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Transcriptional Control of Brown Adipogenesis and Energy Homeostasis

Obesity is a disorder of energy balance, and can occur when food intake exceeds energy expenditure. We have been particularly interested in the transcriptional pathways controlling energy expenditure through regulation of mitochondrial function, using brown adipose cells as a rich source from which to “mine” molecules with broad roles in these processes. Most recently, we have found that the large, nuclear zinc‐finger protein PRDM16 is a “master” regulator of the determination of brown fat cell fate. This molecule can alter the differentiation pathway of fat cell precursors and hence, might represent a new pathway for the treatment of obesity. PRDM16 can alter the gene expression pattern of white fat precursor cells, so that they differentiate into brown fat cells. Expression of sh‐RNA against PRDM16 in immortalized brown fat cells shows that PRDM16 is required for essentially the entire brown fat program. Interestingly, when the same sh‐RNA against PRDM16 is expressed in primary brown preadipose cells, these cells differentiate into muscle cells, strongly suggesting a relationship between brown fat and skeletal muscle. Conversely, expression of PRDM16 alone is sufficient to convert primary brown fat precursor cells into skeletal muscle cells, replete with expression of myofibrillar proteins. Fate mapping experiments indicate that skeletal muscle and brown adipose arise from myf‐5‐expressing cells, while white fat does not come from this lineage. Finally, purification of the PRDM16 complex in brown fat cells indicates that PRDM16 binds to PPAR‐γ and C/EBPβ. The coactivation of these proteins indicates how this protein can be adipogenic in a muscle cell. These data, taken together, show that PRDM16 is a “master” regulator of the brown fat lineage and shows that brown fat and skeletal muscle arise from a similar or identical cell lineage. Thus brown and white fat represent a cellular and biochemical convergence through expression and function of PPAR‐γ but they arise from very different developmental pathways. The potential uses of the PRDM16 pathway in novel approaches to the therapy of human obesity will be discussed.