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Cited by 182Estrogen and related hormone effectsOvarian function and disordersRegulation of Appetite and Obesity

Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency

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Takeda, K, Toda, K, Saibara, T, Nakagawa, M, Saika, K, Onishi, T, Sugiura, T, Shizuta, Y·2003·Journal of Endocrinology
DOI 10.1677/joe.0.1760237
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Abstract

Aromatase (CYP19) is a cytochrome P450 enzyme that catalyzes the formation of aromatic C18 estrogens from C19 androgens. It is expressed in various tissues and contributes to sex-specific differences in cellular metabolism. We have generated aromatase-knockout (ArKO) mice in order to study the role of estrogen in the regulation of glucose metabolism. The mean body weights of male ArKO (-/-) mice (n=7) and wild-type littermates (+/+) (n=7) at 10 and 12 weeks of age were 26.7+/-1.9 g vs 26.1+/-0.8 g and 28.8+/-1.4 g vs 26.9+/-1.0 g respectively. The body weights of the ArKO and wild-type mice diverged between 10 and 12 weeks of age with the ArKO males weighing significantly more than their wild-type littermates (P<0.05). The ArKO males showed significantly higher blood glucose levels during an intraperitoneal glucose tolerance test compared with wild-type littermates beginning at 18 weeks of age. By 24 weeks of age, they had higher fasting blood glucose levels compared with wild-type littermates (133.8+/-22.8 mg/dl vs 87.8+/-20.3 mg/dl respectively; P<0.01). An intraperitoneal injection of insulin (0.75 mU insulin/g) caused a continuous decline in blood glucose levels in wild-type mice whereas ArKO males at 18 weeks and older exhibited a rebound increase in glucose levels 30 min after insulin injection. Thus, ArKO male mice appear to develop glucose intolerance and insulin resistance in an age-dependent manner. There was no difference in fasting serum triglyceride and total cholesterol levels between ArKO male mice and wild-type littermates at 13 and 25 weeks of age. However, serum triglyceride and cholesterol levels were significantly elevated following a meal in ArKO mice at 36 weeks of age. Serum testosterone levels in ArKO male mice were continuously higher compared with wild-type littermates. Treatment of ArKO males with 17beta-estradiol improved the glucose response as measured by intraperitoneal glucose and insulin tolerance tests. Treatment with fibrates and thiazolidinediones also led to an improvement in insulin resistance and reduced androgen levels. As complete aromatase deficiency in man is associated with insulin resistance, obesity and hyperlipidemia, the ArKO mouse may be a useful animal model for examining the role of estrogens in the control of glucose and lipid homeostasis.

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Crossref · 10.1677/joe.0.1760237

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  • Mice with global aromatase deficiency consistently show an increased propensity towards obesity and insulin resistance.

    “Studies of mice with global aromatase deficiency consistently show an increased propensity towards obesity and insulin resistance (94–96), and mice with adipocyte-specific aromatase overexpression exhibit improved insulin sensitivity and reduced inflammation (97).”

    From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [95]

    The Discussion reports that complete aromatase deficiency in male mice led to obesity and decreased insulin sensitivity, developing progressively from about 10–12 weeks of age. This supports the claim for the males studied, but does not establish that the pattern holds consistently across mice of both sexes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Mice globally deficient in aromatase (Cyp19a1 knockout) are more prone to aging-associated increase in abdominal obesity and insulin resistance.

    “Mice globally deficient in aromatase (Cyp19a1 KO) are more prone to aging-associated increase in abdominal obesity and insulin resistance (94–96).”

    From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [95]

    The Discussion reports that visceral fat deposits increased gradually with age and insulin sensitivity declined in aromatase-knockout male mice. The claim omits the study's male-only qualification, so the finding is not established here for knockout mice generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Providing exogenous E2 rescues the obesogenic phenotype in Cyp19a1 knockout mice, suggesting the lack of E2 drives the increased adiposity.

    “Providing exogenous E2 rescues the obesogenic phenotype in Cyp19a1 KO mice, suggesting the lack of E2 drives the increased adiposity.”

    From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [95]

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Research works printed but not linked: 3

  1. Balfour J, McTavish D & Heel RC 1990 Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidemia. Drugs 40 260-290.
  2. Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J & Auwerx J 1995 Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. Journal of Clinical Investigation 95 705-712.
  3. Toda K, Okada T, Takeda K, Akira S, Saibara T, Shiraishi M, Onishi S & Shizuta Y 2001a Oestrogen at neonatal stage is critical for reproductive ability of male mice as revealed by supplementation with 17 -oestradiol to aromatase (CYP19) gene knockout mice. Journal of Endocrinology 168 455-463.

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Authors
Takeda, K., Toda, K., Saibara, T., Nakagawa, M., Saika, K., Onishi, T., Sugiura, T., & Shizuta, Y.
Affiliations
  • Kochi Medical School Hospital (JP)
  • St. Luke's International Hospital (JP)
ORCID
Venue
Journal of Endocrinology
Publisher
Bioscientifica
Published
2003-02-01
Volume
176
Issue
2
Pages
237-246
ISSN
  • 0022-0795 (ISSN-L)
  • 1479-6805
DOI
10.1677/joe.0.1760237
OpenAlex
W2118723360
Cited by
182
References
47
Citations by year
2026: 1 · 2025: 4 · 2024: 4 · 2023: 9 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 12 · 2017: 7 · 2016: 5 · 2015: 11 · 2014: 6 · 2013: 15 · 2012: 10
FWCI
3.35
Type
journal article
Language
en
Open access
Locations
  • Journal of Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Nakatomi Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
insulin resistance, impaired glucose tolerance, estrogen, glucose metabolism, testosterone, estradiol, fibrates, thiazolidinediones, age-related development, sex differences in metabolism, hypertriglyceridemia, hypercholesterolemia, insulin tolerance test, weight gain, androgen metabolism
MeSH terms
Pioglitazone, Aging, Animals, Aromatase, Bezafibrate, Blood Glucose, Cholesterol, Estradiol, Glucose Tolerance Test, Insulin, Insulin Resistance, Male, Obesity, Testosterone, Thiazoles, Triglycerides, Mice, Knockout, Models, Animal, Thiazolidinediones, Mice

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