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Journal of Endocrinology (2008) 199, 275-286       DOI: 10.1677/JOE-08-0192
© 2008 Society for Endocrinology
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The estrogen receptor {alpha}-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms

 L Lundholm1,*, G Bryzgalova*, H Gao1, N Portwood, S Fält1, K D Berndt1, A Dicker2, D Galuska3, J R Zierath3, J-Å Gustafsson1, S Efendic, K Dahlman-Wright1 and A Khan

Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden1 Department of Biosciences and Nutrition, Karolinska Institute, SE-14157 Huddinge, Sweden2 Department of Medicine, Karolinska Institute, Karolinska University Hospital, SE-14186 Huddinge, Sweden3 Department of Molecular Medicine and Surgery, Karolinska Institute, SE-17176 Stockholm, Sweden

(Correspondence should be addressed to A Khan; Email: akhtar.khan{at}ki.se)

* (L Lundholm and G Bryzgalova contributed equally to this study)

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 agonist propyl pyrazole triol (PPT) or 17β-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, and insulin secretion was determined from 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 E2 treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E2 treatment. However, PPT and 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 PPT and 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. In summary, our data demonstrate that PPT exerts anti-diabetic effects, and these effects are mediated via ER{alpha}.






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