Progress and challenges in the biology of FNDC5 and irisin.

In 2002, a transmembrane protein now known as FNDC5 was discovered and shown to be expressed in skeletal muscle, heart and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved,traveled to white adipose tissue and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1,000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions are questioned for use of flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin to bone remodeling and to brain, with effects potentially related to Alzheimer's disease. We also discuss some discrepancies between research groups and mechanisms that need to be determined. Some important questions raised in the initial discovery of irisin like the role of the mutant start codon of human FNDC5, the mechanism of ectodomain cleavage remain to be answered. Apart from these specific questions, a promising new tool has been developed - mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.