Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
Endocrinology. 2023 Jun 6;164(7). doi: 10.1210/endocr/bqad091.
Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induce CD36 expression, increase ectopic lipid accumulation, and result in systemic and tissue insulin resistance. Here, we have further investigated whether endothelial cell (EC)-specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance, and dysfunction. Six-week-old female ECMR knockout (ECMR-/-) and wild-type (ECMR+/+) mice were fed either a WD or a chow diet for 16 weeks. ECMR-/- mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16 weeks. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. Additionally, ECMR-/- also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Moreover, in vitro and in vivo activation of ECMR increased EC-derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC-derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance.
西方饮食（WD）中过量的脂肪和碳水化合物的摄入会激活肾素-血管紧张素-醛固酮系统，这已成为全身和组织胰岛素抵抗的一个重要危险因素。我们最近发现，饮食诱导肥胖中激活的盐皮质激素受体（MRs）诱导 CD36 表达，增加异位脂质积累，并导致全身和组织胰岛素抵抗。在这里，我们进一步研究了内皮细胞（EC）特异性 MR（ECMR）的激活是否参与 WD 诱导的异位骨骼肌脂质积累、胰岛素抵抗和功能障碍。将 6 周龄的雌性 ECMR 敲除（ECMR-/-）和野生型（ECMR+/+）小鼠分别用 WD 或标准饮食喂养 16 周。结果发现，ECMR-/-小鼠在 16 周时，WD 诱导的体内葡萄糖不耐受和胰岛素抵抗降低。胰岛素敏感性的改善伴随着葡萄糖转运蛋白 4 表达的增加，以及磷酸肌醇 3-激酶/蛋白激酶 B 和内皮型一氧化氮合酶激活的比目鱼肌胰岛素代谢信号的改善。此外，ECMR-/-还减弱了 WD 诱导的 CD36 表达增加以及比目鱼肌游离脂肪酸、总细胞内脂质含量、氧化应激和比目鱼肌纤维化的增加。此外，ECMR 的体外和体内激活增加了 EC 来源的外泌体 CD36，这些 CD36 进一步被骨骼肌细胞摄取，导致骨骼肌 CD36 水平升高。这些发现表明，在致肥胖 WD 的情况下，增强的 ECMR 信号增加了 EC 来源的外泌体 CD36，导致骨骼肌细胞摄取和 CD36 浓度升高，从而导致脂质代谢紊乱和比目鱼肌胰岛素抵抗增加。
