The adipocyte clock controls brown adipogenesis via TGF-β/BMP signaling pathway

Mar 10, 2015Journal of cell science

The fat cell’s internal clock may control brown fat formation through TGF-β and BMP signals

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Abstract

Global ablation of Bmal1 in mice increases brown fat mass and cold tolerance.

Bmal1 inhibits the formation of brown fat and thermogenic capacity.
Loss of Bmal1 leads to increased brown adipocyte development and differentiation.
Bmal1's role in brown adipocyte development is cell-autonomous.
Bmal1 affects brown adipocyte lineage commitment and terminal differentiation.
Bmal1 regulates brown adipogenesis through transcriptional control of the TGF-β pathway and BMP signaling.

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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-β pathway together with reciprocally altered BMP signaling; activation of TGF-β 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.

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The adipocyte clock controls brown adipogenesis via TGF-β/BMP signaling pathway

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