The clock gene, brain and muscle Arnt‐like 1, regulates adipogenesis via Wnt signaling pathway

Abstract

Circadian clocks in adipose tissue are known to regulate adipocyte biology. Although circadian dysregulation is associated with development of obesity, the underlying mechanism has not been established. Here we report that disruption of the clock gene, brain and muscle Arnt-like 1 (Bmal1), in mice led to increased adipogenesis, adipocyte hypertrophy, and obesity, compared to wild-type (WT) mice. This is due to its cell-autonomous effect, as Bmal1 deficiency in embryonic fibroblasts, as well as stable shRNA knockdown (KD) in 3T3-L1 preadipocyte and C3H10T1/2 mesenchymal stem cells, promoted adipogenic differentiation. We demonstrate that attenuation of Bmal1 function resulted in down-regulation of genes in the canonical Wnt pathway, known to suppress adipogenesis. Promoters of these genes (Wnt10a, β-catenin, Dishevelled2, TCF3) displayed Bmal1 occupancy, indicating direct circadian regulation by Bmal1. As a result, Wnt signaling activity was attenuated by Bmal1 KD and augmented by its overexpression. Furthermore, stabilizing β-catenin through Wnt ligand or GSK-3β inhibition achieved partial restoration of blunted Wnt activity and suppression of increased adipogenesis induced by Bmal1 KD. Taken together, our study demonstrates that Bmal1 is a critical negative regulator of adipocyte development through transcriptional control of components of the canonical Wnt signaling cascade, and provides a mechanistic link between circadian disruption and obesity.

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

“…These factors in turn inhibit the transcriptional activity of Bmal1-CLOCK, which, coupled with temporally controlled proteasome-mediated degradation mechanisms, leads to rhythmic oscillation of the molecular clock and thus generates the daily rhythm. Interestingly, despite studies demonstrating that Bmal1 plays key roles in metabolic regulation (Cho et al, 2012;Rudic et al, 2004;Solt et al, 2012) and adipogenesis (Fontaine et al, 2003;Guo et al, 2012;Wang and Lazar, 2008), its function in brown adipocytes has not been studied.…”

Circadian rhythms and clocks in adipose tissues: current insights

“…Whereas its knockdown leads to an upregulation of adipogenic genes during early differentiation (by suppression of the canonical Wnt pathway), fewer mature adipocytes survive at later stages. 27,35 Interestingly, adipose PPARγ (and clock gene) expression rhythms are dampened under high-fat diet (HFD) conditions in male mice. 36 This effect was not observed in female animals, 37 in line with a persistent normal diurnal food intake …”

“…48,61 Mice with mutations in the gene encoding the CLOCK partner protein BMAL1 show less ambiguous phenotypes with elevated adiposity, despite unaffected food intake. 7,35,[62][63][64][65][66][67] This could be explained by the WNT-mediated suppressive effect of Bmal1 on adipogenesis. 35 However, since Bmal1 knockout (KO) mice show an early aging phenotype, the adipose phenotype can only be observed in young animals.…”

“…7,35,[62][63][64][65][66][67] This could be explained by the WNT-mediated suppressive effect of Bmal1 on adipogenesis. 35 However, since Bmal1 knockout (KO) mice show an early aging phenotype, the adipose phenotype can only be observed in young animals. 66 Genetic deletions in the negative limb of the circadian feedback loop provide varying results with regard to appetite and body weight control.…”

Circadian Rhythms in Stem Cell Biology and Function

“…Mice with altered circadian rhythms display bone remodeling and more than 26 % of the bone transcriptome exhibits circadian rhythmicity (Fu et al 2005 ;Zvonic et al 2007 ). Other functions of MSCs, such as adipose tissue homeostasis , also showed to be under circadian control (Guo et al 2012 ).…”