Natural killer T cells in adipose tissue prevent insulin resistance
Henk S. Schipper, … , Marianne Boes, Eric Kalkhoven
Henk S. Schipper, … , Marianne Boes, Eric Kalkhoven
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3343-3354. https://doi.org/10.1172/JCI62739.
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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.

Authors

Henk S. Schipper, Maryam Rakhshandehroo, Stan F.J. van de Graaf, Koen Venken, Arjen Koppen, Rinke Stienstra, Serge Prop, Jenny Meerding, Nicole Hamers, Gurdyal Besra, Louis Boon, Edward E.S. Nieuwenhuis, Dirk Elewaut, Berent Prakken, Sander Kersten, Marianne Boes, Eric Kalkhoven

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Figure 2

AT-resident iNKT cells show an activated phenotype and are downregulated on a long-term HFD.

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AT-resident iNKT cells show an activated phenotype and are downregulated...
(A) Stromal vascular fraction of visceral adipose tissue (VAT) from WT and CD1d-null mice was stained for TCRβ, CD1d tetramer, CD4, and CD8. FSC, forward scatter; SSC, side scatter. Numbers in graphs indicate the percentage of cells in that gate. Second and third panel, percentage of TCRβ+ cells; fourth panel, CD4 and CD8 staining of iNKT cells. (B) Intracellular staining of spleen and visceral AT-extracted iNKT cells from 4 WT mice, injected intraperitoneally with αGalCer (5 εg) or vehicle. Shown are representative histograms and averages in bar graphs. (C) Quantitative RT-PCR on VAT of WT and CD1d-null mice on the LFD and HFD regimens. n = 9 mice per group; total 36 mice. (D and E) Percentage of CD4–CD8– and NK1.1+ iNKT cells (gated on TCRβ and CD1d/αGC-loaded tetramer) extracted from spleen and VAT of WT mice on a LFD. n = 10 mice per group; total 20 mice. (F) Number of iNKT cells per gram of SCAT and VAT of WT mice on LFD and HFD regimens. n = 10 mice per group; total 20 mice. *P < 0.05.