Summary Invariant Natural Killer T (iNKT) cells are evolutionarily conserved innate T cells that influence inflammatory responses. We have shown that iNKT cells, previously thought to be rare in huamns, were highly enriched in human and murine adipose tissue, and that as adipose tissue expands in obesity, iNKT cells were depleted, correlating with proinflammatory macrophage infiltration. iNKT cell numbers were restored in mice and humans after weight loss. Mice lacking iNKT cells had enhanced weight gain, larger adipocytes, fatty livers and insulin resistance on high fat diet. Adoptive transfer of iNKT cells into obese mice or in vivo activation of iNKT cells with their lipid ligand alpha-galactocylceramide decreased body fat, triglycerides, leptin, fatty liver, and improved insulin sensitivity through Th2 cell-type cytokine production by adipose-derived iNKT cells. This finding highlights the potential of iNKT cell-targeted therapies, previously proven to be safe in humans, in the management of obesity and its consequences.

ore than 1.9 billion adults are overweight or obese, representing over one third of the worldwide adult population 1. The biggest health and economic burden of obesity is the large number of obesity-related co-morbidities. In addition to type 2 diabetes and cardiovascular disease, obesity is associated with an increased risk of cancer and infections 2-4. Indeed, up to 49% of certain types of cancer are now attributed to obesity 3 , and weight loss through bariatric surgery can reverse cancer risk 5. Potential mechanisms for the increased risk of cancer associated with obesity include overproduction of hormones (for example, oestrogens), adipokines (for example, leptin), and insulin, which favor cell proliferation and tumor growth 6,7. Peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of cellular metabolism. It has recently been shown that obesity induces a PPAR-driven lipid metabolism program in metastatic tumor cells, which enhances metastasis and tumor cell survival 8. In intestinal stem cells, obesitydriven PPAR signaling enhances stemness and tumor progression 9. However, despite the increasing attention to the role of the immune system and inflammation in obesity-driven insulin resistance, the impact of obesity-induced dysfunction on immunosurveillance and cancer risk is not well understood. Natural killer (NK) cells have crucial roles in protective immunity against tumors and viral infections 10. NK cells kill their targets through the directed secretion of lytic granules, which contain pore-forming perforin and apoptosis-inducing granzymes 11-13. Cellular metabolism has a critical role in the function of immune cells. NK cells switch the balance of the core metabolic program from oxidative phosphorylation (OXPHOS) to glycolysis to meet the increased energy required to kill tumor cells 14,15 , although the steps in the killing process that require this metabolic activation are unknown. Humans and mice with obesity display numerical and functional defects in NK cells and have an increased risk of cancer and infections. As obesity is a state of altered metabolism, we investigated the effect of obesity on the cellular metabolism, gene expression, and function of NK cells, and its contribution to cancer development. Our data show that NK cell uptake of lipids from the environment in human obesity interfered with their cellular bioenergetics, inducing 'metabolic paralysis'. Lipid-induced metabolic defects caused NK cell incompetence by inhibiting trafficking of the cytotoxic machinery, leading to loss of antitumor functions in vitro and in vivo. Our data suggest that obesity targets immunometabolic pathways and that this may be partly responsible for the increased cancer and infection risks in obesity, and suggest that metabolic reprogramming may improve innate immunosurveillance in obesity. Results Obesity induces lipid metabolism in NK cells. To better understand the effects of obesity on NK cells, we examined mouse models of diet-induced obesity. We performed transcriptional a...