weight gain, adiposity, and food intake compared with control vector groups, and restored LepR expression (p< 0.05). Overexpression of JMJD3 significantly increased leptin sensitivity, as indicated by increased pSTAT3 expression in the VMH. Levels of H3K27me3 at the LepRb promoter were significantly reduced in JMJD3-overexpressing mice compared with the mutant and control groups (p< 0.05). Summary of Result: Increased p-STAT3 levels in VMH neurons indicate improved downstream leptin signaling under HFD conditions. The observed effect occurred exclusively in JMJD3-overexpressing mice, but not in the mutant group, indicating that the metabolic improvement depends on JMJD3 histone demethylase activity and is therefore mediated by an epigenetic mechanism. Conclusions: JMJD3 is an epigenetic regulator of VMH leptin signaling that is suppressed by HFD. Restoring JMJD3 expression in the VMH improves LepR signaling and leptin responsiveness and is associated with reduced hyperphagia and adiposity in HFD-fed mice, supporting JMJD3 as a potential therapeutic target to counter leptin resistance and obesity. Funding: NIH/NIDDK R01 DK139038 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Oladun et al. (Fri,) studied this question.