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

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 (Bmall), 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 Bmall 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 Bmall function resulted in down-regulation of genes in the canonical Wnt pathway, known to suppress adipogenesis. Promoters of these genes (Wnt10a, beta-catenin, Dishevelled2, TCF3) displayed Bmall occupancy, indicating direct circadian regulation by Bmall. As a result, Wnt signaling activity was attenuated by Bmall KD and augmented by its overexpression. Furthermore, stabilizing beta-catenin through Wnt ligand or GSK-3 beta inhibition achieved partial restoration of blunted Wnt activity and suppression of increased adipogenesis induced by Bmall KD. Taken together, our study demonstrates that Bmall 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.-Guo, B., Chatterjee, S., Li, L., Kim, J. M., Lee, J., Yechoor, V. K., Minze, L. J., Hsueh, W., Ma, K. The clock gene, brain and muscle Arnt-like 1, regulates adipogenesis via Wnt signaling pathway. FASEB J. 26, 3453-3463 (2012). www.fasebj.org