The Journal of Steroid Biochemistry and Molecular Biology
Aromatase-deficient (ArKO) mice accumulate excess adipose tissue☆
Introduction
Estrogen plays an integral role in lipid homeostasis and adipose tissue deposition and distribution. The sexually dimorphic distribution of adipose tissue in humans has implicated sex steroids in the regulation of adiposity and distribution of fat depots [1], [2]. Thus, whereas premenopausal women tend to have a lower body or gynoid distribution of fat, men and postmenopausal women tend to have an upper body or android distribution of fat [3], [4]. This phenotype is associated with a greater risk of insulin-resistant diabetes, cardiovascular disease and breast cancer [5], [6]. Estrogen insufficiency is thought to be largely responsible for the increase in adiposity during menopause since postmenopausal women who receive estrogen replacement therapy do not display the characteristic abdominal weight gain pattern usually associated with menopause [7], [8]. The role that estrogens play in lipid metabolism in the body is also highlighted by the fact that individuals of both sexes with natural mutations of the gene encoding aromatase, the enzyme responsible for estrogen biosynthesis, develop truncal obesity, insulin resistance, hypercholesterolemia and hypertriglyceridemia [9], [10], [11], [12].
We have recently developed a mouse model of estrogen insufficiency by targeted disruption of the aromatase gene (the ArKO mouse) [13]. Aromatase is encoded by the Cyp19 gene and catalyses the final step in the biosynthesis of C18 estrogens from C19 steroids. Hence, we have further investigated the relationship between estrogen and fat by exploring the phenotype of our estrogen-deficient mouse model. In the course of these studies, we observed that the animals displayed a progressive increase in adiposity as compared to wildtype (WT) litter mates. The aim of the present investigation was to characterise the obese phenotype of these animals in the expectation that this would provide new evidence for the role of estrogens in lipid homeostasis.
Section snippets
Mice
The ArKO mice were generated by disrupting the Cyp19 gene as previously been described [13]. Heterozygous males and females were bred to produce WT and homozygous null offspring. Mice were genotyped by PCR as described [14]. Animals were maintained under SPF conditions and had unlimited access to drinking water and a mouse diet containing 15% of calories as fat, 20% of calories as protein and 65% of calories as carbohydrate (manufactured by Glen Forrest Stockfeeders, Western Australia) [15].
Tissue collection and histology
Body and fat pad masses
Adult female ArKO mice were significantly heavier and had significantly larger gonadal and infra-renal fat pads than WT litter mates from 3 months of age onwards (Table 1). Male ArKO mice also had significantly heavier gonadal fat pads than WT males from 3 months of age and heavier infra-renal fat pads from 4 months of age (Table 1). However, their body weight failed to show a significant increase until 1 year of age. Administration of exogenous 17β-estradiol for 21 days to 7-week-old female
Discussion
The present studies reinforce and extend the concept that estrogens play an important role in the regulation of adiposity as a function of age in both males and females [21]. The data presented here has shown that ArKO mice of both sexes with estrogen insufficiency develop a progressive increase in adiposity, primarily as an accumulation of intra-abdominal fat. This excess fat accretion was associated with an increase in adipocyte volume and number, hyperleptinemia, hyperinsulinemia, and
Acknowledgements
This work is supported by USPHS Grant #R37-AG 08174, Grant #981126 from the NHMRC, and by the Victorian Breast Cancer Research Consortium.
References (50)
- et al.
Sex differences in the relation of visceral adipose tissue accumulation to total body fatness
Am. J. Clin. Nutr.
(1993) - et al.
Sex-and menopause-associated changes in body fat distribution
Am. J. Clin. Nutr.
(1992) - et al.
Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause
Metabolism: Clin. Exp.
(1991) - et al.
The role of local estrogen biosynthesis in males and females
TEM
(2000) Gonadal hormones and behavioural regulation of body weight
Physiol. Behav.
(1972)- et al.
The effect of ovarian steroids and photoperiod on body fat stores and uncoupling protein 2 in the marsupial Sminthopsis crassicaudata
Physiol. Behav.
(2000) - et al.
Pharmacologic manipulation of ob expression in a dietary model of obesity
J. Biol. Chem.
(1996) - et al.
Enhanced expression of rat obese (ob) gene in adipose tissues of ventromedial hypothalamus (VMH)-lesioned rats
Biochem. Biophys. Res. Commun.
(1995) - et al.
Lower plasma levels and accelerated clearance of high density lipoprotein (HDL) and non-HDL cholesterol in scavenger receptor class B type I transgenic mice
J. Biol. Chem.
(1999) - et al.
Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality
Maturitas
(1995)
Regulation of plasma cholesterol by hepatic low-density lipoprotein receptors
Am. Heart J.
Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha
Cell
Withdrawal of estrogen increases hypthalamic neuropeptide Y (NPY) mRNA expression in ovariectomised obese rats
Neurosci. Lett.
Gonadal regulation of corticotrophin-releasing factor immunoreactivity in hypothalamus
Brain Res. Bull.
Estradiol enhances brain glucose uptake in ovariectomized rats
Brain Res. Bull.
Body fat mass, body fat distribution, and plasma hormones in early puberty in females
J. Clin. Endocrinol. Metab.
Effects of sex steroid hormones on regional fat depots as assessed by magnetic resonance imaging in transsexuals
Am. J. Physiol.
Genetic and nongenetic determinants of regional fat distribution
Endocrine Rev.
Effects of the menopause transition on body fatness and body fat distribution
Obes. Res.
Body weight, body fat distribution, and hormone replacement therapy in early postmenopausal women
J. Clin. Endocrinol. Metab.
Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens
J. Clin. Endocrinol. Metab.
Effect of testosterone and estradiol in a man with aromatase deficiency
New. Engl. J. Med.
Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency
New. Engl. J. Med.
A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)
J. Clin. Endocrinol. Metab.
Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the Cyp19 gene
Proc. Natl. Acad. Sci. U.S.A.
Cited by (109)
Obesity I: Overview and molecular and biochemical mechanisms
2022, Biochemical PharmacologySex hormones regulate metainflammation in diet-induced obesity in mice
2021, Journal of Biological ChemistryTestosterone metabolites differentially regulate obesogenesis and fat distribution
2021, Molecular MetabolismClinical epidemiology studies on potential effects of endocrine disrupting chemicals (EDCs) should exclude subjects with obesity as determined by BMI
2020, Regulatory Toxicology and Pharmacology
- ☆
Proceedings of the Symposium: ‘Aromatase 2000 and the Third Generation’ (Port Douglas, Australia, 3–7 November 2000).