Irisin improves obesity and glucose intolerance through an IL-33-ST2 pathway

Irisin is secreted by muscle, increased with exercise, and conveys certain physiological benefits. Earlier studies showed that short-term irisin treatment caused browning of subcutaneous adipose tissue (SAT) in mice, with improved glucose tolerance; the effects of more chronic irisin treatment and mechanisms at play have not been explored. We demonstrate here that chronic irisin application improves obesity and dramatically reduces glucose intolerance. This treatment increases an IL-33+ mesenchymal stromal cell (mSC) population in visceral fat tissue while genetic ablation of irisin reduces plasma IL-33 levels and decreases thermogenic gene expression in SAT. Importantly, irisin directly induces IL-33 expression in mSCs and preserves ST2+ regulatory T (Treg) cells. Inhibition of IL-33 blunts these irisin-mediated effects on energy expenditure and glucose homeostasis, largely through IL33-mediated regulation of ST2+ Treg cells. These data indicate that irisin improves obesity and glucose intolerance, with no muscle loss, through a key immunomodulatory pathway in obese mice. Overall design: RNAseq profiling of iWAT and eWAT tissues from C57BL6 mice administered AAV-irisin or control AAV (AAV-GFP) and fed a high-fat diet or normal chow for 18 weeks.