Elsevier

Molecular Metabolism

Volume 3, Issue 2, April 2014, Pages 177-190
Molecular Metabolism

Original article
Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice

https://doi.org/10.1016/j.molmet.2013.12.009Get rights and content
Under a Creative Commons license
open access

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.

Abbreviations

Akt
protein kinase B
AMPKα
AMP-activated protein kinase α
AUC
area-under the curve
BAT
brown adipose tissue
BZA
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
Lcn2
lipocalin 2
LPL
lipoprotein lipase
NAFLD
non-alcoholic fatty liver disease
OGTT
oral glucose tolerance test
OVX
ovariectomy
PTT
pyruvate tolerance test
RBP4
retinol binding protein 4
Rd
rate of whole-body glucose disappearance
RER
respiratory exchange ratio
SERM
selective estrogen receptor modulator
TBARS
thiobarbituric acid reactive substances
TG
triacylglycerol
TSEC
tissue-selective estrogen complex
UCPs
uncoupling proteins
VO2
oxygen consumption
WAT
white adipose tissue.

Keywords

Tissue-selective estrogen complexes
Bazedoxifene
Menopause
Metabolic syndrome
Insulin resistance
Type 2 diabetes

Cited by (0)

5

Present address: Department of Food and Biotechnology, Korea University, Sejong 339-700, South Korea

6

Present address: CNRS, UMR6265, INRA, UMR1324, University of Bourgogne, CSGA, F-21000 Dijon, France