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Null Mice
Bourne Behavioral Research Laboratory, Department of Psychiatry, New York-Presbyterian Hospital-Weill Medical College of Cornell University (N.G., L.A.), White Plains, New York 10605; Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental and Health Sciences (K.S.K.), Research Triangle Park, North Carolina 27709; and Laboratory of Neurobiology and Behavior, Rockefeller University (D.K., S.O.), New York, New York 10021
Address all correspondence and requests for reprints to: Nori Geary, Ph.D., Bourne Behavioral Research Laboratory, New York-Presbyterian Hospital, 21 Bloomingdale Road, White Plains, New York 10605. E-mail: ndgeary{at}med.cornell.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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) in
the inhibitory effects of E on food intake and body weight, we
ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to
wild-type (WT) mice and mice with a null mutation of ER (ERKO).
Mice were ovariectomized at age 9 wk, at which time there was no
significant effect of genotype on food intake or body weight. During an
18-d test after recovery from ovariectomy, vehicle-treated WT mice
increased daily food intake and gained more body weight than E2-treated
WT mice, whereas food intake and body weight gain were not different in
E2- and vehicle-treated ERKO mice. Carcass analysis revealed
parallel changes in body lipid content, but not water or protein
content. Because an increase in the potency of the peripheral
cholecystokinin (CCK) satiation-signaling system mediates part of E2’s
influence on feeding in rats, the influence of ip injections of 250
µg of the selective CCKA receptor antagonist devazepide
was then tested. Devazepide increased 3-h food intake in E2-treated WT
mice, but was ineffective in both groups of ERKO mice. Furthermore,
ip injections of 4 µg/kg CCK-8 increased the number of cells
expressing c-Fos immunoreactivity in the nuclei of the solitary tract
of E2-treated WT mice more than it did in vehicle-treated WT mice,
whereas E2 had no such effect in ERKO mice. Thus, ER is necessary
for normal responsivity of food intake, body weight, adiposity, and the
peripheral CCK satiation-signaling system to E2 in mice, and ERß is
not sufficient for any of these effects. This is the first
demonstration that ER gene expression is involved in the estrogenic
control of feeding behavior and weight regulation of female
mice. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There has been rapid progress in recent years in understanding the
molecular biology of estrogenic actions (21, 22). The
classical ER, ER, was cloned and sequenced (23, 24),
and a second ER, ERß, was identified (25). In addition,
gene targeting and transgenic methods were used to generate mice with a
null mutation of the classical ER, ER (ERKO mice) (26, 27). Dozens of studies of the physiology and behavior of the
ERKO mouse have already appeared and indicate that although ER is
not essential for survival, it appears necessary for the normal
expression of all the E2-dependent responses studied to date (reviewed
in Ref. 21). Thus, for example, female ERKO mice
display aberrant social and reproductive behaviors that resemble those
of intact males more than those of intact females (28, 29). Little is known, however, about the feeding behavior of
ERKO mice. Heine et al. (6) reported that
male ERKO and wild-type (WT) mice eat virtually identical amounts
through the first 11 months of life. Food intake in females was not
reported. Body weight and adiposity were increased, however, in both
male and female ERKO mice by 3 months of age (6, 9).
Adiposity was also increased by 3 months of age in male and female
aromatase-deficient mice, although these animals ate less, not more,
than WT mice (7). To further investigate the roles of E2
and ER in the control of feeding and body weight, we tested the
effects of ovariectomy and E2 treatment on food intake, body weight
gain, and the behavioral and central neural responsivity to
manipulation of the CCK satiation-signaling system in female ERKO
mice and their WT littermates. Our findings indicate that E2’s effects
on basal food intake, maintenance of body weight, and CCK satiation in
female mice all require ER, and therefore by itself ERß is not
sufficient.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ERKO mice and WT littermates that were
bred at Rockefeller University using a line of mixed C57BL/6J and 129
strain mice in which the ER gene was disrupted, as described
previously (26, 27). The experiments were performed with
the approval of the Rockefeller University institutional animal care
and use committee. At age 4 wk, litters of mice were separated from
their dams and housed five or six per cage in plastic cages (30 x
20 x 13 cm) with ad libitum food (Purina 5001,
Ralston Purina Co., St. Louis, MO) and water in a colony
room with a 12-h light, 12-h dark cycle (lights on, 0700 h) and
constant temperature (22 C). During wk 5 they were anesthetized with
methoxyflurane (Metofane, Mallinckrodt, Inc., Mundelein,
IL), and 1-mm tissue samples were taken from the tips of the tails and
genotyped by PCR. During wk 7 about 20 each of the ERKO and WT
female mice were separated into individual cages, and during wk 8 body
weights (±0.1 g), 24-h food intakes (±0.01 g), and smears of the
vaginal mucosa were obtained daily.
