Transcriptional control of brown adipocyte development and physiological function--of mice and men

Abstract

The last several years have seen an explosion of information relating to the transcriptional control of brown fat cell development. At the same time, new data have emerged that clearly demonstrate that adult humans do indeed have substantial amounts of functioning brown adipose tissue (BAT). Together, these advances are stimulating a reassessment of the role of brown adipose tissue in human physiology and pathophysiology. These data have also opened up exciting new opportunities for the development of entirely novel classes of therapeutics for metabolic diseases like obesity and type 2 diabetes.

Figure 1.

Transcriptional cascades in brown fat development through PRDM16. PRDM16 expression in myoblasts or preadipocytes induces PGC-1α gene expression. PRDM16 coactivates the transcriptional activity of PGC-1α and PGC-1β as well as PPARα and PPARγ through direct interaction. The cAMP-dependent thermogenic program is potentiated by FoxC2 and PRDM16. RIP140, Rb, and p107 antagonize the expression or function of PGC-1α. On the other hand, PRDM16 represses the expression of white fat cell or skeletal muscle-specific genes, mediated through its regulated association with the corepressors CtBP1 and CtBP2.

Figure 2.

Model for PRDM16 function in specifying brown fat versus skeletal muscle cell fate. Lineage tracing experiments suggest a model in which tripotent, Engrailed-1-expressing cells in the central dermomyotome give rise to dermis, epaxial muscle, and brown fat. Wnt signals appear to direct these precursor cells to the dermal fate (Atit et al. 2006). Brown fat and skeletal muscle arise from precursor cells that have expressed Myf5, a gene that has been assumed to selectively mark skeletal myogenic progenitors. Gain-of-function and loss-of-function experiments suggest that PRDM16 specifies brown fat cell identity from “myoblast-like” precursors by activating brown adipogenesis and suppressing skeletal myogenesis. The cues that control PRDM16 expression in the presumptive brown fat/skeletal muscle precursors are unknown. By contrast, white fat cells belong to a completely independent cell lineage. A recent report suggests that at least some precursors for white fat cells are derived from mural cells associated with blood vessels (Tang et al. 2008).