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A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome
Neetu Srivastava, … , John D. Chisholm, William G. Kerr
Neetu Srivastava, … , John D. Chisholm, William G. Kerr
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e88544. https://doi.org/10.1172/jci.insight.88544.
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Research Article Immunology Metabolism

A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome

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Abstract

Low-grade chronic inflammation is a key etiological phenomenon responsible for the initiation and perpetuation of obesity and diabetes. Novel therapeutic approaches that can specifically target inflammatory pathways are needed to avert this looming epidemic of metabolic disorders. Genetic and chemical inhibition of SH2-containing inositol 5′ phosphatase 1 (SHIP1) has been associated with systemic expansion of immunoregulatory cells that promote a lean-body state; however, SHIP1 function in immunometabolism has never been assessed. This led us to investigate the role of SHIP1 in metabolic disorders during excess caloric intake in mice. Using a small-molecule inhibitor of SHIP1 (SHIPi), here we show that SHIPi treatment in mice significantly reduces body weight and fat content, improves control of blood glucose and insulin sensitivity, and increases energy expenditure, despite continued consumption of a high-fat diet. Additionally, SHIPi reduces age-associated fat in mice. We found that SHIPi treatment reverses diet-associated obesity by attenuating inflammation in the visceral adipose tissue (VAT). SHIPi treatment increases IL-4–producing eosinophils in VAT and consequently increases both alternatively activated macrophages and myeloid-derived suppressor cells. In addition, SHIPi decreases the number of IFN-γ–producing T cells and NK cells in VAT. Thus, SHIPi represents an approach that permits control of obesity and diet-induced metabolic syndrome without apparent toxicity.

Authors

Neetu Srivastava, Sonia Iyer, Raki Sudan, Christie Youngs, Robert W. Engelman, Kyle T. Howard, Christopher M. Russo, John D. Chisholm, William G. Kerr

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Figure 5

K118 treatment abrogates formation of inflammatory T and NK cells in the WAT of HFD mice.

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K118 treatment abrogates formation of inflammatory T and NK cells in the...
(A and B) DIO mice were treated with K118 or water (vehicle) for 2 weeks, and the eWAT was analyzed for the indicated immune cell populations. (A) Frequency and (B) number of CD3+CD4+ and CD3+CD8+ T cells in eWAT (n = 9–11). Plots were pregated on live CD45+ cells. (C and D) Representative flow cytometry plots showing IFN-γ–expressing CD4 and CD8 T cells after in vitro stimulation of stromal vascular fraction (SVF) cells with PMA and ionomycin for 4 hours, with box-and-whisker plots indicating frequencies of CD4 and CD8 IFN-γ–producing T cells pregated on live CD45+CD3+CD4+ and CD4+CD3+CD8+ cells, respectively, and their numbers in the eWAT (n = 10–11). (E) Percentage of CD25–FoxP3+ cells (iTreg) and CD25+FoxP3+ cells (nTreg) pregated on live CD45+CD3+CD4+ cells (n = 8–10). (F and G) Flow plots showing live CD45+CD3–NK1.1+ cells (NK cells) and CD45+CD3+NK1.1+ NKT cells, with box-and-whisker plots indicating frequencies and numbers of (F) NK cells and (G) NKT cells (n = 9–11). (H and I) Flow cytometry of IFN-γ–expressing (H) NK cells and (I) NKT cells in the eWAT of K118- and vehicle-treated HFD mice after in vitro stimulation with PMA and ionomycin for 4 hours. Cells were pregated on live CD45+CD3–NK1.1+ cells (n = 10–11). Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data are represented as mean ± SEM. Sample sizes are biological replicates. Box-and-whisker plots are defined as follows: the bounds of the boxes indicate SD; the lines within the boxes indicate means, and the whiskers represent minimum and maximum values.

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