In recent studies, we and others have defined a regulatory role for iNKT cells in managing inflammation in adipose tissue.  Insulin resistance, type 2 diabetes and obesity occur or are more severe in the absence of iNKT cells.  iNKT cells in adipose tissue display unique characteristics as they lack PLZF and upregulate E4BP4.  Upon activation they secrete IL-10 which drives M2 macrophage differentiation, and IL-2 that regulates the number and function adipose tissue Tregs.  In fact, Tregs cell numbers are markedly reduced in iNKT deficient mice. Together, these studies further define the mechanisms by which regulatory iNKT cells control adipose inflammation and metabolic syndrome.

Besides these roles in regulating inflammation, we now report that iNKT cells also play a key role in thermogenesis, adipocyte metabolism and control of weight unrelated to inflammation. Activation of iNKT cells with αGalCer induces potent weight loss and restores glycemic control in obesity. We show that activation of iNKT cells induced fibroblast-growth factor 21 (FGF21) production in adipose tissue, without affecting food intake. Furthermore, iNKT cell activation induced fatty acid oxidation, thermogenesis, and potent weight loss without illness. This iNKT-FGF21 pathway was also involved in the beneficial actions of the glucagon-like peptide-1 (GLP-1) analog therapy. Unexpectedly, Liraglutide activated iNKT cells in humans and mice in vivo. Liraglutide promoted satiety but failed to induce FGF21 in iNKT-deficient mice, resulting in less weight loss. These findings reveal a novel GLP-1-iNKT cell-FGF-21 axis illuminating a new pathway that could be targeted for weight regulation.  This appears to be the first non-immune function ascribed to iNKT cells.