The adipocyte clock controls brown adipogenesis through the TGF-b and BMP signaling pathways.

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 Bmall in mice increases brown fat mass and cold tolerance, and adipocyte-selective inactivation of Bmall 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 Bmall inhibits brown adipocyte lineage commitment and terminal differentiation. Mechanistically, Bmall inhibits brown adipogenesis through direct transcriptional control of key components of the TGF-b pathway together with reciprocally altered BMP signaling; activation of TGF-b or blockade of BMP pathways suppresses enhanced differentiation in Bmall-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. [ABSTRACT FROM AUTHOR]