Thrombospondin1 Deficiency Reduces Obesity-Associated Inflammation and Improves Insulin Sensitivity in a Diet-Induced Obese Mouse Model

BACKGROUND: Obesity is prevalent worldwide and is associated with insulin resistance. Advanced studies suggest that obesity-associated low-grade chronic inflammation contributes to the development of insulin resistance and other metabolic complications. Thrombospondin 1 (TSP1) is a multifunctional extracellular matrix protein that is up-regulated in inflamed adipose tissue. A recent study suggests a positive correlation of TSP1 with obesity, adipose inflammation, and insulin resistance. However, the direct effect of TSP1 on obesity and insulin resistance is not known. Therefore, we investigated the role of TSP1 in mediating obesity-associated inflammation and insulin resistance by using TSP1 knockout mice. METHODOLOGY/PRINCIPAL FINDINGS: Male TSP1-/- mice and wild type littermate controls were fed a low-fat (LF) or a high-fat (HF) diet for 16 weeks. Throughout the study, body weight and fat mass increased similarly between the TSP1-/- mice and WT mice under HF feeding conditions, suggesting that TSP1 deficiency does not affect the development of obesity. However, obese TSP1-/- mice had improved glucose tolerance and increased insulin sensitivity compared to the obese wild type mice. Macrophage accumulation and inflammatory cytokine expression in adipose tissue were reduced in obese TSP1-/- mice. Consistent with the local decrease in pro-inflammatory cytokine levels, systemic inflammation was also decreased in the obese TSP1-/- mice. Furthermore, in vitro data demonstrated that TSP1 deficient macrophages had decreased mobility and a reduced inflammatory phenotype. CONCLUSION: TSP1 deficiency did not affect the development of high-fat diet induced obesity. However, TSP1 deficiency reduced macrophage accumulation in adipose tissue and protected against obesity related inflammation and insulin resistance. Our data demonstrate that TSP1 may play an important role in regulating macrophage function and mediating obesity-induced inflammation and insulin resistance. These data suggest that TSP1 may serve as a potential therapeutic target to improve the inflammatory and metabolic complications of obesity.