title: Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract.
abstract: Despite the capacity of estrogens to favorably regulate body composition and glucose homeostasis, their use to combat obesity and type 2 diabetes is not feasible, because they promote sex steroid-responsive cancers. The novel selective estrogen receptor modulator (SERM) bazedoxifene acetate (BZA) uniquely antagonizes both breast cancer development and estrogen-related changes in the female reproductive tract. How BZA administered with conjugated estrogen (CE) or alone impacts metabolism is unknown. The effects of BZA or CE + BZA on body composition and glucose homeostasis were determined in ovariectomized female mice fed a Western diet for 10-12 wk. In contrast to vehicle, estradiol (E₂), CE, BZA, and CE + BZA equally prevented body weight gain by 50%. In parallel, all treatments caused equal attenuation of the increase in body fat mass invoked by the diet as well as the increases in subcutaneous and visceral white adipose tissue. Diet-induced hepatic steatosis was attenuated by E₂ or CE, and BZA alone or with CE provided even greater steatosis prevention; all interventions improved pyruvate tolerance tests. Glucose tolerance tests and HOMA-IR were improved by E₂, CE, and CE + BZA. Whereas E₂ or CE alone invoked a uterotrophic response, BZA alone or CE + BZA had negligible impact on the uterus. Thus, CE + BZA affords protection from diet-induced adiposity, hepatic steatosis, and insulin resistance with minimal impact on the female reproductive tract in mice. These combined agents may provide a valuable new means to favorably regulate body composition and glucose homeostasis and combat fatty liver.
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Jose
authors.initials: J
authors.lastname: Barrera
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanigaki
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Bonne
authors.initials: B
authors.lastname: Thompson
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and Philip.shaul@utsouthwestern.edu.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D050153:Abdominal Fat / Q000187:drug effects / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000517:prevention & control*; D059305:Diet, High-Fat / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000009:adverse effects; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005234:Fatty Liver / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy / Q000009:adverse effects; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014599:Uterus / Q000187:drug effects / Q000473:pathology
chemical_list: D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D007211:Indoles; D020845:Selective Estrogen Receptor Modulators; C447119:bazedoxifene
keywords: bazedoxifene; conjugated estrogen; hepatic steatosis; obesity; type 2 diabetes