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Updated: Mar 17, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and
Monique C de Oliveira1, Eduardo H Gilglioni1, Bouke A de Boer2
1Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Meibergdreef 69-71, 1105, BK, Amsterdam, The Netherlands; Laboratory of Biological Oxidations, Dept. of Biochemistry, University of Maringá, Maringá, Brazil.
Selective bile acid receptor agonists effectively reversed obesity and non-alcoholic fatty liver disease (NAFLD) in a mouse model of postmenopausal metabolic changes. These findings suggest potential therapeutic applications for these compounds.
Area of Science:
- Endocrinology and Metabolism
- Hepatology
- Pharmacology
Background:
- Menopause is frequently associated with obesity and non-alcoholic fatty liver disease (NAFLD).
- Bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, are potential therapeutic targets for metabolic disorders.
Purpose of the Study:
- To assess the efficacy of selective FXR agonist INT747 (obeticholic acid) and TGR5 agonist INT777 in treating metabolic disturbances caused by estrogen deficiency.
- To investigate the impact of these agonists on body weight, energy expenditure, liver fat accumulation, and metabolic gene expression in an ovariectomized (OVX) mouse model.
Main Methods:
- Ovariectomized (OVX) and sham-operated (SHAM) mice were fed a high-fat diet (HFD).
- OVX and SHAM mice received either INT747- or INT777-supplemented HFD during the final four weeks of the five-week study.
- Evaluated body weight gain, food intake, physical activity, energy expenditure, liver triglyceride and cholesterol levels, and gene expression in liver, muscle, and adipose tissues.
Main Results:
- OVX mice exhibited increased body weight gain and liver fat accumulation compared to SHAM mice, which was attenuated by INT747 and INT777 treatment.
- Treatment with INT747 and INT777 partially restored energy expenditure in OVX mice.
- Significant alterations in metabolic gene expression were observed in the liver, muscle, and adipose tissues of treated OVX mice, including the novel finding of FXR expression and target gene induction in skeletal muscle.
Conclusions:
- Selective bile acid receptor agonists (INT747 and INT777) are effective in ameliorating postmenopausal metabolic changes in an OVX mouse model.
- These agonists may represent promising therapeutic agents for managing obesity and NAFLD associated with estrogen deficiency.
- Potential mechanisms involve enhanced energy expenditure and modulation of key metabolic gene expression in multiple tissues.
