2-hydroxyestradiol attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats

A pandemic of obesity is contributing importantly to the prevalence of the metabolic syndrome characterized by hypertension, insulin resistance, and h yperlipidemia. In turn, the metabolic syndrome is contributing to vascular disease and the accelerating epidemic of chronic renal failure. Currently, pharmacological approaches to attenuate obesity and its cardiovascular/rena l sequelae are limited. The purpose of this study was to determine the effe cts of 2-hydroxyestradiol, a metabolite of 17 beta -estradiol with minimal estrogenic activity, on the development of obesity, the metabolic syndrome, and heart, vascular, and renal dysfunction in obese ZSF1 rats, a well-char acterized genetic model of obesity and the metabolic syndrome with concomit ant heart, vascular, and kidney disease. ZSF1 rats were treated, beginning at 12 weeks of age, for 26 weeks with vehicle or 2-hydroxyestradiol (10 mug /kg/h). At baseline and after 24 weeks of treatment, animals were placed in metabolic cages, and food intake, water intake, urine output, and urinary excretion of proteins and glucose were determined. Next, in fasting animals , plasma cholesterol was measured, an oral glucose tolerance test was condu cted, and total glycated hemoglobin levels were determined. At the end of t he study, animals were anesthetized and instrumented for assessment of hear t performance, renal hemodynamics, and mesenteric vascular reactivity. 2-Hy droxyestradiol attenuated the development of obesity and improved endotheli al function, decreased nephropathy, decreased the severity of diabetes, low ered arterial blood pressure, and reduced plasma cholesterol. 2-Hydroxyestr adiol may be an important lead for the development of safe and effect drugs to attenuate obesity and its metabolic, vascular, and renal sequelae.