Roles of hypothalamic JMJD3 in the regulation of leptin sensitivity and energy homeostasis

Project Summary/Abstract The prevalence of obesity has reached alarming levels, impacting approximately one-third of the adult population in the United States. This epidemic poses a significant risk to individuals, increasing the susceptibility to metabolic syndrome. In most cases, obesity is characterized by hypothalamic resistance to the

anorexigenic hormone leptin. Leptin resistance impedes the efficacy of leptin therapy in addressing obesity and metabolic syndrome. While several regulators have been implicated in leptin resistance, it is critical to identify additional regulators of leptin signaling to gain a full understanding in the development of leptin resistance,

particularly nuclear factors that influence the epigenetic landscape of chromatin architecture, which can be susceptible to obesogenic environmental factors. Aberrant epigenetic modifications are increasingly recognized to trigger the onset of numerous diseases, including metabolic diseases. However, the interaction between

obesogenic diet and the epigenetic reprogramming of hypothalamus, where leptin elicits its action, remains largely unknown. Jumonji D3 (JMJD3; KDM6B) is a histone lysine demethylase that epigenetically activates genes by demethylating the repressive histone mark H3K27me3. While JMJD3's involvement in various

biological processes, such as development, immunity, and autophagy, has been demonstrated, its metabolic roles in the hypothalamus remain unexplored. In our preliminary study using mice, we observed that a high-fat diet (HFD) leads to the specific downregulation of JMJD3 expression in the ventromedial hypothalamic nucleus

(VMH), a region characterized by high leptin signaling activity. shRNA-mediated VMH-specific downregulation of JMJD3 disrupts hypothalamic leptin signaling, contributing to the development of obesity. Conversely, lentivirus-mediated VMH-specific overexpression of JMJD3 enhances leptin signaling, offering protection

against obesity and metabolic syndrome induced by HFD. The present study aims to demonstrate the crucial role of JMJD3 as an epigenetic modifier in regulating hypothalamic leptin signaling and energy homeostasis. Aim 1 aims to examine whether hypothalamic JMJD3 protects against obesity through an epigenetic

mechanism. We will create Jmjd3 knockout mouse models that are specific to the ventromedial hypothalamus (VMH) region and leptin receptor-expressing cells to investigate the anatomical and functional role of JMJD3 in hypothalamic leptin signaling and obesity development. Aim 2 will explore the molecular mechanism by which

JMJD3 influences leptin signaling. We will investigate whether JMJD3 induces epigenetic modifications in known regulators of leptin signaling, such as the leptin receptor. Additionally, we will use ChIP-seq and RNA- seq to identify other targets of JMJD3 in an unbiased manner. Aim 3 will explore nonpharmacological strategies

to enhance hypothalamic JMJD3 expression, aiming to alleviate leptin resistance. This proposal will establish the significance of hypothalamic JMJD3 in the leptin signaling pathway, potentially identifying JMJD3 activation as a therapeutic target for combating obesity by enhancing leptin sensitivity.