Ovariectomy and E2 treatment
At 9 wk of age, mice were bilaterally ovariectomized under
methoxyflurane anesthesia. Ovaries were exposed via a single midline
skin incision and bilateral penetrations of the retroperitoneal
musculature with fine forceps. A 5-0 silk ligature was placed between
the ovary and the tip of the uterine horn, and the ovary was excised. A
pellet containing either E2 or vehicle alone was placed into the
interscapular sc space (Innovative Research of America,
Sarasota, FL; pellets weighed 15 mg and contained 180 µg ß-E2
3-benzoate in a carrier-binder matrix of cholesterol, lactose,
cellulose, phosphates, and stearates that released a constant dose of
75 pg/d). The muscle was closed with silk suture, and the skin was
closed with 9-mm wound clips. There were seven to nine roughly
weight-matched mice per treatment group. After recovery from surgery,
they were tested sequentially in the procedures described below.
Food intake and body weight
Although some mice were hypophagic for several days after
ovariectomy, all returned to preoperative levels of food intake and
body weight by 1 wk postsurgery. Daily ad libitum food
intake and body weight were then recorded for 18 d (d 8–25
postoperatively).
CCKA receptor antagonist tests
Beginning 27 d postovariectomy, mice were adapted to a
schedule where food was removed 2 h before the onset of the dark
period, 0.2 ml 0.15 M NaCl was ip injected 30 min before
dark, two preweighed food pellets were returned at dark onset, and food
intake was measured 45, 90, and 180 min after dark onset. The effects
on feeding of ip injections of 250 µg devazepide (Merck, Sharpe, &
Dohme Research Laboratories, West Point, PA), a potent and selective
CCKA receptor antagonist (30), were then
compared with the effects of the 0.5% carboxymethylcellulose vehicle
using a cross-over design. The selection of this design and devazepide
dose were based on previously reported positive results in C57BL/6J
mice (31).
CCK-induced c-Fos immunoreactivity
After the CCKA receptor antagonist tests,
ad libitum food access was reinstated for 1 wk. The mice
were then rerandomized into treatment groups, food-deprived at
0730 h, received ip injections of 4 µg/kg CCK-8 at 0800 h,
and at 0930 h were anesthetized by ip injections (0.2 ml)
containing 0.15 mg ketamine (Ketaset, Fort Dodge, Inc., Fort Dodge, IA)
and 0.1 mg xylazine (Rompun, Mobay, Inc., Shawnee, KS) and
transcardially perfused with 4% paraformaldehyde in 0.1
M phosphate buffer solution. Brains were removed,
blocked, postfixed for 2 h in the same 4% paraformaldehyde
solution, and immersed for 2 d in 20% sucrose in 0.1
M phosphate buffer solution with 0.1% sodium
azide. The hindbrain was cut in 40-µm horizontal sections. When this
is done, nearly the entire rostral-caudal extent of the nucleus of the
solitary tract (NTS) is contained in sections that are just ventral to
the area postrema (32, 33). Alternate sections were
processed for c-Fos immunocytochemistry and mounted on microscope
slides. The section that was closest to the ventral extreme of the area
postrema was identified, and it and the next ventral alternate section
were used. The numbers of c-Fos-stained cells were counted
in the medial halves of these sections from 1.5 mm anterior to the
posterior extent of the fourth ventricle to 1.5 mm posterior to it, an
area that includes the entire NTS, using NIH Image (version 1.4).
Carcass analysis
After lavage of the gastrointestinal tracts, the body
compositions of the beheaded, perfused carcasses were analyzed for
water, protein, and fat contents by Dr. Carol Boozer of the New York
Obesity Research Center. Carcasses were autoclaved at 125 C in 50 ml
distilled water for 30 min, cooled, and homogenized. Total body water
was determined by drying duplicate 1-g samples of homogenate at 90 C to
constant weight. Total carcass lipid was determined in triplicate by
chloroform/methanol extraction of homogenate samples. Nitrogen was
determined by the Kjeldahl method, and total carcass protein was
calculated assuming a nitrogen/protein ratio of 0.16. Further details
were previously reported (34).
