title: Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation.
abstract: As a typical matricellular protein, thrombospondin (TSP)-1, binds to the structural matrix and regulates cellular behavior by modulating growth factor and cytokine signaling. Obesity and diabetes are associated with marked upregulation of TSP-1 in adipose tissue. We hypothesized that endogenous TSP-1 may play an important role in the pathogenesis of diet-induced obesity and metabolic dysfunction. Accordingly, we examined the effects of TSP-1 gene disruption on weight gain, adiposity, and adipose tissue inflammation in mice receiving a high-fat diet (HFD: 60% fat, 20% carbohydrate) or a high-carbohydrate low-fat diet (HCLFD: 10% fat, 70% carbohydrate). HFD mice had significantly higher TSP-1 expression in perigonadal adipose tissue; TSP-1 was predominantly localized in the adipose interstitium. TSP-1 loss attenuated weight gain and fat accumulation in HFD and HCLFD groups. Compared with corresponding wild-type animals, TSP-1-null mice had decreased insulin levels but exhibited elevated free fatty acid and triglyceride levels, suggesting impaired fatty acid uptake. TSP-1 loss did not affect adipocyte size and had no effect on adipose vascular density. However, TSP-1-null mice exhibited attenuated tumor necrosis factor-α mRNA expression and reduced macrophage infiltration, suggesting a role for TSP-1 in mediating obesity-associated inflammation. In vitro, TSP-1 enhanced proliferation of 3T3-L1 preadipocytes but did not modulate inflammatory cytokine and chemokine synthesis. In conclusion, TSP-1 upregulation contributes to weight gain, adipose growth, and the pathogenesis of metabolic dysfunction. The effects of TSP-1 may involve stimulation of adipocyte proliferation, activation of inflammatory signaling, and facilitated fatty acid uptake by adipocytes.
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine Cardiology Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Kong
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Quesada
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Michele
authors.initials: M
authors.lastname: Cavalera
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Lee
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000502:physiology*; D000273:Adipose Tissue / Q000098:blood supply / Q000503:physiopathology*; D050154:Adiposity / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002153:Calorimetry, Indirect; D049109:Cell Proliferation; D004032:Diet; D059305:Diet, High-Fat; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
chemical_list: D007328:Insulin; D019700:Thrombospondin 1
keywords: adipocyte; inflammation; macrophage; matricellular proteins; obesity