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 (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.

METHODS

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.

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 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.

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 receptor on adipocytes.