Adipocyte-specific ET receptor overexpression induces obesity, insulin resistance, and dyslipidemia in high-fat diet-fed female mice.

In rodent models of diet-induced obesity, a metabolic syndrome-like phenotype develops that is more pronounced in males compared to females. Our lab reported that endothelin-1 (ET-1) is increased in visceral adipose of high-fat diet-fed (HFD) mice where it inhibits adiponectin production through activation of the ET-1 type B receptor (ET). Further, adipocyte-specific knockout of ET improves insulin sensitivity in HFD-fed male mice. We report that males produce significantly more ET-1 with higher expression of ET in visceral adipose compared to females. We hypothesized that adipocyte-specific overexpression of the ET receptor (adETOX) would abolish or attenuate protection against HFD observed in female mice. The data indicate that female adETOX mice placed on HFD for 10 weeks had increased adiposity compared to floxed controls, while no detectable difference was observed between adETOX and floxed controls fed NMD. Compared to NMD floxed control mice, insulin tolerance was impaired in adETOX fed either NMD or HFD. Finally, HFD-fed adETOX had exacerbated dyslipidemia and insulin intolerance compared to floxed controls. These data indicate that reduced ET-1 signaling on adipocytes at least partially mediates protection against HFD-induced metabolic disease in female mice.