The adipocyte clock controls brown adipogenesis through the TGF-β 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 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.
Center for Diabetes Research, Department of Medicine, The Methodist Hospital Research Institute, Houston, TX, 77030, USA.
Deokhwa
D
Nam
Department of Cardiovascular Medicine, Second Affiliated Hospital, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
Bingyan
B
Guo
Center for Diabetes Research, Department of Medicine, The Methodist Hospital Research Institute, Houston, TX, 77030, USA.
Somik
S
Chatterjee
Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Miao-Hsueh
MH
Chen
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
David
D
Nelson
Diabetes and Endocrinology Research Center, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Vijay K
VK
Yechoor
Center for Diabetes Research, Department of Medicine, The Methodist Hospital Research Institute, Houston, TX, 77030, USA kma@tmhs.org.
Ke
K
Ma
D056930:ARNTL Transcription Factors / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis; D002001:Adipose Tissue, Brown; D000818:Animals; D001683:Biological Clocks / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D019070:Cell Lineage; D002940:Circadian Rhythm / Q000235:genetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051379:Mice; D015398:Signal Transduction; D022722:Thermogenesis; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta
Adipogenesis; Brown adipocyte differentiation; Circadian rhythm; Obesity; TGF‐β signaling pathway