Irisin ameliorates obesity and insulin-resistance via adipose-tissue IL-33 and regulatory T cells

Irisin is an exercise-induced myokine that confers multiple physiological benefits, including browning of subcutaneous adipose tissue (SAT) in mice. However, the underlying cellular and molecular mechanisms of irisin’s effects on obesity are unclear. Here, we show that irisin modulates adipose-tissue inflammation by increasing IL-33 production and preserving ST2+ regulatory T cells in white adipose tissues. Administered chronically to high-fat-diet-fed male mice, irisin preserves in visceral adipose tissue (VAT) levels of ST2+ regulatory T cells, an important immunomodulatory population that usually contracts after long-term high-fat-diet feeding. This protection results from increases in IL-33-producing mesenchymal stromal cells (mSCs) and IL-33 levels in VAT. These effects are primary, as irisin directly induces IL-33 expression in cultured VAT mSCs. Irisin-mediated changes in VAT IL-33 dynamics are accompanied by IL-33-dependent upregulation of thermogenic gene expression in SAT. These irisin-driven cell-cell and inter-tissue interactions improve obesity and glucose intolerance, and increase energy expenditure, with no reduced food intake and muscle loss in obese mice