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.
View: Text | PDF
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

×

Figure 4

K118 treatment expands myeloid suppressor cells and promotes M2 polarization of visceral adipose tissue macrophages.

Options: View larger image (or click on image) Download as PowerPoint
K118 treatment expands myeloid suppressor cells and promotes M2 polariza...
(A) Flow cytometry plots showing CD11b+Gr1+ cells (MDSC) in vehicle- and K118-treated mice, with box-and-whisker plots indicating their frequencies and numbers (n = 14–15). (B) Histogram showing expression of Arginase1 and IL4Rα (red) compared to fluorescence minus one (FMO, gray) control stain on CD11b+Gr1+ cells of K118-treated eWAT. (C) Expression of SHIP1 in the CD11b+Gr1+ cells of eWAT of DIO mice treated for 2 weeks with K118 (red) or vehicle (blue); FMO control is shown in gray (n = 5). (D) Flow cytometry plot showing M1 and M2 macrophages after first gating for live CD11b+F4/80+ cells (n = 14–15). (E) Expression of IL4Rα (n = 14–15) and (F) Arginase1 (n = 10) in M2 macrophages of K118-treated (red) and vehicle-treated (blue) eWAT. Student’s t test,*P < 0.05, **P < 0.001, ***P < 0.001, ****P<0.0001. Data are represented as mean ± SEM. Sample sizes are biological replicates. eWAT, epidydimal white adipose tissue. 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.