Interleukin-10 and IL-4 are known to play potent and direct roles in promoting alternatively activated macrophages and suppressing inflammation in macrophages and other cells,[73, 74] which indirectly influence adipocyte function. However, in obese humans and mice, adipose iNKT cells are greatly reduced, and therefore their protective effects may be blunted.[2, 3] One potent way to activate iNKT cells in vivo is through αGalCer treatment, which selleck kinase inhibitor increases iNKT cell levels 10-fold even in obesity.[3] We, and others, have shown that adipose iNKT cell activation

promotes M2 macrophage polarization as well as inducing weight loss and improved fatty liver and insulin resistance.[3, 39] Importantly, we did not observe any negative side effects of activating iNKT cells with αGalCer such as hypoglycaemia or cachexia, nor did αGalCer have any effects in mice lacking iNKT cells. While obvious caution needs to be considered given the potential of a cytokine storm, the effects of αGalCer treatment to loss of fat mass but not

lean mass in obesity is striking and warrants further study to elucidate the pathway from activation of iNKT cells to weight loss. Also, in obese humans, iNKT cells are found at a much lower frequency in liver and spleen, so administration of αGalCer may not have the potential side effects seen in older Bafilomycin A1 supplier mice after repeated injections. Administration tetracosactide of αGalCer to humans has been performed in many different clinical trials for cancer and has proven safe, capable of activating human iNKT cells in vivo, with minimal side effects. However, the effects of chronic iNKT

cell activation in humans has not yet been fully studied. In the case of type 2 diabetes and obesity, an ideal scenario might be to specifically activate anti-inflammatory adipose iNKT cells rather than whole body iNKT cells, which predominantly produce IFN-γ when activated (in mice at least). There is currently no method to specifically target particular populations of iNKT cells, but one may speculate that certain lipids may more potently activate different iNKT cell populations based on TCR affinity and co-stimulatory signals present or enriched in a particular environment. Indeed, indirect but strong evidence suggests that adipose tissue itself may contain an endogenous lipid that activates iNKT cells. First, CD1d is highly expressed in human[2] and murine adipose tissue.[7, 8] Moreover, not only is CD1d expressed on immune cells in the stromovascular fraction of adipose tissue, but CD1d is also expressed by adipocytes themselves.[7, 8] Furthermore, adipose iNKT cells appear to be constitutively activated in adipose tissue even in lean steady state, as measured by high CD69 expression. Therefore it makes sense that endogenous lipid antigens may be present in the lipid-rich environment of adipose tissue where CD1d is highly expressed.