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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-? 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.

SUBMITTER: Kong P

PROVIDER: S-EPMC3742854 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation.

Kong Ping P Gonzalez-Quesada Carlos C Li Na N Cavalera Michele M Lee Dong-Wook DW Frangogiannis Nikolaos G NG

American journal of physiology. Endocrinology and metabolism 20130611 3

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 ...[more]

PMID: 23757408

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Project description:ObjectiveDysfunctional, unhealthy expansion of white adipose tissue due to excess dietary intake is a process at the root of obesity and Type 2 Diabetes development. The objective of this study is to contribute to a better understanding of the underlying mechanism(s) regulating the early stages of adipose tissue expansion and adaptation to dietary stress due to an acute, high-fat diet (HFD) challenge, with a focus on the communication between adipocytes and other stromal cells.MethodsWe profiled the early response to high-fat diet exposure in wildtype and adipocyte-specific GPS2-KO (GPS2-AKO) mice at the cellular, tissue and organismal level. A multi-pronged approach was employed to disentangle the complex cellular interactions dictating tissue remodeling, via single-cell RNA sequencing and FACS profiling of the stromal fraction, and semi-quantitative proteomics of the adipocyte-derived exosomal cargo after 5 weeks of HFD feeding.ResultsOur results indicate that loss of GPS2 in mature adipocytes leads to impaired adaptation to the metabolic stress imposed by HFD feeding. GPS2-AKO mice are significantly more inflamed, insulin resistant, and obese, compared to the WT counterparts. At the cellular level, lack of GPS2 in adipocytes impacts upon other stromal populations, with both the eWAT and scWAT depots exhibiting changes in the immune and non-immune compartments that contribute to an increase in inflammatory and anti-adipogenic cell types. Our studies also revealed that adipocyte to stromal cell communication is facilitated by exosomes, and that transcriptional rewiring of the exosomal cargo is crucial for tissue remodeling. Loss of GPS2 results in increased expression of secreted factors promoting a TGFβ-driven fibrotic microenvironment favoring unhealthy tissue remodeling and expansion.ConclusionsAdipocytes serve as an intercellular signaling hub, communicating with the stromal compartment via paracrine signaling. Our study highlights the importance of proper regulation of the 'secretome' released by energetically stressed adipocytes at the onset of obesity. Altered transcriptional regulation of factors secreted via adipocyte-derived exosomes (AdExos), in the absence of GPS2, contributes to the establishment of an anti-adipogenic, pro-fibrotic adipose tissue environment, and to hastened progression towards a metabolically dysfunctional phenotype.

Dataset Information

Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation.

Publications

Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation.

Similar Datasets

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