Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica Pub Date : 2024-08-03 DOI:10.1111/apha.14214

Osvaldo Rivera-Gonzalez, Megumi F. Mills, Bridget D. Konadu, Natalie A. Wilson, Hayley A. Murphy, Madison K. Newberry, Kelly A. Hyndman, Michael R. Garrett, David J. Webb, Joshua S. Speed

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Abstract

Aims

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_B) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ET_B 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_B receptor.

Methods

Male adipocyte-specific ET_B receptor knockout (adET_BKO), overexpression (adET_BOX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks.

Results

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 adET_BKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adET_BKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adET_BKO 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_B antagonist.

Conclusion

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_B receptor on adipocytes.

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肥胖小鼠的脂肪细胞内皮素 B 受体激活会抑制脂肪生成素并导致胰岛素抵抗。

目的：内皮素-1（ET-1）在肥胖症患者和以高脂饮食（HFD）喂养的肥胖小鼠的脂肪组织中升高，但其对肥胖症病理生理学的作用尚未完全明了。遗传性 B 型内皮素受体（ETB）缺失可改善大鼠的胰岛素敏感性，并导致循环中的脂肪连蛋白增加，这表明脂肪细胞上的 ETB 激活可能有助于肥胖症的病理生理学。我们假设肥胖症中升高的 ET-1 会通过 ETB 受体减少胰岛素敏感性脂肪因子的分泌，从而促进胰岛素抵抗：雄性脂肪细胞特异性 ETB 受体敲除（adETBKO）、过表达（adETBOX）或对照组同窝鼠喂养正常饮食（NMD）或高脂饮食（HFD）8 周：附睾脂肪（eWAT）的 RNA 序列分析表明，5500 多个基因（p BKO 小鼠）的表达存在差异。KEGG 分析表明代谢信号通路明显增加。与高脂饮食对照组相比，高脂饮食 adETBKO 小鼠的葡萄糖和胰岛素耐受性明显改善。此外，adETBKO 还减轻了高脂血症与 NMD 对照组小鼠血浆脂肪连素、胰岛素和瘦素的变化。用 ET-1 处理原代脂肪细胞会导致脂肪生成素的减少，而用 ETB 拮抗剂预处理细胞会减弱这种减少：这些数据表明，高频分解膳食小鼠脂肪组织中升高的 ET-1 可抑制脂肪生成素的产生，并通过激活脂肪细胞上的 ETB 受体导致胰岛素抵抗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Physiologica 医学-生理学

CiteScore

11.80

自引率

15.90%

发文量

182

审稿时长

4-8 weeks

期刊介绍： Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.