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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
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Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice
Jun Ho Kim1, Matthew S Meyers1, Saja S Khuder2
1Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Molecular Metabolism
|March 18, 2014
Summary
Novel menopausal therapies, estrogen, bazedoxifene (BZA), and tissue-selective estrogen complexes (TSEC) prevent obesity and improve glucose control in mice. These treatments enhance energy expenditure and insulin action without adverse effects on uterine health.
Area of Science:
- Endocrinology
- Metabolic Research
- Pharmacology
Background:
- Menopause is associated with metabolic changes, including increased risk of obesity and insulin resistance.
- Tissue-selective estrogen complexes (TSEC) offer a novel therapeutic approach for menopausal symptoms.
- Estrogen and selective estrogen receptor modulators (SERMs) have known metabolic effects.
Purpose of the Study:
- To investigate the effects of estrogen, bazedoxifene (BZA), and a TSEC on preventing obesity and improving metabolic parameters in ovariectomized mice.
- To determine the impact of these treatments on insulin resistance, glucose intolerance, and energy homeostasis.
- To elucidate the molecular mechanisms underlying the metabolic benefits of BZA and TSEC.
Main Methods:
- Ovariectomized mice were fed a high-fat diet.
- Mice were treated with estrogen, BZA, or a TSEC.
- Metabolic parameters including fat accumulation, insulin resistance, glucose tolerance, energy expenditure, and lipid oxidation were assessed.
- Hepatic gene expression (FGF21, Sirtuin1, PPARα) and AMPK activity were measured.
- Experiments were repeated in estrogen receptor-α deficient mice.
Main Results:
- Estrogen, BZA, and TSEC treatments effectively prevented fat accumulation in adipose tissue, liver, and skeletal muscle.
- All treatments improved insulin resistance and glucose intolerance without causing uterine proliferation.
- Metabolic homeostasis was enhanced through increased lipid oxidation and energy expenditure.
- Estrogen increased hepatic FGF21 production, while BZA upregulated hepatic Sirtuin1, PPARα, and AMPK activity.
- The metabolic benefits of BZA were dependent on estrogen receptor-α signaling.
Conclusions:
- Estrogen, BZA, and TSEC are effective in preventing diet-induced obesity and improving glucose metabolism in female mice.
- BZA alone or in TSEC mimics fasting/caloric restriction signaling pathways, improving energy and glucose homeostasis.
- These findings support the potential of BZA and TSEC as therapeutic strategies for metabolic disorders in postmenopausal women.
Keywords:
AMPKα, AMP-activated protein kinase αAUC, area-under the curveAkt, protein kinase BBAT, brown adipose tissueBZA, bazedoxifeneBazedoxifeneCE, conjugated equine estrogensE2, 17β-estradiolER, estrogen receptorFAS, fatty acid synthaseFGF21, fibroblast growth factor 21GIR, glucose infusion rateH&E, hematoxylin and eosinHFD, high-fat dietHGP, hepatic glucose productionITT, insulin tolerance testInsulin resistanceLPL, lipoprotein lipaseLcn2, lipocalin 2MenopauseMetabolic syndromeNAFLD, non-alcoholic fatty liver diseaseOGTT, oral glucose tolerance testOVX, ovariectomyPTT, pyruvate tolerance testRBP4, retinol binding protein 4RER, respiratory exchange ratioRd, rate of whole-body glucose disappearanceSERM, selective estrogen receptor modulatorTBARS, thiobarbituric acid reactive substancesTG, triacylglycerolTSEC, tissue-selective estrogen complexTissue-selective estrogen complexesType 2 diabetesUCPs, uncoupling proteinsVO2, oxygen consumptionWAT, white adipose tissue.
