title: 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.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Neetu
authors.initials: N
authors.lastname: Srivastava
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Raki
authors.initials: R
authors.lastname: Sudan
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Christie
authors.initials: C
authors.lastname: Youngs
authors.affiliation: Departments of Pathology and Cell Biology and Pediatrics, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, Florida, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Engelman
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, New York, USA.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Howard
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, New York, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Russo
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, New York, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Chisholm
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA; Department of Chemistry, Syracuse University, Syracuse, New York, USA; Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr