Becoming Brown Fat

Abstract

Humans, like other mammals, contain two functionally distinct types of fat cells: white fat cells, which store chemical energy and are associated with obesity, and brown fat cells, which are specialized to produce heat and can help combat obesity (see Cannon and Nedergaard). Noting that some bone morphogenetic proteins (BMPs) promote white adipogenesis, Tseng et al . investigated the effects of various BMPs on the differentiation of brown adipocytes. Although several BMPs stimulated lipid accumulation in brown preadipocytes, BMP7 alone stimulated expression of uncoupling protein 1 (UCP1, a marker for brown fat that is crucial to its thermogenic role). BMP7 stimulated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and that of the downstream transcription factor ATF-2 in brown preadipocytes, and pharmacologic inhibition of p38 MAPK blocked BMP7-dependent expression of UCP1. BMP7 suppressed expression of the mRNA that encodes early inhibitors of adipogenesis, enabling the expression of the early regulator of brown cell fate PRDM16 (PR-domain-containing 16), adipogenic transcription factors, and genes crucial to mitochondrial function and biogenesis. Further, BMP7 stimulated a substantial increase in mitochondrial density. Pretreatment of C3H10T1/2 cells (multipotent mesenchymal progenitor cells) with BMP7 before exposure to an adipogenic cocktail led to their differentiation into brown adipocytes; indeed, subcutaneous implantation of BMP7-treated C3H10T1/2 cells into nude mice led to development of a fat pad largely consisting of brown adipocytes. Embryonic Bmp7 knockout mice showed a substantial decrease in brown fat mass and brown adipocytes and little or no UCP1. Injection of adenovirus encoding BMP7 into 4-week-old mice led to an increase in brown fat mass and basal body temperature and a decrease in weight gain (compared with mice receiving adenovirus encoding LacZ). The authors conclude that BMP7 plays a critical role in brown adipogenesis and may provide a previously unexplored approach to treating obesity. In a second article, Seale et al . provided further insight into the origins and development of brown fat by showing that brown adipocytes, but not white adipocytes, arise from precursor cells expressing the myogenic regulatory factor gene Myf5 and that development into brown adipocytes or muscle cells depends on PRDM16. Thus, PRDM16 knockdown in cultured brown preadipocytes led to the development of myocytes, whereas its transduction into myoblasts elicited the production of brown adipocytes. Y.-H. Tseng, E. Kokkotou, T. J. Schulz, T. L. Huang, J. N. Winnay, C. M. Taniguchi, T. T. Tran, R. Suzuki, D. O. Espinoza, Y. Yamamoto, M. J. Ahrens, A. T. Dudley, A. W. Norris, R. N. Kulkarni, C. R. Kahn, New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454 , 1000-1004 (2008). [PubMed] P. Seale, B. Bjork, W. Yang, S. Kajimura, S. Chin, S. Kuang, A. Scimè, S. Devarakonda, H. M. Conroe, H. Erdjument-Bromage, P. Tempst, M. A. Rudnicki, D. R. Beier, B. M. Spiegelman, PRDM16 controls a brown fat/skeletal muscle switch. Nature 454 , 961-967 (2008). [PubMed] B. Cannon, J. Nedergaard, Neither fat nor flesh. Nature 454 , 947-948 (2008). [PubMed]