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Circadian clock control of MRTF/SRF pathway suppresses beige adipocyte thermogenic recruitment
Xuekai Xiong1 , Weini Li1 , Ruya Liu2 , Pradip Saha3 , Vijay Yechoor2 , Ke Ma1,*
1Department of Diabetes Complications & Metabolism, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
2Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
3Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
*Correspondence to:Ke Ma ,
J Mol Cell Biol, Volume 14, Issue 12, December 2022, mjac079,
Keyword: circadian rhythm, actin cytoskeleton, adipocyte differentiation, thermogenesis, energy balance, glucose metabolism, insulin sensitivity

The morphological transformation of adipogenic progenitors into mature adipocytes requires dissolution of actin cytoskeleton with loss of myocardin-related transcription factor (MRTF)/serum response factor (SRF) activity. Circadian clock confers temporal control in adipogenic differentiation, while the actin cytoskeleton–MRTF/SRF signaling transduces extracellular physical niche cues. Here, we define a novel circadian transcriptional control involved in actin cytoskeleton–MRTF/SRF signaling cascade that modulates beige fat thermogenic function. Key components of actin dynamic–MRTF/SRF pathway display circadian regulation in beige fat depot. The core clock regulator, brain and muscle arnt-like 1 (Bmal1), exerts direct transcriptional control of genes within the actin dynamic–MRTF/SRF cascade that impacts actin cytoskeleton organization and SRF activity. Employing beige fat-selective gene-targeting models together with pharmacological rescues, we further demonstrate that Bmal1 inhibits beige adipogenesis and thermogenic capacity in vivo via the MRTF/SRF pathway. Selective ablation of Bmal1 induces beigeing with improved glucose homeostasis, whereas its targeted overexpression attenuates thermogenic induction resulting in obesity. Collectively, our findings identify the clock–MRTF/SRF regulatory axis as an inhibitory mechanism of beige fat thermogenic recruitment with significant contribution to systemic metabolic homeostasis.