(PTFS05-07-24) Epigenetic Regulation of Leptin Signaling by Hypothalamic JMJD3 Mitigates High-Fat Diet-Induced Obesity in Mice

Objectives: Leptin, a hormone produced by adipose tissue, plays a vital role in regulating appetite and metabolism, and its dysregulation is intricately linked to the development and progression of obesity. The disruption of the leptin receptor (LepRb) in the ventromedial hypothalamus (VMH) leads to leptin resistance. Recently, epigenetics has received more attention in understanding the mechanism of obesity and metabolic syndrome. However, the interaction between obesogenic diets and the epigenetic reprogramming of hypothalamic neural circuits of leptin actions remains largely unknown. Here, we show that Jumonji D3(JMJD3), a histone lysine demethylase with the Jmjc domain, is a critical epigenetic modifier that regulates leptin signaling.

Methods: C57BL/6J male mice were fed a normal chow or a high-fat diet (HFD) for 10 weeks. Overexpression of target genes was conducted by stereotaxically injecting LV-CMV-JMJD3, LV-CMV-ΔEpi (a JMJD3 mutant without epigenetic activity; dominant-negative control), or LV-CMV-eGFP (negative control) to the VMH.

Results: JMJD3 expression was markedly reduced in the VMH of HFD-fed obese mice compared to normal chow-fed mice. Mice injected with LV-CMV-JMJD3 in the VMH, displayed significantly reduced body weight, fat content, blood glucose, blood insulin, and food intake compared to the control groups, indicating that JMJD3 overexpression protects against obesity. Leptin sensitivity was increased as depicted by significantly elevated phosphorylated-STAT3(a marker of leptin activation) levels in LV-CMV-JMJD3 compared to the control groups. This indicates that JMJD3 overexpression can potentiate hypothalamic leptin signaling. Interestingly, we observed a decrease in H3K27me3 levels, (a repressive epigenetic mark) at the LepRb promoter region in the VMH of mice injected with LV-CMV-JMJD3, accompanied by an increase in the expression of LepRb mRNA compared to the control groups. This suggests that JMJD3-mediated demethylation of H3K27me3 upregulates LepRb, thereby enhancing leptin signaling.

Conclusions: Our result unveils a critical role for JMJD3 in the epigenetic regulation of leptin signaling in the VMH. Targeting JMJD3 in the VMH could be a potential novel therapeutic strategy in ameliorating leptin resistance in obesity.

Funding Sources: This study was supported by grants NIH F32DK120111 and ASU CHS startup funding.