title: Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice.
abstract: Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Meyers
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
authors.forename: Saja S
authors.initials: SS
authors.lastname: Khuder
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Abdallah
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
authors.forename: Harrison T
authors.initials: HT
authors.lastname: Muturi
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Chandra R
authors.initials: CR
authors.lastname: Tate
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Leloup
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA ; Department of Medicine, Division of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
keywords: AMPKα, AMP-activated protein kinase α; AUC, area-under the curve; Akt, protein kinase B; BAT, brown adipose tissue; BZA, bazedoxifene; Bazedoxifene; CE, conjugated equine estrogens; E2, 17β-estradiol; ER, estrogen receptor; FAS, fatty acid synthase; FGF21, fibroblast growth factor 21; GIR, glucose infusion rate; H&E, hematoxylin and eosin; HFD, high-fat diet; HGP, hepatic glucose production; ITT, insulin tolerance test; Insulin resistance; LPL, lipoprotein lipase; Lcn2, lipocalin 2; Menopause; Metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; OGTT, oral glucose tolerance test; OVX, ovariectomy; PTT, pyruvate tolerance test; RBP4, retinol binding protein 4; RER, respiratory exchange ratio; Rd, rate of whole-body glucose disappearance; SERM, selective estrogen receptor modulator; TBARS, thiobarbituric acid reactive substances; TG, triacylglycerol; TSEC, tissue-selective estrogen complex; Tissue-selective estrogen complexes; Type 2 diabetes; UCPs, uncoupling proteins; VO2, oxygen consumption; WAT, white adipose tissue.