The Estrogen Receptor Alpha-Selective Agonist Propyl Pyrazole Triol Improves Glucose Tolerance In Ob/Ob Mice; Potential Molecular Mechanisms

The aim of this study was to validate the role of estrogen receptor alpha (ER alpha) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the ER alpha-selective agoinst propyl pyrazole triol (PPT) or 17 beta-estradiol (E-2) in ob/ob mice. Female ob/ob mice were treated with PPT, E, or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed, and insulin secretion was determined front isolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performed using Affymetrix microarrays, and the expression of selected genes was studied by real-time PCR analysis. PPT and E, treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E2 treatment. However, PPT and E, had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPT and vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E, treatment. In the liver, treatment with E and PPT increased and decreased the respective expression levels of the transcription factor signal transducer and activator of transcription 3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPT exerts anti-diabetic effects, and these effects are mediated via EP alpha.