Circadian clock control of MRTF/SRF pathway suppresses beige adipocyte thermogenic recruitment

查看全文 作　　者：Xuekai [1]Xiong;Weini [1]Li;Ruya [2]Liu;Pradip [3]Saha;Vijay [2]Yechoor;Ke [1]Ma 机构地区：[1]Department of Diabetes Complications&Metabolism,Beckman Research Institute of City of Hope,Duarte,CA 91010,USA;[2]Diabetes and Beta Cell Biology Center,Division of Endocrinology,Diabetes&Metabolism,Department of Medicine,University of Pittsburgh,Pittsburgh,PA 15213,USA;[3]Department of Medicine,Baylor College of Medicine,Houston,TX 77030,USA 出　　处：《Journal of Molecular Cell Biology》索引2022年第14卷第12期,共17页 基　　金：supported by grants from National Institutes of Health(1R01DK112794);American Heart Association(17GRNT33370012);K.M.and from National Institutes of Health(DK097160-01 and 1R01DK130499)to V.Y。 摘　　要：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. 关 键 词：circadian rhythm actin cytoskeleton adipocyte differentiation THERMOGENESIS energy balance glucose metabolism insulin sensitivity