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

ABSTRACT The morphological transformation of adipogenic progenitors into mature adipocytes requires dissolution of cytoskeleton driven by progressive loss of MRTF-SRF activity. Circadian clock confers temporal control in adipogenic differentiation, and MRTF-SRF inhibits beige adipocyte development. Here we identify that key components of the actin cytoskeleton-MRTF/SRF signaling cascade are direct transcriptional targets of circadian clock, and a clock-MRTF/SRF regulatory axis suppresses beige adipocyte thermogenic recruitment. Genetic loss- or gain-of-functions of the core clock regulator, Brain and Muscle Arnt-like 1 (Bmal1), altered actin cytoskeleton organization, cell shape and SRF activity. Genes involved in actin dynamic-MRTF-SRF pathway display diurnal expression profiles in beige adipose tissue, with identification of Bmal1 direct transcriptional regulation. Using beige adipocyte-selective genetic models together with pharmacological approaches, we demonstrate that Bmal1 inhibits beige adipogenesis and thermogenic capacity via the MRTF-SRF pathway. Selective ablation of Bmal1 induced beigeing, whereas its targeted overexpression attenuated the beige thermogenic program resulting in obesity. Collectively, our findings define a novel circadian clock control in actin cytoskeleton-MRTF-SRF signaling that suppresses beige adipogenesis to maintain metabolic homeostasis.