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Session: Personalizing Nutrition - Select Genetic, Epigenetic and Microbiome Interactions Influencing Diet and Diet-related Diseases (Oral 13)

(OR13-05-23) Hypothalamic JMJD3 Regulates Leptin Signaling via Epigenetic Mechanisms

Sunday, July 23, 2023
4:48 PM – 5:00 PM ET
Location:  Constitution B
ECRAC

    Presenting Author(s)

  • Min-Hyun Kim, PhD (he/him/his)

    Assistant Professor
    Arizona State University
    phoenix, Arizona, United States

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • BF

    Baochan Fan

    Arizona State University

  • JD

    Justin Dao

    Arizona State University

Disclosure(s):
Min-Hyun Kim, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: Leptin is a potent anorexigenic hormone that promotes body weight loss by activating the long-form leptin receptor (LepRb) in the hypothalamus. While leptin is a compelling candidate to treat diet-induced obesity, most obese individuals are relatively unresponsive to leptin. While this syndrome, termed leptin resistance, limits the potential of leptin therapy, the molecular mechanisms of leptin resistance, particularly potential role of epigenetic mechanisms, remain unclear. Jumonji domain-containing protein D3 (JMJD3) is a histone demethylase that mediates epigenetic activation of genes by eliciting the demethylation of histone H3 lysine 27 (H3K27). While JMJD3 has been studied in immune diseases and cancer, its metabolic function in the brain has not been explored.

Methods: To investigate whether JMJD3 has a role in hypothalamic control of energy metabolism, AAV-CMV-JMJD3 and AAV-CMV-EGFP (control) vectors were generated. These vectors were stereotaxically microinjected into the mediobasal hypothalamus (MBH) of C57BL/6 mice, which is a key region for energy homeostasis. Metabolic phenotypes including body weight, food intake, blood glucose, and leptin sensitivity were assessed in these mice.

Results: In response to chronic high-fat diet (HFD), MBH-specific JMJD3-overexpressed mice (MBH-JMJD3) displayed lower levels of food intake, body weight gain, and fasting blood glucose relative to EGFP-overexpressed control mice. Exogenous leptin stimulated hypothalamic STAT3 phosphorylation and weight loss to a greater level in MBH-JMJD3 mice than in control mice. Conversely, pharmacological inhibition of brain JMJD3 activity, mediated by an intracerebroventricular administration of GSK-J4, increased food intake and body weight gain, partially due to reduced responsiveness to leptin. Mechanistically, JMJD3 epigenetically activated the transcription of LepRb gene by H3K27 demethylation of LepRb promoter, thereby enhancing the leptin signaling in the hypothalamus.

Conclusions: Overall, our data suggest that hypothalamic JMJD3 is a previously unrecognized epigenetic regulator of leptin signaling.

Funding Sources: This study was supported by startup funding from the College of Health Solutions, Arizona State University.