Diabesity alters the protective effects of estrogens on endothelial function through adipose tissue secretome

Estrogens have a well-known protective role in the development of the metabolic syndrome. Nevertheless, recent epidemiological data question the cardioprotective effect of estrogens in obese and diabetic women. In this context, white adipose tissue (WAT) becomes dysfunctional, which has an impact on the cardiovascular system. The aim of the study was to elucidate the role of 17β-estradiol (E2) in the interplay between adipose tissue and endothelial function in an animal model of diabesity. We used ZDF (fa/fa) female rats subjected to ovariectomy (OVA), OVA + E2 or sham operated, as well as non-obese non-diabetic ZDF (fa/+) rats. Endothelial function and vascular remodeling markers were assessed in the aorta, while mitochondrial function, oxidative stress, and adiponectin production were analyzed in gonadal WAT. Conditioned media from gonadal WAT explants were used to assess the effects of WAT secretome on HUVEC. Additionally, the adiponectin receptor agonist AdipoRON and E2 were utilized to examine potential interactions. Ovariectomy ameliorated the WAT dysfunction associated to the obese and diabetic state and promoted adiponectin secretion, effects that were linked to a reduction of endothelial dysfunction and inflammatory markers in the aorta of OVA rats and in HUVEC treated with OVA-conditioned media. Our findings provide evidence supporting the idea that in the context of obesity and diabetes, ovariectomy improves WAT secretome and positively impacts endothelial function, suggesting a detrimental role for E2. Additionally, our results point to adiponectin as the primary driver of the effects exerted by ovariectomy on the adipovascular axis.