Impact of estradiol, estrogen receptor subtype specific agonists and genistein on food intake, body weight, and glucose metabolism in leptin resistant ovariectomized Zucker diabetic fatty rats

The leptin resistant female Zucker diabetic fatty (ZDF fa/fa) rats are described to be hyperphagic and obese, but compared to its male counterparts they remain euglycaemic. Since estrogens are known to affect glucose metabolism we investigated the long-term effect of estradiol (E2 (4 µg/kg b. wt per day)), ER subtype specific agonists (Alpha (10 µg/kg b. wt per day) and Beta (100 µg/kg b. wt per day)) and genistein (Gen (42 mg/kg b. wt per day)) in ovariectomized ZDF rats. After 4 months food intake, body weight, systemic glucose tolerance, muscular glucose transporter 4 (GLUT4) expression and fiber sizes were determined. Additionally, the impact of E2 and Alpha on glucose uptake in liver, skeletal muscle, and adipose tissue as well as localization of muscular GLUT4 was analyzed. Food intake and body weight were markedly reduced by E2 and Alpha. Glucose tolerance was improved by treatment with E2, Alpha, Beta, and Gen. Glucose absorbance in liver, skeletal muscle and adipose tissue was accelerated in E2 and Alpha treated animals compared to untreated OVX rats (impact of Beta and Gen was not investigated). In the muscle, treatment with Alpha enhanced the expression and translocation of GLUT4 to the cell membrane, whereas Beta substitution resulted in the largest muscle fibers. Administration of Gen suggested affecting both GLUT4 expression and muscle fiber sizes.

Thus, our data demonstrates that the ER alpha mediates lower food intake and body weight in leptin resistant female ZDF rats. Activation of ER alpha and beta improves glucose tolerance, but at least in the muscle via different pathways. Further, the ER alpha activation accelerates the glucose absorbance in liver and adipose tissue.