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Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice.

Inoue M, Jiang Y, Barnes RH, Tokunaga M, Martinez-SantibaƱez G, Geletka L, Lumeng CN, Buchner DA, Chun TH
Endocrinology. 2013 154 (12): 4548-59

PMID: 24140711 · PMCID: PMC3836064 · DOI:10.1210/en.2013-1587

Thrombospondin 1 (THBS1 or TSP-1) is a circulating glycoprotein highly expressed in hypertrophic visceral adipose tissues of humans and mice. High-fat diet (HFD) feeding induces the robust increase of circulating THBS1 in the early stages of HFD challenge. The loss of Thbs1 protects male mice from diet-induced weight gain and adipocyte hypertrophy. Hyperinsulinemic euglycemic clamp study has demonstrated that Thbs1-null mice are protected from HFD-induced insulin resistance. Tissue-specific glucose uptake study has revealed that the insulin-sensitive phenotype of Thbs1-null mice is mostly mediated by skeletal muscles. Further assessments of the muscle phenotype using RNA sequencing, quantitative PCR, and histological studies have demonstrated that Thbs1-null skeletal muscles are protected from the HFD-dependent induction of Col3a1 and Col6a1, coupled with a new collagen deposition. At the same time, the Thbs1-null mice display a better circadian rhythm and higher amplitude of energy expenditure with a browning phenotype in sc adipose tissues. These results suggest that THBS1, which circulates in response to a HFD, may induce insulin resistance and fibrotic tissue damage in skeletal muscles as well as the de-browning of sc adipose tissues in the early stages of a HFD challenge. Our study may shed new light on the pathogenic role played by a circulating extracellular matrix protein in the cross talk between adipose tissues and skeletal muscles during obesity progression.

MeSH Terms (19)

3T3-L1 Cells Adipose Tissue, White Animals Dietary Fats Dose-Response Relationship, Drug Epididymis Fibrosis Gene Expression Regulation Glucose Clamp Technique Insulin Resistance Male Mice Mice, Inbred C57BL Mice, Knockout Muscle, Skeletal Muscular Diseases Obesity Thrombospondin 1 Transcriptome

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