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

Authors :
Somik Chatterjee
Bingyan Guo
Miao Hsueh Chen
David L. Nelson
Ke Ma
Deok Hwa Nam
Vijay Yechoor
Source :
Journal of Cell Science.
Publication Year :
2015
Publisher :
The Company of Biologists, 2015.

Abstract

The molecular clock is intimately linked with 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, the essential clock transcription activator, inhibits brown adipogenesis to adversely impact brown fat formation and thermogenic capacity. Global ablation of Bmal1 in mice increases brown fat mass and cold tolerance, while 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, and 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 impact brown fat formation and thermogenic regulation, which may be targeted therapeutically to combat obesity.

Details

ISSN :
14779137 and 00219533
Database :
OpenAIRE
Journal :
Journal of Cell Science
Accession number :
edsair.doi...........73c4d428b37d1838fbd190ad412d5384
Full Text :
https://doi.org/10.1242/jcs.167643