增强的 ECCD36 信号可促进雌性小鼠骨骼肌的胰岛素抵抗。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Austin Dada, Javad Habibi, Huma Naz, Dongqing Chen, Guido Lastra, Brian P Bostick, Adam Whaley-Connell, Michael A Hill, James R Sowers, Guanghong Jia
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引用次数: 0

摘要

西式饮食(WD)会增加血管、肝脏和骨骼肌组织中 CD36 的表达,促进脂质代谢紊乱和胰岛素抵抗。我们进一步研究了内皮细胞特异性 CD36(ECCD36)信号在导致骨骼肌脂质代谢紊乱和胰岛素抵抗中的作用及其潜在的分子机制。雌性 ECCD36 野生型(ECCD36+/+)和基因敲除型(ECCD36-/-)小鼠年龄为 6 周,以 WD 或标准饲料喂养 16 周。ECCD36+/+ WD小鼠的特征是空腹血浆葡萄糖和胰岛素水平升高、胰岛素抵抗的稳态模型评估增加以及葡萄糖不耐受,而ECCD36-/-小鼠的这些特征被减弱。ECCD36-/-小鼠胰岛素敏感性的改善表现为磷脂酰肌醇3-激酶/蛋白激酶B信号的增加,这进一步增强了葡萄糖转运体4型的表达和葡萄糖摄取。同时,饲喂 16 周的 WD 还会增加骨骼肌游离脂肪酸(FFA)和脂质积累,而血浆中的 FFA 水平却没有发生任何变化。这些脂质代谢紊乱在 ECCD36-/- 小鼠中被减弱。此外,ECCD36 还在体外介导棕榈酸诱导的培养 EC 中的脂质积累,随后导致 FFA 释放到培养基中。此外,摄入 WD 会增加 FFA 氧化、线粒体功能障碍、线粒体呼吸受损、骨骼肌纤维类型转换和纤维化。这些由 WD 引起的异常在 ECCD36-/- 小鼠体内被减弱。这些研究结果表明,内皮特异性 ECCD36 信号传导参与了饮食诱导肥胖症的骨骼肌脂肪酸摄取、异位脂质积累、线粒体功能障碍、胰岛素抵抗和相关骨骼肌功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enhanced ECCD36 signaling promotes skeletal muscle insulin resistance in female mice.

Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell-specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild-type (ECCD36+/+) and knock-out (ECCD36-/-) mice, aged 6 wk, were provided with either a WD or a standard chow diet for a duration of 16 wk. ECCD36+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that was blunted in ECCD36-/- mice. Improved insulin sensitivity in ECCD36-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 wk of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36-/- mice. These findings demonstrate that endothelial-specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.NEW & NOTEWORTHY ECCD36 exerts "extra endothelial cell" actions in skeletal muscle insulin resistance. ECCD36 is a major mediator of Western diet-induced lipid metabolic disorders and insulin resistance in skeletal muscle. Mitochondrial dysfunction is associated with diet-induced CD36 activation and related skeletal muscle insulin resistance.

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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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