Marcela González-Granillo1, Christina Savva2, Xidan Li3, Mark Fitch4, Matteo Pedrelli5, Marc Hellerstein4, Paolo Parini6, Marion Korach-André7, Jan-Åke Gustafsson8. 1. Department of Medicine, Metabolism Unit and KI/AZ Integrated CardioMetabolic Center (ICMC), Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Biosciences and Nutrition Huddinge, Karolinska Institutet, Sweden. Electronic address: marcela.gonzalez@ki.se. 2. Department of Medicine, Metabolism Unit and KI/AZ Integrated CardioMetabolic Center (ICMC), Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Biosciences and Nutrition Huddinge, Karolinska Institutet, Sweden. 3. Department of Medicine, Metabolism Unit and KI/AZ Integrated CardioMetabolic Center (ICMC), Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. 4. Department of Nutritional Sciences & Toxicology, University of California, Berkeley, USA. 5. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Sweden. 6. Department of Medicine and Department of Laboratory Medicine, Karolinska Institutet, Sweden. 7. Department of Medicine, Metabolism Unit and KI/AZ Integrated CardioMetabolic Center (ICMC), Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Biosciences and Nutrition Huddinge, Karolinska Institutet, Sweden. Electronic address: marion.korach-andre@ki.se. 8. Department of Biosciences and Nutrition Huddinge, Karolinska Institutet, Sweden; Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signalling, University of Houston, Houston, TX, USA.
Abstract
OBJECTIVE: Estrogens play a key role in the distribution of adipose tissue and have their action by binding to both estrogen receptors (ER), α and β. Although ERβ has a role in the energy metabolism, limited data of the physiological mechanism and metabolic response involved in the pharmacological activation of ERβ is available. METHODS: For clinical relevance, non-ovariectomized female mice were subjected to high fat diet together with pharmacological (DIP - 4-(2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl)phenol) interventions to ERβ selective activation. The physiological mechanism was assessed in vivo by magnetic resonance imaging and spectroscopy, and oral glucose and intraperitoneal insulin tolerance test before and after DIP treatment. Liver and adipose tissue metabolic response was measured in HFD + vehicle and HFD + DIP by stable isotope, RNA sequencing and protein content. RESULTS: HFD-fed females treated with DIP had a tissue-specific response towards ERβ selective activation. The metabolic profile showed an improved fasting glucose level, insulin sensitivity and reduced liver steatosis. CONCLUSIONS: Our data demonstrate that selective activation of ERβ exerts a tissue-specific activity which promotes a beneficial effect on whole body metabolic response to obesity.
OBJECTIVE: Estrogens play a key role in the distribution of adipose tissue and have their action by binding to both estrogen receptors (ER), α and β. Although ERβ has a role in the energy metabolism, limited data of the physiological mechanism and metabolic response involved in the pharmacological activation of ERβ is available. METHODS: For clinical relevance, non-ovariectomized female mice were subjected to high fat diet together with pharmacological (DIP - 4-(2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl)phenol) interventions to ERβ selective activation. The physiological mechanism was assessed in vivo by magnetic resonance imaging and spectroscopy, and oral glucose and intraperitoneal insulin tolerance test before and after DIP treatment. Liver and adipose tissue metabolic response was measured in HFD + vehicle and HFD + DIP by stable isotope, RNA sequencing and protein content. RESULTS: HFD-fed females treated with DIP had a tissue-specific response towards ERβ selective activation. The metabolic profile showed an improved fasting glucose level, insulin sensitivity and reduced liver steatosis. CONCLUSIONS: Our data demonstrate that selective activation of ERβ exerts a tissue-specific activity which promotes a beneficial effect on whole body metabolic response to obesity.
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