Dieting reverses histone methylation and hypothalamic AgRP regulation in obese rats

by Selleckchem | Jun 01 2023

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 in vivo.

Results: In DIO, downregulation of Kdm4d mRNA results in both enrichment of H3K9me2 on the AgRP promoter and transcriptional repression of AgRP. Because epigenetic modifications are dynamic, it is possible for some of these modifications to be reversed when external cues are altered. The reversal phenomenon was observed in calorically restricted rats, in which upregulation of Kdm4d mRNA resulted in demethylation of H3K9 on the AgRP promoter and transcriptional increase of AgRP. In order to verify that KDM4D is necessary to reverse obesity by dieting, we demonstrated that in vivo inhibition of KDM4D activity by pharmacological agent JIB-04 in naïve rats resulted in transcriptional repression of AgRP, decreasing orexigenic signaling, thus inhibiting hunger.

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.

Comments：

The study suggests that histone methylation malprogramming impairs energy balance control and that the role of KDM4D, a specific demethylase of residue H3K9, plays a key role in reversing this phenotype through direct modulation of AgRP expression, a key neuropeptide that regulates hunger response.

Using a rodent model of diet-induced obesity (DIO), the researchers found that downregulation of Kdm4d mRNA resulted in both enrichment of H3K9me2 on the AgRP promoter and transcriptional repression of AgRP. However, in calorically restricted rats, upregulation of Kdm4d mRNA resulted in demethylation of H3K9 on the AgRP promoter and transcriptional increase of AgRP.

To verify that KDM4D is necessary to reverse obesity through dieting, the researchers demonstrated that in vivo inhibition of KDM4D activity by the pharmacological agent JIB-04 in naïve rats resulted in transcriptional repression of AgRP, decreasing orexigenic signaling and inhibiting hunger.

The findings suggest 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. Further research is needed to determine whether KDM4D plays a similar role in humans and to assess the safety and efficacy of targeting KDM4D as a therapeutic strategy for obesity.