Fibronectin type III domain containing 5 (Fndc5) is a transmembrane protein highly expressed in the skeletal muscle. It was reported that exercise promotes the shedding of the extracellular domain of Fndc5, generating a circulating peptide (irisin) that cross‐talks to adipose tissues to convert lipid‐storing white adipocytes to energy‐catabolizing beige adipocytes. However, the requirement of Fndc5 in mediating the beneficial effect of exercise remains to be determined. Here, we created a mouse model of Fndc5 mutation through transcription activator–like effector nuclease–mediated DNA targeting. The Fndc5 mutant mice have normal skeletal muscle development, growth, regeneration, as well as glucose and lipid metabolism at resting state, even when fed a high‐fat diet. In response to running exercise, however, the Fndc5 mutant mice exhibit reduced glucose tolerance and insulin sensitivity and have lower maximal oxygen consumption compared with the exercised wild‐type mice. Mechanistically, Fndc5 mutation attenuates exercise‐induced browning of white adipose tissue that is crucial for the metabolic benefits of physical activities. These data provide genetic evidence that Fndc5 is dispensable for muscle development and basal metabolism but essential for exercise‐induced browning of white adipose tissues in mice.—Xiong, Y., Wu, Z., Zhang, B., Wang, C., Mao, F., Liu, X., Hu, K., Sun, X., Jin, W., Kuang, S. Fndc5 loss‐of‐function attenuates exercise‐induced browning of white adipose tissue in mice. FASEB J. 33, 5876–5886 (2019).http://www.fasebj.org
