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

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 adipocyteselective 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-b pathway together with reciprocally altered BMP signaling; activation of TGF-b or blockade of BMP pathways suppresses enhanced differentiation in Bmal1-deficient brown adipocytes. Collectively, our study demonstrates a novel temporal regulatory mechanism in finetuning brown adipocyte lineage progression to affect brown fat formation and thermogenic regulation, which could be targeted therapeutically to combat obesity.

High-Energy Diet and Shorter Light Exposure Drives Markers of Adipocyte Dysfunction in Visceral and Subcutaneous Adipose Depots of Psammomys obesus

“…However, in this study, Tgf-β1 levels were lower in animals exposed to a short photoperiod, suggesting circadian rhythm disruptions may influence this regulation. In support of this, a recent study showed that BMAL1, an essential clock transcription activator, inhibits brown adipogenesis via direct transcriptional control of key components of the TGF-β pathway, including TGF-β1 [46].…”

Bone Morphogenetic Proteins

“…BMP-8b is also expressed in brown adipose tissue and increases thermogenesis not only locally but also systemically through central nerve systems (Whittle et al 2012). Furthermore, a balance between BMP and TGF-b signaling regulates brown adipogenesis through a regulation by Bmal1, a circadian clock transcription factor (Nam et al 2015). These finding indicate that multiple BMP ligands regulate both white and brown adipocyte differentiation in vivo.…”

Icariin promotes osteogenic differentiation of BMSCs by upregulating BMAL1 expression via BMP signaling

“…one study reported that regulation of clock genes controlled BMP2 expression in osteoblasts (26). Meanwhile, BMAL1 regulation of TGF-β and BMP signaling in the control of fat adipogenesis has also been reported (27). a recent study showed that BMal1 silencing-induced BMP2 was found in rat uterus endometrium stromal cells (28).…”