A Novel mechanism for depot-specific leptin gene expression regulation and its persistence after weight loss

TL;DR

This study finds that DNA methylation and a non-coding RNA regulate leptin gene expression differently in fat depots, and these changes persist even after weight loss.

Contribution

The paper identifies a novel epigenetic mechanism involving DNA methylation and lncOb that regulates leptin expression in a depot-specific manner during obesity.

Findings

Lep enhancer methylation represses leptin expression in epididymal fat during obesity.

LncOb expression decreases in epididymal fat and remains low after weight loss.

Epigenetic changes in Lep regulation persist even after prolonged weight loss.

Abstract

Leptin gene (Lep) expression correlates with fat mass but differs between epididymal and inguinal fat depots in obesity. We investigated whether DNA methylation of a Lep enhancer (RS1) and the long non-coding RNA lncOb epigenetically regulate this depot-specific expression.

We analyzed DNA methylation, Lep and lncOb expression in fat depots across metabolic states in male C57BL/6 mice using CRISPR-dCas9-KRAB-mediated repression, methylation-sensitive luciferase assays, and mass spectrometry.

Under obesogenic conditions, RS1 methylation increased specifically in hypertrophic adipocytes of epididymal fat, repressing Lep transcription. This methylation persisted after long-term weight loss. LncOb expression correlated with Lep levels but was reduced in epididymal fat during obesity and remained suppressed post-weight loss.

Together, our findings demonstrate that adipocyte Lep expression is dynamically regulated by depot-specific epigenetic mechanisms that become dysregulated in obesity and resist reversal by weight loss, providing a unifying molecular mechanism for depot-specific Lep expression differences in a state of obesity.

•Lep enhancer DNA methylation and lncOb determine fat depot-specific Lep regulation•Lep enhancer methylation represses Lep in epididymal fat in obese; lncOb decreases•This epigenetic reprogramming is triggered by hypertrophic adipocytes in obesity•Lep enhancer DNA methylation and lncOb changes persist after prolonged weight loss

Lep enhancer DNA methylation and lncOb determine fat depot-specific Lep regulation

Lep enhancer methylation represses Lep in epididymal fat in obese; lncOb decreases

This epigenetic reprogramming is triggered by hypertrophic adipocytes in obesity

Lep enhancer DNA methylation and lncOb changes persist after prolonged weight loss

Human metabolism; Epigenetics

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