A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise. In mice, expression of PGC1-α in muscles is shown to stimulate expression of FNDC5, which is cleaved and secreted in the circulation as the newly identified hormone irisin; on exercise, this hormone stimulates browning of subcutaneous adipose tissue. Exercise is an effective therapy for obesity and type II diabetes. The transcriptional coactivator PGC1-α has been shown to mediate many of the effects of exercise in skeletal muscle, and here it is shown that PGC1-α expression in muscle stimulates the expression of the membrane protein FNDC5 in mice. FNDC5 is cleaved and secreted in the circulation as a previously unrecognized hormone, dubbed irisin, after Iris, the Greek messenger goddess. Irisin is elevated in the blood of humans and mice on exercising. It is a very powerful activator of a thermogenic program in primary white fat cells and causes a 'browning' of this cell type, including increased expression of UCP1 and enhanced respiration. These data identify irisin as a possible novel therapeutic for metabolic disorders.