Unravelling metabolic factors impacting iNKT cell biology in obesity

Obesity and related diseases have reached epidemic proportions and continue to rise. Beyond creating an economical burden, obesity and its co-morbidities are associated with shortened human life expectancy. Despite major advances, the underlying mechanisms of obesity remain not fully elucidated. Recently, several studies have highlighted that various immune cells are metabolically reprogrammed in obesity, thereby profoundly affecting the immune system. This sheds light on a new field of interest: the impact of obesity-related systemic metabolic changes affecting immune system that could lead to immunosurveillance loss. Among immune cells altered by obesity, invariant Natural Killer T (iNKT) cells have recently garnered intense focus due to their ability to recognize lipid antigen. While iNKT cells are well-described to be affected by obesity, how and to what extent immunometabolic factors (e.g., lipids, glucose, cytokines, adipokines, insulin and free fatty acids) can drive iNKT cells alterations remains unclear, but represent an emerging field of research. Here, we review the current knowledge on iNKT cells in obesity and discuss the immunometabolic factors that could modulate their phenotype and activity. Abbreviations: αGC, α-galactosylceramide; AMPK, AMP-activated protein kinase; APCs, antigen presenting cells; ApoE, Apolipoprotein E; AT, adipose tissue; ATMs, AT-macrophages; BMI, body mass index; DCs, dendritic cells; E4BP4, E4-binding Protein 4; ER, endoplasmic reticulum; FA, fatty acid; FFAs, free fatty acids; HDL, high-density lipoprotein; HFD, high-fat diet; IFN-γ, interferon gamma; IL, interleukin; iNKT, invariant Natural Killer T; IRE1α, inositol-requiring enzyme 1α; LDL, low-density lipoprotein; LDLR, LDL receptor; MHC, Major histocompatibility complex class; NK, Natural Killer; PBMCs, peripheral blood mononuclear cells; PERK, protein kinase RNA-like ER kinase; PLZF, promyelocytic leukemia zinc finger; SFAs, Saturated fatty acid; TCR, T-cell receptor; TNF-α, tumor-necrosis factor-α; UPR, unfolded protein response; VLDL, very-low-density lipoprotein.