The estrogen receptor α-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 a (ERa) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatmentwiththeERa-selectiveagonistpropylpyrazoletriol (PPT) or 17b-estradiol (E2) in ob/ob mice. Female ob/ob mice were treated with PPT, E2 or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed,andinsulinsecretionwasdeterminedfromisolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performedusingAffymetrixmicroarrays,andtheexpressionof selectedgeneswasstudied byreal-timePCRanalysis.PPTand E2 treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPTand E2 treatment. However, PPTand E2 had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPTand vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E2 treatment. In the liver, treatment with E2 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.Insummary,ourdatademonstratethat PPTexerts anti-diabetic effects, and these effects are mediated via ERa.