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

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 17 -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.

Estrogen Receptor .ALPHA. Regulates Insulin Sensitivity through IRS-1 Tyrosine Phosphorylation in Mature 3T3-L1 Adipocytes

“…These results are consistent with clinical and experimental observations that estrogen excesses, as in pregnancy [2,3], trans-sexuality [4], and during menstrual cycles [5], or estrogen deficiencies as in aromatase deficient [6] and OVX animals [7], cause insulin resistance. Moreover, a selective ER-α antagonist, MPP, diminished the beneficial effect of E2 at 10 -8 M on glucose uptake.…”

“…On the other hand, there is considerable evidence against adverse effects of estrogens on glucose metabolism and some for beneficial actions of estrogen. In male mice with complete aromatase deficiency, which are unable to catalyze the formation of estrogens from androgens, progressive insulin resistance is observed [6]. Ovaryectomized (OVX) mice are more insulin-resistant than sham controls and treatment of these OVX mice with estrogen normalizes both glucose tolerance and insulin sensitivity [7].…”

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

“…Several models of oestrogen insufficiency have been used to examine the mechanism(s) of these regulatory events. In male aromatase gene knockout mice, glucose intolerance and insulin resistance developed after 12 weeks of age, and were accompanied by an increase in body weight [3]. The effects of oestrogens are mediated by two receptors: ERα and ERβ.…”

The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms

“…Accordingly, ovariectomy increased body weight, basal glucose levels and caused impaired glucose tolerance) in mice (Bailey & Ahmed-Sorour 1980). Furthermore, aromatase knockout (ARKO) mice, which possess a genetic impairment in endogenous estrogen synthesis, exhibit decreased glucose tolerance, insulin resistance, and increased adiposity (Jones et al 2000, Takeda et al 2003. To investigate whether the above effects of estrogens are mediated via ERa or ERb, isoform-specific knockout animals were studied.…”