Multi-layered transcriptional control of glycogen metabolism coordinates thermogenic remodeling of white adipocytes in male mice

TL;DR

This study reveals how glycogen metabolism is controlled in white fat cells during thermogenic activation in male mice.

Contribution

The paper identifies a multilayered transcriptional axis involving PGC1α and ERRs that sustains glycogen metabolism during thermogenesis.

Findings

Gys2 is a direct transcriptional target of PKA-CREB signaling in adipocytes.

PGC1α and ERRs regulate chromatin accessibility and gene expression for glycogen metabolism.

Combined deletion of ERRα/β/γ abolishes glycogen metabolism and thermogenic gene expression.

Abstract

Thermogenic activation of subcutaneous white adipocytes requires glycogen synthesis and turnover. Here we show that β-adrenergic stimulation induces a distinct glycogen metabolism gene program in inguinal white adipose tissue in a cell-autonomous and adipocyte-specific manner. Among these, Gys2 and Ppp1r3c are rapidly induced following acute β3-adrenergic receptor activation. We identify Gys2 as a direct transcriptional target of PKA-CREB signaling. In contrast, sustained expression of glycogen metabolism genes under chronic β3-adrenergic activation requires the coactivator PGC1α, whose loss blunts glycogen accumulation and thermogenic capacity. Mechanistically, PGC1α cooperates with estrogen-related receptors (ERRs) to regulate chromatin accessibility and gene transcription. Although deletion of ERRα is compensated by ERRγ, combined deletion of ERRα/β/γ abolishes expression of glycogen metabolism and thermogenic genes. Chromatin profiling confirm that ERRs directly control the glycogen metabolic program in beige adipocytes. Together, our results identify a multilayered transcriptional axis that sustains glycogen metabolism during β-adrenergic activation in male mice.

Previous studies suggested that glycogen metabolism played a role in beiging of subcutaneous adipocytes. This work identifies a β-adrenergic–driven transcriptional program that promotes glycogen synthesis and turnover during thermogenic activation of adipocytes. PGC1α and estrogen-related receptors (ERRs) cooperatively sustain this program by regulating chromatin accessibility and gene expression.

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