Bmp4 Promotes a Brown to White-like Adipocyte Shift

Abstract

While Bmp4 has a well-established role in the commitment of mesenchymal stem cells into the adipogenic lineage, its role in brown adipocyte formation and activity is not well defined. Here, we show that Bmp4 has a dual function in adipogenesis by inducing adipocyte commitment while inhibiting the acquisition of a brown phenotype during terminal differentiation. Selective brown adipose tissue overexpression of Bmp4 in mice induces a shift from a brown to a white-like adipocyte phenotype. This effect is mediated by Smad signaling and might be in part due to suppression of lipolysis, via regulation of hormone sensitive lipase expression linked to reduced Ppar activity. Given that we observed a strong correlation between BMP4 levels and adipocyte size, as well as insulin sensitivity in humans, we propose that Bmp4 is an important factor in the context of obesity and type 2 diabetes.

The dual role of BMP4 in adipogenesis and metabolism

“…There are several possibilities which could explain the different findings of our work, 27 or the one from Kahn's group, 22 compared with the other studies mentioned above. [23][24][25] One possibility is the use of immortalized pre-adipocytes and MSCs versus the use of a whole SVF from WAT.…”

“…27 We could demonstrate that besides its well-established function in triggering MSCs into the adipogenic lineage, Bmp4 has a secondary function during terminal differentiation. Thus, while Bmp4 can induce commitment of MSCs to pre-adipocytes of both white and brown lineage, Bmp4 signaling during the terminal differentiation phase impairs the acquisition of a mature brown adipocyte phenotype in favor of a more white-like phenotype.…”

“…Interestingly, selectively overexpression of Bmp4 in the liver leads to the same metabolic phenotype as reported by Qian et al, which furthermore underscores the importance of defining the roles of Bmp4 in an organ context specific manner. 23,27 That BMP4 might have also an endocrine effect is suggested by the fact that obese human subjects show increased circulating levels of BMP4.…”

“…Secondly, differences in the differentiation media could account for the divergent results. We 27 and others, 31,32 could show that the use of PPARg agonists such as the thiazolidindiones on WAT-derived SVF is sufficient to promote commitment and/or trans-differentiation to brown-like adipocytes. Thus, the association of these drugs to the mitogenic BMP4 in the differentiation media would definitively account for an increase in the number of brown-like fat cells with consequent detection of higher mitochondria number and expression of brown fat genes.…”

“…In fact, activation of the sympathetic system has been demonstrated to promote browning in WAT. 44 In our in vivo experiments reported recently, 27 we achieved a selective overexpression of Bmp4 in BAT by controlled administration of adenovirus into the tissue. Using such an approach, we were able to exclude exogenous Bmp4 expression from other tissues such as liver, in line with the observation that circulating levels of Bmp4 were unchanged.…”