Data analysis
Daily body weights and food intakes from the last cycle before
ovariectomy were analyzed for each of the two genotypes using one-way
ANOVAs. As there were no significant effects of cycle day, mean weights
were used for a preovariectomy value. These were compared between
genotypes with t tests. Body weights and food intakes during
the 18-d ad libitum feeding period were collapsed into six
3-d blocks. Cumulative body weight gains (grams per 3 d compared
with the preovariectomy weights), food intakes during each block (grams
per 3 d), and food intakes during the entire test (grams per
18 d) were analyzed with one-way ANOVAs. The mean number of cells
expressing c-Fos immunoreactivity in the two sample hindbrain sections
after CCK-8 or control treatment as well as data from each carcass
analysis (protein, lipid, and water contents in grams) were analyzed
with one-way ANOVAs. Food intakes after devazepide injection were
analyzed with a split-plot, two-way ANOVA, with drug treatment as the
within-subject variable.
Contrasts between individual means after significant ANOVA results were
performed with Tukey’s honestly significant difference test.
Differences were considered significant when 2 < 0.05. Unless
otherwise noted, all significance levels reported refer to the results
of Tukey’s honestly significant difference tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ERKO mice (18.0 ± 0.3 g) were not
significantly different [t(35) = 0.67;
P = NS]. After ovariectomy, vehicle-treated WT mice
gained significantly more weight than E2-treated WT mice or either
group of ERKO mice, whereas vehicle-treated ERKO mice did not
gain more weight than E2-treated ERKO mice (Fig. 1
). Significant differences first
appeared 16 and 19 d postovariectomy [F(3, 33) = 4.01 and
4.88, respectively; P < 0.01], when vehicle-treated
WT mice had gained more than vehicle-treated ERKO mice
(P < 0.05). After 22 and 25 d postovariectomy,
vehicle-treated WT mice had gained more than each of the other three
groups [F(3, 33) = 7.64 and 7.11, respectively; P
< 0.001]. At d 25, the vehicle-treated WT mice had gained, on the
average, 2.0 g more than E2-treated WT mice, whereas
vehicle-treated ERKO mice had gained 0.4 g less than E2-treated
ERKO mice. This difference in the effectiveness of E2 on weight gain
was significant (P < 0.05).
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ERKO mice
(4.40 ± 0.16 vs. 3.94 ± 0.14 g/d, respectively),
but this difference was not quite statistically significant
[t(35) = 2.02; P < 0.051]. None of
the analyses of 3-d food intakes after ovariectomy detected significant
differences among the groups (data not shown). Analysis of the 18-d
cumulative food intake, however, revealed that postovariectomy food
intake paralleled body weight gain [F(3, 32) = 4.28;
P < 0.02; Table 1].
That is, vehicle-treated WT mice ate more than E2-treated WT mice,
whereas vehicle-treated ERKO mice did not eat more than E2-treated
ERKO. Furthermore, the mean vehicle-E2 difference was significantly
larger in WT than ERKO mice.
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ERKO
mice [F(3, 26) = 3.01; P < 0.05; Fig. 2]. The stimulatory effect of devazepide
in E2-treated WT mice was larger than in any other group. The effects
of devazepide at 45 and 90 min were not significant (data not
shown).
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ERKO
mice (Fig. 3). Typical photomicrographs
are shown in Fig. 4.
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ERKO mice
[F(3, 23) = 5.90; P < 0.005; Table 2]. The vehicle-E2 differences in lipid
contents were not different between the genotypes. Body water and
protein contents did not differ significantly among the four groups
[F(3, 23) = 1.44 and 0.58, respectively].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ERKO mouse to
investigate for the first time the ER mechanism mediating these feeding
effects. We report that daily food intake, adiposity and body weight,
and the behavioral and neural responsivity of the CCK
satiation-signaling system were all affected by E2 treatment in
ovariectomized WT mice, whereas none of these measures was affected by
E2 treatment in ovariectomized ERKO mice. Therefore, ER is a
necessary component of the E signaling pathway mediating each of these
effects in female mice, and ERß alone is not sufficient for any of
them.
