Regulation of brown adipogenesis by the Tgf-β family: Involvement of Srebp1c in Tgf-β- and Activin-induced inhibition of adipogenesis

Background: Brown adipocytes generate heat through the expression of mitochondrial Ucp1. Compared with the information on the regulatory differentiation of white preadipocytes, the factors affecting brown adipogenesis are not as well understood. The present study examined the roles of the Tgf-beta family members Bmp, Tgf-beta and Activin during differentiation of HB2 brown preadipocytes. Methods: Endogenous Bmp activity and effects of exogenous Tgf-beta family members were examined. Role of Srebp1c in brown adipogenesis was further explored. Results: Although Bmp7 has been suggested to be a potent stimulator of brown adipogenesis, it affected neither the expression of brown adipocyte-selective genes nor Ucp1 induction in response to a p adrenergic receptor agonist. Unlike Unlike in 3T3-L1 white preadipocytes, endogenous Bmp activity was not required for brown adipogenesis; treatment with inhibitors of the Bmp pathway did not affect differentiation of preadipocytes. Administration of Tgf-beta 1 or Activin A efficiently decreased the insulin-induced expression of brown adipocyte-selective genes. Tgf-beta 1 and Activin A decreased the expression of Ppary2 and C/ebp alpha, suggesting the inhibition of adipogenesis. The Tgf-beta- and Activin-induced inhibition of brown adipogenesis was mediated by the repression of Srebp1c expression; Tgf-beta 1 and Activin A blocked Srebp1c gene induction in response to the differentiation induction, and knock-down of Srebpl expression inhibited brown adipogenesis. Conclusion: Endogenous Bmp is dispensable for brown adipogenesis, and Srebp1c is indispensable, which is negatively regulated by Tgf-beta and Activin. General significance: Control of activity of the Tgf-beta family is potentially useful for maintenance of energy homeostasis through manipulation of brown adipogenesis. (C) 2013 Elsevier B.V. All rights reserved.