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 2

K118 limits adiposity and increase energy expenditure in DIO mice.

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K118 limits adiposity and increase energy expenditure in DIO mice. (A) M...
(A) Metabolic parameters were assessed in diet-induced obese (DIO) mice treated with K118 (10 mg/kg body weight) or vehicle for 2 weeks (twice per week). Body weight measurements before treatment and after K118 or vehicle treatment of DIO mice (n = 26). (B and C) Body composition measurement showing (B) percentage of body fat and (C) percentage of lean mass after 2 weeks of K118 treatment (n = 7–8). (D–F) Body composition analysis of chow-fed lean young mice treated with K118 or vehicle for 2 weeks (n = 8). (G) Representative image and (H) weight of epidydimal white adipose tissue (eWAT) of K118- and vehicle-treated DIO mice (n = 13–15). Student’s t test. Data are represented as mean ± SEM. (I) Representative H&E-stained sections of iWAT of vehicle- and K118-administered mice (top) and UCP1 (bottom) (original magnification, ×200). (J) Representative H&E-stained sections (scale bar: 300 μm) and UCP1-stained sections (scale bar: 200 μm) of brown adipose tissue (BAT) of vehicle- and K118-administered mice. (K–M) CLAMS analysis using individually housed groups of K118- and vehicle-administered mice after 2 weeks of treatment. Plots represent variations in (K) oxygen consumption, (L) CO2 release, and (M) energy expenditure over time in vehicle- vs. K118-treated mice (n = 7–8) as indicated. Statistical analysis was performed using 2-way repeated-measures ANOVA for energy expenditure experiments. Error bars represent the mean ± SEM. White and black rectangular lines on the X-axis represent light and dark cycles respectively. (N) Cumulative food intake and (O) total physical activity in K118- and vehicle-treated DIO mice (n = 7–8). 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. Experiments in B–F and K–O were performed independently by the Mouse Metabolic Phenotyping Center at the University of Cincinnati. CLAMS, Comprehensive Laboratory Animals Monitoring System. 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.