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 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 interleukin (IL)-33 production and preserving ST2+ regulatory T cells in white adipose tissues. Administered chronically to high-fat-diet-fed male mice, irisin preserves 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 and IL-33 levels in VAT. These effects are primary, as irisin directly induces IL-33 expression in cultured VAT mesenchymal stromal cells. Irisin-mediated changes in VAT IL-33 dynamics are accompanied by IL-33-dependent upregulation of thermogenic gene expression in subcutaneous adipose tissue. 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. This study demonstrates that overexpression of irisin, an exercise-induced myokine, ameliorates obesity and insulin resistance in high-fat-diet-fed mice by increasing local IL-33 production and preserving ST2+ regulatory T cells in white adipose tissues.