E signaling and weight regulation
In young adult mice and rats, ovariectomy leads to a weight gain
of 10–25%, almost all in the form of adipose tissue (4, 5, 8, 12, 35, 36). The main cause of this weight gain is typically a
tonic increase in feeding, although reductions in physical activity and
altered metabolism also contribute (36). This increase in
feeding is mediated by an increase in meal size, with no change or a
decrease in meal frequency (3, 12, 13). E2 appears to
cause these feeding effects, because E2 treatment is sufficient to
normalize meal patterns and adiposity (3, 12, 13). In the
present study ovariectomized wild-type mice that received E2 treatment
ate less, had a smaller percentage of body fat, and gained less body
weight than mice that did not receive E2. In contrast, ovariectomized
ERKO mice that received E2 were not significantly different from
mice that did not receive E2 in any of these measures. Thus, ER is
necessary, and ERß alone is not sufficient for the restraining
effects of E2 on basal level of food intake, adiposity, and body weight
in female mice.
Despite the differences in the feeding and body weight responses of WT
and ERKO mice reported here, there was no difference in the body
weights of the two genotypes before ovariectomy. This is consistent
with two studies of the development of adiposity and body weight
through the life span in ERKO mice (6, 9) and one study
in transgenic mice with a null mutation of the gene encoding aromatase,
the enzyme mediating E synthesis (7). In these studies
both male and female knockouts increased adiposity and body weight
slowly, so that weight differences were evident only when the mice were
3 months of age or older. In ERKO mice food intake was measured only
in males and was not different from that in WT mice (6);
in aromatase knockouts food intake decreased in both males and females
(7). Thus, changes in metabolism or physical activity
apparently produced the weight and adiposity increases. The lack of an
increase in food intake in these studies is consistent with our finding
that the daily food intake of ERKO mice was similar to that of
E2-treated ovariectomized WT mice and less than that of untreated
ovariectomized WT mice. The apparent discrepancy between the tonic
feeding effects of genetic disruption of the E-signaling system and the
effects of ovariectomy in adult animals clearly requires research.
E signaling and feeding in intact cycling rats and mice
E2 also produces a cyclic decrease in meal size and food intake
during the estrous phase of the ovarian cycle in rats and mice
(13, 14, 19, 37). Several results indicate that this
inhibition is due in large part to a cyclic increase in the potency of
the negative feedback control of meal size that originates from small
intestinal food stimuli that cause the release of CCK (3, 10, 15, 19, 20). The most direct evidence is that antagonism of
endogenous CCK by administration of the selective
CCKA receptor antagonist devazepide
(30) produced larger increases in meal size during estrus
than diestrus in intact rats (19) and during the phase of
cyclic E2 treatment that modeled estrus than during the phase that
modeled diestrus in ovariectomized rats (10). Here we
demonstrated a similar E2-dependent increase in the satiating potency
of endogenous CCK in ovariectomized WT mice. In contrast, devazepide
did not increase feeding in either E2-treated or vehicle-treated
ERKO mice. Thus, ER is necessary, and ERß alone is not
sufficient, for the increase in CCK’s satiating potency by E2 in
female mice. Because we tested devazepide’s effect only in
ovariectomized mice, we can only speculate that in mice, as in rats,
the E2-dependent increase in CCK’s satiating action in ovariectomized
animals parallels a cyclic decrease in CCK’s satiating potency during
the estrous phase of the ovarian cycle in intact animals.
Neural mechanisms of the estrogenic control of feeding
Peripheral CCK-8 injections selectively increased the number of
NTS cells expressing c-Fos-like immunoreactivity, a marker for neuronal
activity, in E2-treated ovariectomized WT mice significantly more than
in vehicle-treated WT mice. Similarly, CCK-8 injection and food
ingestion both increased NTS c-Fos in E2-treated ovariectomized rats,
but not in untreated ovariectomized rats (38, 39). The NTS
is the first central relay of the vagal afferent neurons that carry
negative feedback information controlling meal size from CCK’s site of
action in the gut to the brain. Thus, that E2 increased CCK-8-mediated
c-Fos in the NTS suggests that the increased potency of the CCK
signaling system may originate from altered information processing in
the initial, more sensory part of the neuronal network controlling meal
size. The lack of effect of E2 on CCK-8-induced c-Fos in the NTS of
ERKO mice indicates that ER is necessary for this apparent
increase in neuronal information processing and that ERß alone is not
sufficient for it.
