A PGC1α-dependent myokine that drives browning of white fat and thermogenesis Exercise improves various organ systems in mammals, with some effects mediated by the transcriptional coactivator PGC1α. This study shows that PGC1α expression in muscle increases Fndc5, a membrane protein that is cleaved and secreted as a new hormone, irisin. Irisin acts on white adipose cells to stimulate UCP1 expression and brown fat-like development. Irisin is induced by exercise in mice and humans, and increased levels in blood cause increased energy expenditure without changes in movement or food intake, leading to improvements in obesity and glucose homeostasis. PGC1α is a transcriptional coactivator that mediates energy metabolism-related biological programs. It is induced in muscle by exercise and stimulates many of the best-known beneficial effects of exercise in muscle, including mitochondrial biogenesis, angiogenesis, and fiber-type switching. It also provides resistance to muscular dystrophy and denervation-linked muscular atrophy. Transgenic mice with elevated muscle PGC1α are resistant to age-related obesity and diabetes and have a prolonged lifespan, suggesting that PGC1α may stimulate the secretion of factors from skeletal muscle that affect other tissues. This study shows that PGC1α stimulates the expression of several muscle gene-products that are potentially secreted, including Fndc5. The Fndc5 gene encodes a type I membrane protein that is processed proteolytically to form a new hormone secreted into blood, termed irisin. Irisin is induced in exercise and activates profound changes in subcutaneous adipose tissue, stimulating browning and UCP1 expression. This causes a significant increase in total body energy expenditure and resistance to obesity-linked insulin resistance. Transgenic PGC1α in skeletal muscle induces browning of subcutaneous adipose tissue. Mice with transgenically increased PGC1α in muscle are resistant to age-related obesity and diabetes, suggesting a fundamental alteration in systemic energy balance. Analysis of adipose tissue in PGC1α transgenic mice showed increased levels of UCP1 and Cidea mRNAs in subcutaneous fat. This suggests that PGC1α may stimulate the secretion of factors from skeletal muscle that affect the function of other tissues. Conditioned media from PGC1α-expressing myocytes induce browning of adipocytes in culture. The effect on browning of adipose tissues from PGC1α-expressing muscle could be due to direct muscle-fat signaling or an indirect mechanism. To investigate this, cultured primary subcutaneous adipocytes were treated with serum-free media conditioned by myocytes expressing PGC1α or cells expressing GFP. The media from cells expressing ectopic PGC1α increased the mRNA levels of several brown fat-specific genes, suggesting that PGC1α causes the muscle cells to secrete molecules that can induce a thermogenic gene program in theA PGC1α-dependent myokine that drives browning of white fat and thermogenesis Exercise improves various organ systems in mammals, with some effects mediated by the transcriptional coactivator PGC1α. This study shows that PGC1α expression in muscle increases Fndc5, a membrane protein that is cleaved and secreted as a new hormone, irisin. Irisin acts on white adipose cells to stimulate UCP1 expression and brown fat-like development. Irisin is induced by exercise in mice and humans, and increased levels in blood cause increased energy expenditure without changes in movement or food intake, leading to improvements in obesity and glucose homeostasis. PGC1α is a transcriptional coactivator that mediates energy metabolism-related biological programs. It is induced in muscle by exercise and stimulates many of the best-known beneficial effects of exercise in muscle, including mitochondrial biogenesis, angiogenesis, and fiber-type switching. It also provides resistance to muscular dystrophy and denervation-linked muscular atrophy. Transgenic mice with elevated muscle PGC1α are resistant to age-related obesity and diabetes and have a prolonged lifespan, suggesting that PGC1α may stimulate the secretion of factors from skeletal muscle that affect other tissues. This study shows that PGC1α stimulates the expression of several muscle gene-products that are potentially secreted, including Fndc5. The Fndc5 gene encodes a type I membrane protein that is processed proteolytically to form a new hormone secreted into blood, termed irisin. Irisin is induced in exercise and activates profound changes in subcutaneous adipose tissue, stimulating browning and UCP1 expression. This causes a significant increase in total body energy expenditure and resistance to obesity-linked insulin resistance. Transgenic PGC1α in skeletal muscle induces browning of subcutaneous adipose tissue. Mice with transgenically increased PGC1α in muscle are resistant to age-related obesity and diabetes, suggesting a fundamental alteration in systemic energy balance. Analysis of adipose tissue in PGC1α transgenic mice showed increased levels of UCP1 and Cidea mRNAs in subcutaneous fat. This suggests that PGC1α may stimulate the secretion of factors from skeletal muscle that affect the function of other tissues. Conditioned media from PGC1α-expressing myocytes induce browning of adipocytes in culture. The effect on browning of adipose tissues from PGC1α-expressing muscle could be due to direct muscle-fat signaling or an indirect mechanism. To investigate this, cultured primary subcutaneous adipocytes were treated with serum-free media conditioned by myocytes expressing PGC1α or cells expressing GFP. The media from cells expressing ectopic PGC1α increased the mRNA levels of several brown fat-specific genes, suggesting that PGC1α causes the muscle cells to secrete molecules that can induce a thermogenic gene program in the