Transcriptional repression of the MRTF/SRF-cytoskeleton pathway by Rev-erba promotes beigeing via adipogenic progenitor fate switch

Abstract

The circadian clock exerts temporal control in metabolic processes to maintain homeostasis, with its disruption leading to the development of obesity and insulin resistance. Adipose fibrosis in obese subjects exacerbates insulin resistance by restricting healthy tissue expansion and remodeling. Rev-erbα is a key circadian clock repressor that displays circadian rhythmic expression in adipose tissue, although its role in adipose tissue fibrosis is not known. Here we show that Rev-ebα inhibits the fibrogenic fate of adipocyte progenitors while promoting beige adipogenic potential via transcription repression of the MRTF/SRF-actin cytoskeleton axis. ChIP-seq analysis of Rev-erbα cistrome in adipogenic precursors identified its transcriptional control of pathways involved in cytoskeleton modulation, including established myofibroblast gene markers small muscle α-actin and Tropomysin. Gain-of-function of Rev-erbα in beige adipogenic precursors markedly suppressed MRTF/SRF activity with enhanced beige differentiation, while Rev-erbα silencing suppressed beige adipogenesis. Prrx1-Cre-mediated subcutaneous beige fat-selective Rev-erbα knock-in induced browning with augmented mitochondrial metabolism, resulting in increased energy expenditure, resistance to obesity and insulin sensitivity. Furthermore, single cell RNA-seq of beige progenitors with Rev-erbα overexpression revealed striking loss of preadipcyte-like (PAL) subpopulations with myofibroblastic characteristics that arise from pericyte lineage. PAL beige progenitors displayed enrichment of epithelial mesenchymal transition-related gene signature and contractile program as compared to preadipocytes. Preadipocyte population with Rev-erbα overexpression exhibited activated oxidative phosphorylation pathway with inhibition of myofibrolast characteristics. Taken together, our findings identify a novel regulatory function of Rev-erbα in modulating adipogenic progenitor fate choice that may promote adipose tissue beigeing while suppressing fibrotic complications. NIDDK grant 1R01DK112794, 1R01DK130499 and AR-DMRI 2023 T2D Innovation Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.