E2 presumably acts centrally to inhibit feeding, but neither the
present nor previous data disclose the site(s) of the ER that
participates in the control of feeding, CCK satiation, body weight, or
adiposity in mice or rats. ER has been localized in neurons in
numerous brain sites implicated in the control of feeding, including
the NTS and various hypothalamic and forebrain loci
(40, 41, 42). As ER is expressed in the NTS, all of the
effects of E2 on feeding in ovariectomized mice that we have reported,
including the increase in c-Fos expression, may have originated from
activation of ER in the NTS. It is also possible that the crucial
population of ER is located more rostrally and that the increase in
CCK-stimulated NTS c-Fos resulted indirectly from a descending neural
projection.
Finally, the selective stimulatory effect of E2 on CCK-8-induced NTS c-Fos expression in WT mice also suggests that the similar selective effect of antagonism of endogenous CCK with devazepide on feeding was not an artifact of the different baseline levels of food intake in the feeding tests. That is, because baseline food intake was less in the E2-treated WT mice, it could be supposed that ceiling effects in the other groups masked similar stimulatory effects of devazepide, but the c-Fos tests produced the same pattern of results in the absence of any such baseline differences. This parallels more direct lines of evidence indicating that the cyclic increases in endogenous CCK’s satiating potency in intact and E2-treated ovariectomized rats are not secondary to baseline differences in food intake (10, 19).
Summary and comment
We demonstrated that E2 treatment reduced food intake, body
weight, and adiposity; increased the stimulation of feeding induced by
antagonism of endogenous CCK; and increased the expression of c-Fos
protein induced by CCK injection in ovariectomized WT mice, but had
none of these effects in ovariectomized ERKO mice. These data
provide the first direct demonstration of a necessary role of ER in
the estrogenic control of feeding in female mice and extend recent
reports of body weight regulation in mice with null mutations of ER
(6, 9). This parallels the apparently necessary
contributions of ER to sexual receptivity in female mice (1, 28, 29), to reproductive and aggressive behaviors in male and
female mice (28, 29, 43, 44), and to many physiological
actions of E2 (21).
The demonstration that ER is necessary and that ERß alone is not
sufficient for E2’s effects on feeding and body weight in female mice
does not rule out a participatory role for ERß in the normal
physiological control of these functions. This issue will have to be
evaluated using more sophisticated methods than simple screening tests
in single gene null mutant, or knockout, animals. Most genetic effects,
including E responsivity (45), are remarkably pleiotropic,
so large arrays of genes normally interact to produce the phenotype
under consideration (46, 47). Thus, although ERß or
other ER species may not be sufficient to produce the phenotypes that
we studied, they may usually make important contributions. Genes with
no clear relationship to the phenotype under study may also have
biologically significant influences. This includes background effects,
i.e. effects of the strain of mouse, which have been
demonstrated both for pharmacological actions of E2 (47)
and for the consequences of null mutation of ER (44).
In addition, individual experience may alter the influence of
particular genes, as was recently shown for the role of ERß in the
control of aggressive behavior (48). Finally, we suggest
that the ER-mediated effects on feeding and body weight that we have
revealed here result from activational effects of circulating E2. We
cannot, however, exclude the possibility that there were important
contributions of developmental abnormalities due to the lack of
organizational effects mediated by ER (21, 27).
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Acknowledgments |
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Footnotes |
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Abbreviations: CCK, Cholecystokinin; ERKO, mice with a null
mutation of ER; NTS, nucleus of the solitary tract; WT, wild type.
Received February 9, 2001.
Accepted for publication July 30, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C. S. Fox, Q. Yang, L. A. Cupples, C.-Y. Guo, L. D. Atwood, J. M. Murabito, D. Levy, M. E. Mendelsohn, D. E. Housman, and A. M. Shearman Sex-Specific Association between Estrogen Receptor-{alpha} Gene Variation and Measures of Adiposity: The Framingham Heart Study J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6257 - 6262. [Abstract] [Full Text] [PDF]
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N. R. Miller, T. Jover, H. W. Cohen, R. S. Zukin, and A. M. Etgen Estrogen Can Act via Estrogen Receptor {alpha} and {beta} to Protect Hippocampal Neurons against Global Ischemia-Induced Cell Death Endocrinology, July 1, 2005; 146(7): 3070 - 3079. [Abstract] [Full Text] [PDF]
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E. Kellokoski, S. M. Poykko, A. H. Karjalainen, O. Ukkola, J. Heikkinen, Y. A. Kesaniemi, and S. Horkko Estrogen Replacement Therapy Increases Plasma Ghrelin Levels J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2954 - 2963. [Abstract] [Full Text] [PDF]
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L. A. Eckel, T. A. |
