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Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency.
[aromatase deficiency]
Aromatase
(
CYP
19
)
is
a
cytochrome
P
450
enzyme
that
catalyzes
the
formation
of
aromatic
C
18
estrogens
from
C
19
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
beta
-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
.
Diseases
Validation
Diseases presenting
"insulin resistance in an age-dependent manner"
symptom
aromatase deficiency
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