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. 2024 Oct;240(10):e14214.
doi: 10.1111/apha.14214. Epub 2024 Aug 3.

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

Osvaldo Rivera-Gonzalez  1 , Megumi F Mills  1 , Bridget D Konadu  1 , Natalie A Wilson  1 , Hayley A Murphy  1 , Madison K Newberry  1 , Kelly A Hyndman  2 , Michael R Garrett  3 , David J Webb  4 , Joshua S Speed  1
Affiliations

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

Osvaldo Rivera-Gonzalez et al. Acta Physiol (Oxf). 2024 Oct.

Erratum in

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 (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.

Keywords: adipocytes; endothelin‐1; insulin sensitivity; obesity.

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Conflict of interest statement

Disclosures: The authors declare no conflicts of interest.

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