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
{"title":"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。","authors":"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","doi":"10.1111/apha.14214","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>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<sub>B</sub>) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ET<sub>B</sub> 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<sub>B</sub> receptor.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Male adipocyte-specific ET<sub>B</sub> receptor knockout (adET<sub>B</sub>KO), overexpression (adET<sub>B</sub>OX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (<i>p</i> < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adET<sub>B</sub>KO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adET<sub>B</sub>KO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adET<sub>B</sub>KO 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<sub>B</sub> antagonist.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>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<sub>B</sub> receptor on adipocytes.</p>\n </section>\n </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice\",\"authors\":\"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\",\"doi\":\"10.1111/apha.14214\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aims</h3>\\n \\n <p>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<sub>B</sub>) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ET<sub>B</sub> 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<sub>B</sub> receptor.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Male adipocyte-specific ET<sub>B</sub> receptor knockout (adET<sub>B</sub>KO), overexpression (adET<sub>B</sub>OX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (<i>p</i> < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adET<sub>B</sub>KO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adET<sub>B</sub>KO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adET<sub>B</sub>KO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. 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Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice
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 (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB 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 ETB receptor.
Methods
Male adipocyte-specific ETB receptor knockout (adETBKO), overexpression (adETBOX), 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 adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO 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 ETB 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 ETB receptor on adipocytes.
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.
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