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-erb?, 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-erb? 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-erb? 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.

Public Health Relevance

Our proposed project seeks to delineate a novel clock-SRF regulatory mechanism in beige adipocyte development and its impact on metabolic homeostasis. Outcomes of our study will uncover circadian etiologies underlying metabolic diseases and lead to discovery of clock-targeting interventions to enhance thermogenic capacity for the treatment of obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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Beckman Research Institute/City of Hope
United States
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Lee, J; Ma, K; Moulik, M et al. (2018) Untimely oxidative stress in ?-cells leads to diabetes - Role of circadian clock in ?-cell function. Free Radic Biol Med 119:69-74