Circadian Clock Control of Adipose Depot Development and Function

米色脂肪细胞是皮下脂肪库中的一种棕色脂肪细胞，具有高代谢活性，有利于能量平衡和代谢稳态。米色脂肪细胞的丰富性和可诱导性使其成为肥胖症和相关代谢紊乱的有吸引力的治疗靶点。更好地了解控制米色功能能力的分子途径可能会导致肥胖症的新疗法。生物钟驱动代谢节律以维持体内平衡。尽管目前认识到生物钟破坏导致肥胖和胰岛素抵抗，脂肪组织含有功能性生物钟，但不同的脂肪组织生物钟如何促进代谢稳态尚未被解剖，生物钟如何在米色脂肪细胞中发挥作用仍然未知。我们最近发现，时钟电路，由必要的转录激活因子Bmal 1和阻遏物Rev-erbα组成，在棕色脂肪形成中发挥协调控制作用，从而影响产热能力。新的初步研究揭示了这些时钟调节器的细胞因子-心肌素相关转录因子（MRTF）/血清反应因子（SRF）信号级联，最近发现的米色脂肪细胞发育的关键抑制途径令人惊讶的规定。此外，米色脂肪选择性Bmal 1消融揭示了其对体内代谢稳态的显著影响。这些发现使我们假设Bmal 1和Rev-erbα对细胞因子-SRF调节级联发挥相反的转录控制，分别抑制和促进米色脂肪形成，并且这种机制是全局代谢调节所必需的。具体而言，我们将确定MRTF/SRF信号通路中Bmal 1和Rev-erbα的转录和功能靶点，这些靶点介导米色脂肪形成的各自的负性和正性调节。此外，这些机制的代谢影响将使用米色脂肪选择性遗传消融模型和药理学方法进行调查。重要的是，我们将解决这些发现的病理生理学相关性，以测试环境时钟中断是否会损害米色产热调节，从而导致全球代谢失调，并进一步确定时钟靶向干预措施，以改善不良后果。总的来说，我们的研究结果将定义米色脂肪细胞发育中一种新型时钟-SRF调控机制的转录和功能控制，剖析其代谢贡献，并揭示时钟靶向策略以增强米色产热能力。目前的项目代表了我们的长期目标，解剖组织内在的生物钟病因代谢疾病的关键一步。

Beige adipocyte, a type of brown adipocyte in subcutaneous fat depots, possesses high metabolic activities beneficial for energy balance and metabolic homeostasis. The abundance and inducible properties of beige adipocytes render them attractive therapeutic targets for obesity and associated metabolic disorders. Better understanding of molecular pathways governing beige functional capacity may lead to novel therapies for obesity. The circadian clock drives metabolic rhythms to maintain homeostasis. Despite the current recognition that clock disruption leads to obesity and insulin resistance and adipose tissue contains functional clock, how distinct adipose tissue clocks contribute to metabolic homeostasis has not been dissected, and how circadian clock may function in beige adipocyte remains unknown. We recently uncovered that the clock circuit, composed of the essential transcription activator Bmal1 and the repressor Rev-erbα, exerts coordinated control in brown adipogenesis that consequently impact thermogenic capacity. New preliminary studies reveal surprising regulations of these clock regulators of the cytoskeleton-Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF) signaling cascade, a recently discovered key inhibitory pathway in beige adipocyte development. Furthermore, beige fat-selective Bmal1 ablation reveal its significant impact on metabolic homeostasis in vivo. These findings led us to hypothesize that Bmal1 and Rev-erbα exert opposing transcriptional control of the cytoskeleton-SRF regulatory cascade to suppress and promote, respectively, beige adipogenesis, and this mechanism is required for global metabolic regulation. Specifically, we will identify the transcriptional and functional targets of Bmal1 and Rev-erbα in the MRTF/SRF signaling pathway that mediate their respective negative and positive regulations of beige adipogenesis. Furthermore, the metabolic impact of these mechanisms will be interrogated using beige fat-selective genetic ablation models and pharmacological approach. Importantly, we will address the pathophysiological relevance of these findings to test whether environmental clock disruption impairs beige thermogenic regulations to contribute to global metabolic dysregulation, and further identify clock-targeting interventions to ameliorate the adverse consequence. Collectively, the outcomes of our research will define the transcriptional and functional control of a novel clock-SRF regulatory mechanism in beige adipocyte development, dissect its metabolic contributions, and uncover clock-targeting strategies to enhance beige thermogenic capacity. The current project represents a key step toward our long-term goal to dissect tissue-intrinsic circadian clock etiologies underlying metabolic diseases.