Author
NAM, DEOKHWA - Methodist Hospital | |
GUO, BINGYAN - Hebei University | |
CHATTERJEE, SOMIK - Methodist Hospital | |
CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC) | |
NELSON, DAVID - Baylor College Of Medicine | |
YECHOOR, VIJAY - Baylor College Of Medicine | |
MA, KE - Methodist Hospital |
Submitted to: Journal of Cell Science
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 2/25/2015 Publication Date: 5/1/2015 Citation: Nam, D., Guo, B., Chatterjee, S., Chen, M., Nelson, D., Yechoor, V., Ma, K. 2015. The adipocyte clock controls brown adipogenesis through the TGF-Beta and BMP signaling pathways. Journal of Cell Science. 128(9):1835-1847. Interpretive Summary: Brown fat tissue, which uses fat as a fuel source to generate body heat, plays an important role in regulating body weight and insulin sensitivity. In this study, we showed that loss of Bmal1, a gene that regulates the body's internal biological clock (circadian rhythm), impaired the development of brown fat in mice. Because the internal biological clock regulates the timing of daily activity and many other important biological processes in humans, the knowledge obtained from this study will help us to understand the diseases; including obesity and diabetes, associated with abnormal biological clock function in humans. Technical Abstract: The molecular clock is intimately linked to metabolic regulation, and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic clock machinery participates in brown adipocyte development is unknown. Here, we show that Bmal1 (also known as ARNTL), the essential clock transcription activator, inhibits brown adipogenesis to adversely affect brown fat formation and thermogenic capacity. Global ablation of "Bmal1" in mice increases brown fat mass and cold tolerance, and adipocyte-selective inactivation of "Bmal1" recapitulates these effects and demonstrates its cell-autonomous role in brown adipocyte formation. Further loss- and gain-of-function studies in mesenchymal precursors and committed brown progenitors reveal that "Bmal1" inhibits brown adipocyte lineage commitment and terminal differentiation. Mechanistically, "Bmal1" inhibits brown adipogenesis through direct transcriptional control of key components of the TGF-Beta pathway together with reciprocally altered BMP signaling; activation of TGF-Beta or blockade of BMP pathways suppresses enhanced differentiation in "Bmal1"-deficient brown adipocytes. Collectively, our study demonstrates a novel temporal regulatory mechanism in fine-tuning brown adipocyte lineage progression to affect brown fat formation and thermogenic regulation, which could be targeted therapeutically to combat obesity. |