200-LB: Circadian Regulation of the MRTF-SRF Signaling Promotes Beige Adipocyte Development

Abstract

The adipogenic progenitor transformation into mature adipocytes requires dissolution of intracellular actin cytoskeleton, and the cytoskeleton-MRTF/SRF signaling blocks adipogenesis. The circadian clock confers temporal control in metabolism, with tissue-intrinsic clock circuits contributing to metabolic homeostasis. In the current study, we identify a novel clock-MRTF/SRF regulatory axis that suppresses beige adipogenesis that is required for whole-body glucose metabolism. Key components of the cytoskeleton-MRTF/SRF signaling cascade display circadian oscillations in beige fat depot mediated by Bmal1 transcriptional activity. Genetic loss- or gain-of-functions of Bmal1 in adipogenic precursors markedly altered actin cytoskeleton organization, with silencing of Bmal1 inhibiting F-actin formation and MRTF/SRF activity whereas its forced expression augmenting actin architecture. Furthermore, we show that Bmal1 circadian control of the MRTF/SRF pathway drives beige thermogenic capacity in vivo. Prrx1-Cre-mediated beige fat-selective Bmal1 ablation induced beige depot browning with augmented mitochondrial metabolism, resulting in improved whole-body insulin sensitivity and resistance to obesity. Conversely, beige fat-specific overexpression of Bmal1 suppressed beige thermogenic program leading to impaired glucose tolerance and adipose expansion. Mechanistically, we show that Bmal1 deficiency enhanced beige precursor differentiation and thermogenic induction. Collectively, our findings uncover a temporal regulation of the cytoskeleton-MRTF/SRF signaling that modulates beige thermogenic capacity to maintain metabolic homeostasis. Disclosure X. Xiong: None. R. Liu: None. V. Yechoor: None. P. Saha: None. K. Ma: None. Funding National Institutes of Health (DK112794, DK097160-01); American Heart Association (17GRNT33370012)