Thrombospondin 1 Mediates High-Fat Diet-Induced Muscle Fibrosis and Insulin Resistance in Male Mice

Abstract

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.

Fat depot-specific gene signature and ECM remodeling of Sca1high adipose-derived stem cells

“…We speculate that visceral adipose tissues are more susceptible to high-fat diet-induced adipose tissue fibrosis than subcutaneous adipose tissues because the delicate balance between the synthesis and the degradation of collagens needs to be maintained at higher levels in visceral adipose tissues. The imbalance in remodeling collagens and other ECM proteins may trigger pro-inflammatory macrophage infiltration that preferentially occurs in visceral adipose tissues (Inoue et al, 2013; Lumeng et al, 2008). …”

The extracellular matrix and insulin resistance

“…In mice, HF feeding acutely induces adipose tissue Thbs1 expression and increases circulating THBS1 levels [14]. Genetic deletion of Thbs1 in mice protects against HFD induced adipose tissue inflammation and insulin resistance [14]. Circulating THBS1 may also induce fibrosis in skeletal muscle and induce insulin resistance [14].…”

“…Genetic deletion of Thbs1 in mice protects against HFD induced adipose tissue inflammation and insulin resistance [14]. Circulating THBS1 may also induce fibrosis in skeletal muscle and induce insulin resistance [14]. This is evident as Thbs1 -null skeletal muscle is protected from HFD-induced collagen deposition and insulin resistance.…”

Extracellular matrix in obesity – cancer interactions

“…Conversely, TSP-1-null mice were protected from the HFDinduced insulin resistance [109]. Furthermore, TSP-1-null mice exhibited attenuated TNF-α mRNA expression and reduced macrophage infiltration, suggesting a role for TSP-1 in mediating obesity-associated inflammation [110].…”