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Updated: Aug 6, 2026
Assessment of the Metabolic Effects of Isocaloric 2:1 Intermittent Fasting in Mice
Published on: November 27, 2019
Alternate-day fasting enhances leptin sensitivity via JMJD3-dependent epigenetic regulation of the leptin receptor in
Busayo Oladun1, Smita Mall1, Baochan Fan2
1College of Health Solutions, Arizona State University, Phoenix, Arizona, USA.
Abstract:
Leptin resistance is a hallmark of obesity. It is characterized by diminished responsiveness to leptin and disrupts energy homeostasis. While multiple pathways contribute to leptin resistance, the transcriptional repression of the leptin receptor (LepRb) is a critical defect that impairs downstream signal transduction. Despite the established metabolic benefits of intermittent fasting, whether fasting directly influences leptin signaling and the underlying mechanisms remains unclear. Here, we investigated whether alternate-day fasting (ADF), a form of intermittent fasting, restores central leptin signaling by upregulating hypothalamic LepRb expression. In male C57BL/6J mice with diet-induced obesity, ADF significantly enhanced leptin-induced reductions in food intake and body weight, while increasing hypothalamic STAT3 phosphorylation, a key downstream mediator of leptin signaling. These metabolic improvements occurred independent of changes in body weight and adiposity, indicating a direct effect of fasting on leptin signaling. Mechanistically, ADF selectively reduced repressive H3K27 methylation at the LepRb promoter, leading to increased LepRb expression in hypothalamic nuclei critical for energy homeostasis. This epigenetic shift was associated with induction of the histone demethylase Jumonji Domain-Containing Protein three (JMJD3). To establish causality, we utilized stereotaxic injection of AAV-shRNA targeting Jmjd3 into the mediobasal hypothalamus. Knockdown of Jmjd3 abolished ADF-induced H3K27 demethylation, prevented LepRb upregulation, and attenuated the metabolic effects of ADF. Collectively, these findings identify JMJD3-dependent epigenetic regulation as a link between ADF and improved leptin signaling. Our study establishes histone modification and chromatin remodeling as a fundamental mechanism by which intermittent fasting reverses leptin resistance, providing a novel framework for leptin-based obesity therapies.
