Myeloid-specific deletion of thrombospondin 1 protects against inflammation and insulin resistance in long-term diet-induced obese male mice

Abstract

Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. Recent studies demonstrate that TSP1 is highly expressed in adipose tissue (AT) and positively associated with AT inflammation and insulin resistance (IR). In this study, the contribution of different cellular sources of TSP1 to obesity-induced metabolic complications is determined by using mice with either adipocyte or myeloid/macrophage-specific deletion of TSP1 in a diet-induced obese model. The results demonstrated that neither adipocyte nor myeloid/macrophage-specific deletion of TSP1 affected the development of long-term high-fat diet-induced obesity. Adipocyte-specific deletion of TSP1 did not protect mice from obesity-induced inflammation and IR. On the contrary, obese mice with myeloid/macrophage loss of TSP1 had reduced macrophage accumulation in AT, which was accompanied with reduced inflammation and improved glucose tolerance and insulin sensitivity compared with obese control mice. Reduced macrophage-derived-TGF-β1 signaling and adipose tissue fibrosis were also observed in long-term high-fat-fed mice with myeloid/macrophage-specific TSP1 deletion. Moreover, in vitro experiments demonstrated an autocrine effect of TSP1-mediated TGF-β activation in macrophages in obesity. Collectively this study highlights the critical contribution of myeloid/macrophage-derived TSP1 to obesity-associated chronic inflammation and IR, which may serve as a new therapeutic target for metabolic disease.

Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease

“…S3B-D). Other obesity-associated complications such as J o u r n a l P r e -p r o o f glucose intolerance and insulin resistance were similarly developed in knock out mice as compared to control (TSP1 fl/fl ) mice 20 . Collectively, these data suggest that adipocytes-derived TSP1 does not contribute significantly to obesity-associated NAFLD.…”

“…Animals were housed individually in standard cages at 22°C in a 12:12-h light-dark cycle. 1) Mice breeding: Female TSP1 floxed mice 20 (TSP1 fl/fl) were bred with male Cre mice (Lyz-Cre for macrophage specific deletion-TSP1 ∆MФ ).…”

“…Therefore, we further determined its contribution to obesity-associated NAFLD/NASH by utilization of our recently generated macrophage specific TSP1 knock out mice (TSP1 ∆mɸ ) 20 .…”

“…We also determined the contribution of other cellular sources of obesity-induced TSP1 (such as adipocytes 29,30 ) to NAFLD/NSH development by utilization of adipocyte specific TSP1 knock out mice (TSP1 ∆adipo ) 20 . As shown in Fig.…”

miR-467 regulates inflammation and blood insulin and glucose

“…Thrombospondin-1 is an extracellular matrix protein involved in regulation of tissue remodeling and inflammation. Studies in Thbs1 -/mice suggest that a lack of TSP-1 may alleviate macrophage accumulation and the pro-inflammatory phenotype observed in insulin resistant metabolic organs, thus protecting the animals from diet-induced inflammation and IR [18][19][20] .…”