(A) Structure of PRDM16 and key domains of its function. PRDM16 directly interacts with canonical transcription factors such as PPARα, PPARγ and C/EBP family members and transcriptional co-activators PGC-1α and PGC-1β through the two sets of zinc finger domains (ZF1 and ZF2). PRDM16 is also associated with the co-repressors CtBP1 and 2 through its PLDLS motif. This interaction mediates the repressive action of PRDM16 on the expression of white fat cell-specific genes. (B) PRDM16-C/EBP-β transcriptional complex acts in myf5-positive myoblastic precursors or pre-adipocytes to induce the expression of PPARγ and PGC-1α. PRDM16 co-activates PPARγ and PGC-1α, which then drives a brown fat differentiation program. The cAMP-dependent thermogenic gene program is potentiated by FoxC2 and PRDM16. RIP140, Rb/p107, and Twist-1 antagonize the expression or transcriptional activity of PGC-1α and repress brown fat genetic program.

BAT (A) and WAT (B) have separate developmental origins in the embryo. (A) BAT and skeletal muscle originate from precursors in the dermomyotome that express Engrailed-1 (En1) and Myf5. Brown adipose fate in the somite may be controlled by members of the transforming growth factor (TGF)-β superfamily of secreted factors such as BMP-7. Canonical Wnt signaling represses the differentiation of brown preadipocytes into mature brown adipose cells. PRDM16, PPARγ, PGC-1α and UCP1 are functional markers of brown adipose cells in the developmental, homogenous deposits of BAT. MyoD expression and skeletal muscle commitment is positively regulated by Wnts, Sonic Hedgehog (Shh) and Noggin. BMPs suppress myogenic commitment. (B) The embryonic stem cells of the white adipose lineage remain to be well defined. White preadipocytes that express PPARγ differentiate into mature white adipose cells in a process that also appears to be stimulated by certain BMPs. The adaptive UCP1-expressing brown-like adipose cells that develop in WAT in response to cold or β-adrenergic stimulation are not descendent from Myf5-expressing cells. These cells may be derived from (1) a specialized compartment of Myf5-negative but committed brown precursors; (2) directed differentiation from white preadipocytes and/or (3) transdifferentiation from mature white adipocytes (as indicated). The broken purple arrows depict hypothetical precursor-product relationships.