Natural killer T cells in adipose tissue prevent insulin resistance

Abstract

Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell-deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue-resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue-resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

“…On day 3, medium was changed for culture medium supplemented with insulin (170 nM) and left for 4 days. Primary adipocytes were prepared by the fractionation of mouse epididymal AT as described before (19). For Western blot analyses, differentiated 3T3-L1 cells were lysed in RIPA lysis buffer (200 mM Tris-HCl, pH 8.0, 0.1% SDS, 1% Triton X-100, 10 mM EDTA, 150 mM NaCl, 1% sodium deoxycholate containing protease inhibitors).…”

“…In the absence of external stimuli, AT-resident iNKT cells exhibit a Th2-biased cytokine profile (e.g. high IL-4 production) as compared with spleen iNKT cells (19). AT-resident iNKT cells are depleted with increased adiposity (15)(16)(17)(18)(19).…”

“…high IL-4 production) as compared with spleen iNKT cells (19). AT-resident iNKT cells are depleted with increased adiposity (15)(16)(17)(18)(19). Recent studies showed the ability of iNKT cells to exert pathogenic and protective effects on AT function and metabolism (15-19, 24 -28).…”

“…Recent studies showed the ability of iNKT cells to exert pathogenic and protective effects on AT function and metabolism (15-19, 24 -28). Interestingly, recent evidence suggests that adipocytes are able to present lipid antigens to iNKTs in a CD1d-dependent manner, and can therefore be considered non-professional lipid APCs (19,29). It is, however, not understood which proteins in adipocytes facilitate the CD1d lipidation and presentation pathway, and how regulation is established to produce and present lipid self-antigens in an immunogenic manner that stimulates T cell responses.…”

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

“…NKT cells react to lipid antigens presented on CD1d, which results in the secretion of various cytokines (IL-4, IL-10, IFN-g, and TNF-a) that may elicit Th1, Th2, and Treg responses. Experiments with mice with loss-and gain-offunction in NKT activity revealed a gamut of outcomes ranging from beneficial (21)(22)(23)(24)(25), to null (26), to detrimental (27)(28)(29) effects of NKT cells on metabolism. These divergent effects may result from the various strategies applied (CD1d 2/2 that affects all NKT cells vs. Ja18 2/2 that affects only type 1 NKT cells), various diets, various durations, or other local, yet not identified factors.…”