This study identifies a novel myokine, irisin, which is induced by exercise and secreted from skeletal muscle. Irisin acts on white adipose cells to stimulate the expression of UCP1 and promote browning, leading to increased energy expenditure. Irisin is a cleaved and secreted fragment of Fndc5, a membrane protein that is upregulated by PGC1α, a transcriptional coactivator. Transgenic mice with increased PGC1α in muscle show resistance to age-related obesity and diabetes, and exhibit increased UCP1 expression in subcutaneous fat. Irisin is present in mouse and human plasma and is increased with exercise. In vivo studies show that moderate increases in circulating irisin levels can induce browning of white adipose tissues and improve glucose tolerance in obese mice. Irisin also reduces diet-induced obesity and insulin resistance in mice, suggesting its therapeutic potential for metabolic disorders.This study identifies a novel myokine, irisin, which is induced by exercise and secreted from skeletal muscle. Irisin acts on white adipose cells to stimulate the expression of UCP1 and promote browning, leading to increased energy expenditure. Irisin is a cleaved and secreted fragment of Fndc5, a membrane protein that is upregulated by PGC1α, a transcriptional coactivator. Transgenic mice with increased PGC1α in muscle show resistance to age-related obesity and diabetes, and exhibit increased UCP1 expression in subcutaneous fat. Irisin is present in mouse and human plasma and is increased with exercise. In vivo studies show that moderate increases in circulating irisin levels can induce browning of white adipose tissues and improve glucose tolerance in obese mice. Irisin also reduces diet-induced obesity and insulin resistance in mice, suggesting its therapeutic potential for metabolic disorders.