Thrombospondin 1 Mediates High-Fat Diet-Induced Muscle Fibrosis and Insulin Resistance in Male Mice
Thrombospondin 1 Mediates High-Fat Diet-Induced Muscle Fibrosis and Insulin Resistance in Male Mice
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DOI：
10.1210/en.2013-1587
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发表时间：
2013-12-01
期刊：
影响因子：
4.8
通讯作者：
Chun, Tae-Hwa
中科院分区：
文献类型：
--
作者：
Inoue, Mayumi;Jiang, Yibin;Chun, Tae-Hwa
血小板反应蛋白1（THBS 1或TSP-1）是一种在人类和小鼠肥大内脏脂肪组织中高度表达的循环糖蛋白。高脂饮食（HFD）喂养在HFD激发的早期阶段诱导循环THBS 1的稳健增加。Thbs 1的缺失可保护雄性小鼠免受饮食诱导的体重增加和脂肪细胞肥大。高胰岛素正葡萄糖钳夹研究表明，Thbs 1-null小鼠受到保护，免受HFD诱导的胰岛素抵抗。组织特异性葡萄糖摄取研究表明，Thbs 1基因敲除小鼠的胰岛素敏感表型主要由骨骼肌介导。使用RNA测序，定量PCR和组织学研究的肌肉表型的进一步评估表明，Thbs 1-null骨骼肌的保护HFD依赖性诱导的Col 3a 1和Col 6a 1，再加上一个新的胶原沉积。同时，Thbs 1基因敲除小鼠表现出更好的昼夜节律和更高的能量消耗幅度，皮下脂肪组织中具有布朗宁表型。这些结果表明，响应于HFD而循环的THBS 1可以在HFD激发的早期阶段诱导骨骼肌中的胰岛素抵抗和纤维化组织损伤以及皮下脂肪组织的去褐化。我们的研究可能揭示了循环细胞外基质蛋白在肥胖进展过程中脂肪组织和骨骼肌之间的相互作用中所起的致病作用。
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.