Estrogens have the potential to afford atheroprotection, to prevent excess adiposity and its metabolic complications including insulin resistance, and to lessen hepatic steatosis. Cellular responses to estrogens occur through gene regulation by nuclear estrogen receptors (ER), and through signal initiation by plasma membrane-associated ER. Leveraging the potentially favorable cardiometabolic actions of estrogens has been challenging because their reproductive tract and cancer-promoting effects adversely impact the risk-benefit ratio of the therapy. In prior works we discovered that an estrogen dendrimer conjugate (EDC) comprised of ethinyl-estradiol (E₂) molecules linked to a poly(amido)amine dendrimer selectively activates non-nuclear ER, and in mice EDC does not invoke a uterotrophic response or support ER-positive breast cancer growth. In the present investigation, we employed EDC to determine how selective non-nuclear ER activation impacts atherosclerosis, adiposity, glucose homeostasis and hepatic steatosis in female mice. In contrast to E₂, EDC did not blunt atherosclerosis in hypercholesterolemic apoE^-/- mice. Also in contrast to E₂, EDC did not prevent the increase in adiposity caused by western diet feeding in wild-type mice, and it did not affect western diet-induced glucose intolerance. However, E₂ and EDC had comparable favorable effect on diet-induced hepatic steatosis, and this was related to downregulation of fatty acid and triglyceride synthesis genes in the liver. Predictably only E₂ caused a uterotrophic response. Thus, although non-nuclear ER activation does not prevent atherosclerosis or diet-induced obesity or glucose intolerance, it may provide a potential new strategy to combat hepatic steatosis without impacting the female reproductive tract or increasing cancer risk. Link