Development: Brown fat: muscle undercover?

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The transcriptional regulator PRDM16 mediates the bidirectional cell fate switch between muscle and brown fat.

If a friend told me that fat is 'muscle undercover', I would take it as an excuse not to join me in the gym. However, two new studies in Nature now reveal that brown fat and muscle have much more in common than was previously thought.

In mammals, white adipose tissue stores energy in the form of fat and is associated with obesity, whereas the brown variant burns fat to generate heat, thereby counteracting obesity. Stimulating an increase in brown fat in humans might therefore be a potential treatment for obesity, but this first requires a full understanding of the developmental origin of the two fat tissues.

Seale et al. used short hairpin RNA in precursor cells to knock down PRDM16, a transcriptional regulator of brown fat cells, and observed that brown-fat-cell markers were repressed, whereas myogenic genes were activated. Furthermore, the cells turned into bona fide muscle cells with fused myotube morphology. Intrigued by these findings, they performed lineage-tracing experiments in mice that were genetically modified to mark the expression of myogenic factor-5 (Myf5), a skeletal muscle-specific gene. Myf5-expressing cells formed skeletal muscle and brown, but not white, fat cells. This suggests that brown fat cells arise from skeletal muscle precursors.

Forced expression of PRDM16 in a muscle progenitor cell line blocked myogenesis and induced brown adipogenesis. To investigate the mechanism of action of PRDM16, Seale et al. purified a PRDM16 protein complex from fat cells and analysed it by mass spectrometry. They identified peroxisome proliferator-activated receptor- gamma (PPAR gamma ), an essential regulator of adipogenic differentiation, as a binding partner of PRDM16. PRDM16 enhanced the expression of a PPAR gamma reporter gene and was unable to promote adipogenesis in PPAR gamma -deficient fibroblasts. So, PRDM16 stimulates brown adipogenesis by inducing PPAR gamma .

In an independent study, Tseng et al. treated fat-cell precursors with bone morphogenetic proteins (BMPs), which are important for numerous processes during embryonic development. They found that BMP7 alone could instruct brown-fat-cell precursors to become mature cells that express brown-fat-cell markers and genes that are involved in the biogenesis and function of mitochondria. Interestingly, Prdm16 was among the BMP7-activated genes.

BMP7 activates the p38 mitogen-activated protein kinase (MAPK) signalling pathway in brown precursor cells, and specific inhibitors of this pathway blocked the BMP7-induced expression of brown-fat-cell markers. Furthermore, BMP7-deficient embryos and newborn mice had reduced brown fat tissue, although other organs were normal. Similarly, Seale et al. observed abnormal morphology of brown fat cells and activation of muscle-specific genes in embryos that lacked PRDM16. By virally delivering BMP7 into wild-type mice, Tseng et al. induced an increase in brown fat mass, which led to higher energy expenditure and a reduction in weight gain compared to control animals.

These studies suggest that treating humans with BMP7 or increasing the levels of PRDM16, which activate brown fat differentiation and increase energy expenditure, might be a new way to combat obesity.

Francesca Cesari

References

Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008) | Article | PubMed |
Tseng, Y.-H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008) | Article | PubMed |