Related Experiment Video
Updated: Aug 29, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse
Kylie N Hewitt1, Kyriakos Pratis, Margaret E E Jones
1Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia. kylie.hewitt@phimr.monash.edu.au
Abstract:
The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to a disruption to the Cyp19 gene. Previously we have shown both male and female ArKO mice have an age progressive obese phenotype and a sexually dimorphic disruption to hepatic cholesterol and triglyceride homeostasis. Only ArKO males have elevated hepatic triglyceride levels leading to hepatic steatosis partly due to an increase in expression of enzymes involved in de novo lipogenesis and transporters involved in fatty acid uptake. In this study ArKO males were treated with 17beta-estradiol (3 microg/ kg x d) at 18 wk old for 6 wk. Wild-type controls were not treated, and ArKO controls received vehicle oil injections. Estrogen replacement reverses the previously reported obese and fatty liver phenotypes; this was achieved by reductions in gonadal, visceral, and brown adipose tissue weights and significantly decreased hepatic triglyceride levels. Estrogen deficiency led to a significant up-regulation of hepatic fatty acid synthase expression, which was reduced with 17beta-estradiol replacement, although not quite reaching significance. Acetyl Coenzyme A carboxylase alpha mRNA expression showed no significant changes. Expression of transcripts encoding adipocyte differentiated regulatory protein, a fatty acid transporter, was significantly elevated in estrogen-deficient males, and 17beta-estradiol replacement significantly reduced these levels. Scavenger receptor class b type 1 showed no significantly changes. This study reveals that the previously reported disruption to triglyceride homeostasis in estrogen-deficient males can be reversed with 17beta-estradiol treatment, indicating an important role for estrogen in maintaining triglyceride and fatty acid homeostasis in males.
Insights
Estrogen deficiency causes obesity and fatty liver in male mice. Replacing estrogen reverses these conditions by improving triglyceride and fatty acid metabolism.
Area of Science:
- Endocrinology
- Metabolic Research
- Molecular Biology
Background:
- Aromatase knockout (ArKO) mice lack endogenous estrogen production due to Cyp19 gene disruption.
- ArKO mice exhibit age-progressive obesity and sexually dimorphic disruptions in hepatic lipid homeostasis.
- Male ArKO mice specifically develop elevated hepatic triglycerides and steatosis, linked to lipogenesis and fatty acid uptake.
Purpose of the Study:
- To investigate the effects of 17beta-estradiol replacement on obesity and hepatic steatosis in male ArKO mice.
- To determine the role of estrogen in regulating genes involved in de novo lipogenesis and fatty acid transport in male mice.
Main Methods:
- Male ArKO mice were treated with 17beta-estradiol for 6 weeks starting at 18 weeks of age.
- Control groups included untreated wild-type mice and ArKO mice receiving vehicle injections.
- Gene expression analysis (fatty acid synthase, acetyl-CoA carboxylase alpha, adipocyte fatty acid-binding protein, scavenger receptor class B type 1) and tissue weight measurements were performed.
Main Results:
- 17beta-estradiol replacement significantly reversed obesity and fatty liver phenotypes in male ArKO mice.
- Adipose tissue weights (gonadal, visceral, brown) and hepatic triglyceride levels were significantly reduced by estrogen treatment.
- Estrogen replacement significantly decreased elevated expression of fatty acid synthase and adipocyte differentiated regulatory protein (a fatty acid transporter) in ArKO males.
Conclusions:
- Estrogen plays a critical role in maintaining triglyceride and fatty acid homeostasis in male mice.
- 17beta-estradiol treatment effectively reverses estrogen deficiency-induced metabolic disruptions, including obesity and hepatic steatosis.
- The findings highlight estrogen's importance in regulating lipogenic enzymes and fatty acid transport in the liver of males.
