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...

Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle ( i ) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; ( ii ) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; ( iii ) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8 . Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male.

Retinoic acid attenuates colitis and is associated with increased IL-22 production from γδ T cells and innate lymphoid cells and enhanced antimicrobial peptide expression.

Retinoic acid (RA) is produced by a number of cell types, including macrophages and dendritic cells, which express retinal dehydrogenases that convert vitamin A to its main biologically active metabolite, all-trans RA. All-trans RA binds to its nuclear retinoic acid receptors that are expressed in lymphoid cells and act as transcription factors to regulate cell homing and differentiation. RA production by CD103+ dendritic cells and alveolar macrophages functions with TGF-β to promote conversion of naive T cells into Foxp3+ regulatory T cells and, thereby, maintain mucosal tolerance. Furthermore, RA inhibits the differentiation of naive T cells into Th17 cells. However, Th1 and Th17 responses are constrained during vitamin A deficiency and in nuclear RA receptor α–defective mice. Furthermore, RA promotes effector T cell responses during infection or autoimmune diseases. Thus, RA plays a role in immune homeostasis in the steady-state but activates pathogenic T cells in conditions of inflammation.