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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.

SUBMITTER: Srivastava N

PROVIDER: S-EPMC4985248 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We show that roscovitine; a cyclin-dependent kinases inhibitor; given to mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation and fibrosis. It also restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that Roscovitine induced a limited set of proteins associated with lipid metabolism, fatty acid oxidation metabolism and adipose tissue remodeling but suppressed expression of a larger array of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. Furthermore, the phosphoproteome analysis identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases [e.g., CDKs and MAPKs], AGC kinases [e.g., S6K and PKC isoforms], and CAMK kinases [e.g., SIK1 and SIK2]). Pathway enrichment analysis of annotated kinase-substrate pairs showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and phosphatidylcholine and creatine biosynthesis are enriched following roscovitine treatment. The increased creatine pathways combined with more active mitochondria in eWAT may contribute to roscovitine-induced weight loss. Surprisingly, we found that unlike for eWAT, roscovitine led to up regulation of large sets of proteins and phosphosites in brown adipose tissue (BAT). Analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups (AGC kinases [e.g., PKD1 and PKA] and CMGC kinases [e.g., CDKs and MAPKs]. Among the top enriched pathways of kinase-substrate pairs were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling, suggesting that roscovitine led to a metabolically more active BAT. Overall, roscovitine treatment led to restoration of mitochondrial activity in BAT and eWAT suppressed by HFD, likely accounting for enhanced energy expenditure and weight loss.

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

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