The transcriptional coactivator PGC-1α [peroxisome proliferator–activated receptor γ (PPARγ) coactivator 1α] stimulates the expression of genes involved in energy metabolism and mitochondrial biogenesis. In addition, PGC-1α participates in the differentiation of brown adipose tissue, which dissipates energy as heat in a process called thermogenesis. Of the major white adipose depots, the subcutaneous layer can be most easily induced to acquire characteristics of brown fat (“browning”), such as increased numbers of mitochondria and the expression of brown fat–specific and thermogenic genes. Mice that overexpress PGC-1α in muscle show systemic physiological changes, such as resistance to diabetes, leading Boström et al. to investigate how PGC-1α in muscle regulates white and brown adipose tissue. In mice overexpressing PGC-1α in muscle, subcutaneous white adipose tissue (but not brown adipose tissue or visceral white adipose tissue) showed increased mRNA and protein abundance of uncoupling protein 1 (UCP1), which is involved in thermogenesis. Primary subcutaneous adipocytes that were exposed to medium conditioned by myocytes overexpressing PGC-1α showed increased abundance of brown fat–specific genes. Five PGC-1α target genes in muscle encoded proteins likely to be secreted, including FNDC5 (fibronectin type III domain containing 5). Exercise increases the expression of the gene encoding PGC-1α in muscle, and the PGC-1α target genes showed increased mRNA abundance in exercised mice and in muscle biopsies taken from human subjects after endurance exercise. Primary subcutaneous white adipocytes treated with FNDC5 showed increased expression of Ucp1, higher mitochondrial density, and increased oxygen consumption. FNDC5 was glycosylated and cleaved at the C terminus to generate a 32-kD secreted fragment that the authors named irisin. The plasma concentration of irisin was decreased in mice with a muscle-specific ablation of PGC-1α and increased by exercise in mice and humans. Adenoviral overexpression of Fndc5 increased Ucp1 mRNA expression in subcutaneous fat in mice on a standard or high-fat diet; in mice on a high-fat diet, it also increased oxygen consumption, improved glucose tolerance and fasting insulin, and slightly reduced body weight. Thus, exercise triggers muscle to release irisin, which induces subcutaneous white adipose tissue to acquire characteristics typical of brown adipose tissue, and could potentially be developed as a treatment to counteract the effects of diet-induced obesity.
P. Boström, J. Wu, M. P. Jedrychowski, A. Korde, L. Ye, J. C. Lo, K. A. Rasbach, E. A. Boström, J. H. Choi, J. Z. Long, S. Kajimura, M. C. Zingaretti, B. F. Vind, H. Tu, S. Cinti, K. Højlund, S. P. Gygi, B. M. Spiegelman, A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012). [PubMed]