biostudies-literatureRivera-Gonzalez ONIDDK NIH HHSNHLBI NIH HHSNIGMS NIH HHSe14214https://www.ebi.ac.uk/biostudies/studies/S-EPMC11421981biostudies-literatureUnknown240(10)<h4>Aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.Acta physiologica (Oxford, England)Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice.PMC11421981U2C DK133422P20 GM144041P30 GM149404P01 HL158500R01 DK124327P20 GM104357T32 HL105324F31 DK125035P20 GM103476R01 DK126664U54 GM115428Garrett MRSpeed JSWilson NAWebb DJRivera-Gonzalez OKonadu BDMurphy HAMills MFHyndman KANewberry MKfalseAdipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice.<h4>Aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.2024-01-01T00:00:00Z2024 Oct2026-06-03T23:18:51.783Z2026-05-03T03:10:24.72ZS-EPMC114219813909607710.1111/apha.14214