Dieting reverses histone methylation and hypothalamic AgRP regulation in obese rats.

Introduction: Although dieting is a key factor in improving physiological functions associated with obesity, the role by which histone methylation modulates satiety/hunger regulation of the hypothalamus through weight loss remains largely elusive. Canonically, H3K9me2 is a transcriptional repressive post-translational epigenetic modification that is involved in obesity, however, its role in the hypothalamic arcuate nucleus (ARC) has not been thoroughly explored. Here we explore the role that KDM4D, a specific demethylase of residue H3K9, plays in energy balance by directly modulating the expression of AgRP, a key neuropeptide that regulates hunger response. Methods: We used a rodent model of diet-induced obesity (DIO) to assess whether histone methylation malprogramming impairs energy balance control and how caloric restriction may reverse this phenotype. Using ChIP-qPCR, we assessed the repressive modification of H3K9me2 at the site of AgRP. To elucidate the functional role of KDM4D in reversing obesity via dieting, a pharmacological agent, JIB-04 was used to inhibit the action of KDM4D Results: In DIO, downregulation of Discussion: We propose that the action of KDM4D through the demethylation of H3K9 is critical in maintaining a stable epigenetic landscape of the AgRP promoter, and may offer a target to develop new treatments for obesity.