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

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 1

K118 treatment prevents obesity and improves glucose homeostasis.

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K118 treatment prevents obesity and improves glucose homeostasis. Phenot...
Phenotypic and metabolic parameters were assessed in 14- to 16-week-old DIO mice treated with K118 (10 mg/kg body weight) or vehicle for 4 weeks (twice per week). (A) Growth curves were plotted to show the changes in body weight of vehicle- and K118-treated mice (n = 6). Two-way ANOVA tests for repeated measurement were performed; P < 0.0001. (B) Percentage of body fat was measured in vehicle- and K118-treated mice before (Pre-Tx) and after treatment (n = 10). (C) Representative gross appearance and comparison of fat depots of DIO mice after either vehicle or K118 treatment. (D) Representative H&E-stained sections of BAT (scale bar: 300 μm) and WAT (scale bar: 500 μm). (E) Fasting and (F) ad libitum blood glucose levels (mg/dl) in pretreated mice and vehicle- and K118-treated DIO C57BL/6 mice (n = 10). (G) Fasting and ad libitum serum insulin levels (pg/ml) measured in vehicle- and K118-treated DIO mice (n = 10). (H) i.p. glucose tolerance test on vehicle- and K118-treated DIO mice (n = 6). Two-way ANOVA tests for repeated measurement were performed followed by post-hoc Bonferroni test. (I and J) Body weight and percentage of fat were measured in aged C57BL/6 mice treated with K118 (10 mg/kg body weight) or vehicle for 4 weeks (twice per week). Changes in body weight of (I) male and (J) female 8- to 12-month-old vehicle- and K118-treated C57BL/6 mice before and after treatment (n = 10). (K and L) Percentage of body fat was measured in vehicle- and K118-treated (K) male and (L) female aged C57BL/6 mice before and after treatment (n = 10). All results are expressed as mean ± SEM. Student’s unpaired, 2-tailed t test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. WAT, white adipose tissue; BAT, brown adipose tissue; DIO, diet-induced obese. 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.