Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Acta Physiol (Oxf). 2024 Oct;240(10):e14214. doi: 10.1111/apha.14214. Epub 2024 Aug 3.
Endothelin-1 (ET-1) is elevated in patients with obesity and adipose tissue of obese mice fed high-fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ET) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ET activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET-1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ET receptor.
Male adipocyte-specific ET receptor knockout (adETKO), overexpression (adETOX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks.
RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET-1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ET antagonist.
These data indicate elevated ET-1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ET receptor on adipocytes.
肥胖患者和高脂肪饮食喂养的肥胖小鼠的脂肪组织中内皮素-1（ET-1）水平升高；然而，其对肥胖病理生理学的贡献尚不完全清楚。内皮素 B 型受体（ET）的基因缺失可改善大鼠的胰岛素敏感性，并导致循环脂联素增加，这表明脂肪细胞上的 ET 激活可能有助于肥胖的病理生理学。我们假设肥胖症中升高的 ET-1 通过减少胰岛素敏化脂肪因子的分泌来促进胰岛素抵抗，这是通过 ET 受体实现的。
雄性脂肪细胞特异性 ET 受体敲除（adETKO）、过表达（adETOX）或对照同窝仔鼠分别给予正常饮食（NMD）或高脂肪饮食（HFD）喂养 8 周。
附睾脂肪（eWAT）的 RNA 测序表明，与 NMD 对照组相比，HFD 组有超过 5500 个基因的表达存在差异（p<0.05），而这些基因中有 1077 个基因的变化在 HFD adETKO 小鼠中被减弱。KEGG 分析表明代谢信号通路显著增加。与 HFD 对照组相比，HFD adETKO 小鼠的葡萄糖和胰岛素耐量有显著改善。此外，adETKO 减弱了 HFD 与 NMD 对照组相比观察到的血浆脂联素、胰岛素和瘦素的变化。ET-1 处理原代脂肪细胞会导致脂联素产生减少，而用 ET 拮抗剂预处理细胞可减轻这种减少。
这些数据表明，HFD 喂养的小鼠脂肪组织中升高的 ET-1 通过激活脂肪细胞上的 ET 受体抑制脂联素的产生，并导致胰岛素抵抗。
