TY - JOUR
T1 - Myeloid-specific deletion of thrombospondin 1 protects against inflammation and insulin resistance in long-term diet-induced obese male mice
AU - Memetimin, Hasiyet
AU - Li, Dong
AU - Tan, Kaiyuan
AU - Zhou, Changcheng
AU - Liang, Ying
AU - Wu, Yadi
AU - Wang, Shuxia
N1 - Publisher Copyright:
© 2018 the American Physiological Society.
PY - 2018/12
Y1 - 2018/12
N2 - 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/mac-rophage-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 macro-phage-derived-TGF-1 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- 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.
AB - 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/mac-rophage-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 macro-phage-derived-TGF-1 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- 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.
KW - Inflammation
KW - Insulin resistance
KW - Macrophage
KW - Obesity
KW - TSP1
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U2 - 10.1152/ajpendo.00273.2018
DO - 10.1152/ajpendo.00273.2018
M3 - Article
C2 - 30351986
AN - SCOPUS:85060186373
SN - 0193-1849
VL - 315
SP - E1194-E1203
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 6
ER -