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L Lundholm, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
G Bryzgalova, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
H Gao, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
N Portwood, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
S Fält, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
K Berndt, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
A Dicker, Department of Medicine, Karolinska Institute, Stockholm, Sweden
D Galuska, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
J Zierath, Stockholm, Sweden
J Gustafsson, Dept of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
S Efendic, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
K Dahlman-Wright, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
A Khan, molecular Medicine & Surgery, Karolinska Institutet, Stockholm, 171 76, Sweden

Correspondence: Akhtar Khan, Email: akhtar.khan{at}ki.se

Abstract

The aim of this study was to validate the role of estrogen receptor alpha (ER) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the estrogen receptor alpha-selective agonist propyl pyrazole triol (PPT) or 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 were decreased after 30 days of PPT and E2 treatment. Additionally, PPT and E2 decreased basal insulin levels and improved the acute insulin response, with no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar between 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 Stat3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPT exerts anti-diabetic effects, and these effects are mediated via ER.