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ELSEVIER
SSDI 0031-9384(95)02168-X
Physiology & Behavior, Vol. 59, Nos. 4/5, pp. 925-929, 1996
Copyright © 1996 Elsevier Science Inc.
Printed in the USA. All rights reserved
0031-9384/96 $15.00 + .00
Liver Denervation Attenuates the Hypophagia
Produced by an Imbalanced Amino Acid Diet
LARRY L. BELLINGER, *~ FRED E. WILLIAMS,* QUINTON R. ROGERSt§ AND DOROTHY W. GIETZEN~§
*Department of Biomedical Sciences, Baylor College of Dentistry, 3302 Gaston Avenue, Dallas, TX 75246 USA,
~Department of Molecular Biosciences, $Department of Anatomy, Physiology and Cell Biology, School of Veterinary
Medicine, and §Food Intake Laboratory University of California, Davis, CA 95616 USA
Received 8 March 1995
BELLINGER, L. L., F. E. WILLIAMS, Q. R. ROGERS AND D. W. GIETZEN.
Liver denervation attenuates the
hypophagia produced by an imbalanced amino acid diet.
PHYSIOL BEHAV 59(4/5) 925-929, 1996.--We observed
previously that totally liver denervated (TLD) rats consumed more of an imbalanced amino acid diet (IAAD) than
sham-operated controls (CON). For the present study rats were either CON, TLD, had only the hepatic-vagal branch
cut (HVX), or had all nerves on the hepatic artery and portal vein removed (HAPV) (n = 10-11). The rats were
prefed a purified basal diet for 9 days then switched to an isoleucine IAAD for 7 days. On days 2-5 all experimental
groups consumed more (p < 0.05) of the IAAD than the CON; they also showed less (p < 0.01) weight loss on days
3-7. This experiment showed that either total or partial liver denervations enhanced the intake of an IAAD compared
to CON. However, when one considers the anatomical arrangement of the nerves and the surgery technique employed
the vital neural pathway may involve the hepatic vagal branch.
Amino acid imbalance Amino acid deficiency Food intake Body weight Rat
RATS have the ability to perceive slight decreases of a single
essential amino acid in their diet and show an attenuated intake
of an imbalanced amino acid diet (IAAD) as soon as 0.5 h after
IAAD presentation (1,11,12,14). After several days of very low
consumption of an IAAD the rats begin to consume more of the
diet; food intake gradually returns to normal by day 6 or 7. Thus,
there is an initial recognition phase where consumption of the
IAAD is low and this is followed by a gradual increase in the
consumption of the IAAD (11). Recent work (11) has explored
the neural mechanisms mediating the anorectic response of rats to
IAAD. These studies have contributed to a description of the
neurochemical mechanisms in specific areas of the brain that are
thought to mediate the anorectic response. Both the nore-
pinephrine systems, in the prepriform cortex and ventromedial
hypothalamus, and the serotonin (5-HT 3) systems, more gener-
ally, appear to be activated when animals eat IAAD (11).
Some forms of anorexia have been associated with develop-
ment of conditioned taste aversion (CTA), and the anorectic
response to IAAD also probably involves the development of
CTA (13). Interestingly, the 5-HT 3 receptor may be involved in
the development of aversion to an IAAD (28). Support for an
involvement of the 5-HT 3 receptor comes from the finding that
blocking 5-HT 3 receptors increases the consumption of the IAAD
(3,11,15).
A study by Washburn et al, (32) found that rats given bilateral
subdiaphragmatic vagotomies increased their intake of an IAAD
on the first day of diet exposure, but not to the extent achieved by
5-HT 3 receptor blockade. After vagotomy the 5-HT 3 blockers
were less effective in increasing the rats' intake of an IAAD. It
was unknown which vagal pathway was responsible for these
effects [hepatic vagal branch (HVB), right or left gastric branches,
or coeliac/accessory coeliac branches or some combination
thereof]. However, the portal vein and liver have been suggested
to be part of amino acid recognition because amino acid respon-
sive afferent fibers come from these areas (26). Hepatic vagal
afferents have also been suggested to influence rats' taste percep-
tion and their subsequent diet selection (18,30).
Subsequently, involvement of the liver in the feeding response
to an IAAD was suggested by a study (3) in which total hepatic
denervated (TLD) rats were used to determine whether: 1) the
innervation of the liver was important in the rats' normal hy-
pophagic response to IAAD, and 2) hepatic innervation was
involved in ability of 5-HT 3 receptor blockers to attenuate the
hypophagia normally induced by an IAAD. The results suggested
that liver innervation was not required for the initial recognition
phase [but see (34) and below] and that the 5-HT 3 blocker's
attenuation of the hypophagia induced by IAAD apparently did
not require liver innervation. However, the TLD rats, after being
t To whom requests for reprints should be addressed.
925
926 BELLINGER ET AL.
on the IAAD for 2 days, consumed significantly more of the
IAAD than did the sham-operated group. This showed that, when
compared to intact animals, rats without hepatic afferent/efferent
innervation (via the HVB, hepatic artery-portal vein, or both)
increased their intake of the IAAD. These results further indi-
cated that the enhanced consumption of the IAAD after 2 day's
exposure of rats with bilateral subdiaphragmatic vagotomy (32)
might be specifically attributed to liver denervation. As noted
above, hepatic innervation was apparently not involved in the
ability of the 5-HT 3 antagonist to attenuate the hypophagia of rats
on IAAD. Therefore, extrahepatic vagal innervation may be
involved in the action of the 5-HT 3 antagonist on the first day of
IAAD ingestion. The present study was undertaken to ascertain
which neural pathway to the liver was important in increasing the
rat's intake of an IAAD.
METHOD
Male Sprague-Dawley rats were purchased from Harlan In-
dustries (Houston, TX), and upon arrival were housed individu-
ally in a temperature-controlled room (23°C) under a 12:12 h
light:dark cycle with lights out at 1300 h. Rats were given Purina
rat chow #5012 and water ad lib unless otherwise indicated.
For surgery the rats were anesthetized with ketamine (90
mg/kg) and xylazine (9 mg/kg) and divided into four groups
that received either: 1) sham operation (SHAM) (n = 10); 2)
HVB transection (HVX), that is, the hepatic vagal branch was
visualized, isolated, and severed by electrocautery, as well as all
connective tissue between the esophagus and liver (n = 10); 3)
hepatic artery-portal vein (HAPV), that is, the hepatic artery was
isolated tied and severed, all connective tissue attachments be-
tween the artery and portal vein were broken, the portal vein and
bile duct were stripped of all loose connective tissue and nerves,
and lastly the surgical areas were treated with a 9% phenol
solution in 47% ethanol (n = 15); and 4) TLD (n = 15) (i.e., a
combination of 2 and 3; [see 2] for further details). Following
surgery, the rats were given chow for 2 days and then presented
with a purified low protein basal diet (3), which supplies approxi-
mately 50% of required protein, and in which isoleucine is the
growth limiting amino acid (Table 1). The basal diet was utilized
because rats demonstrate a dramatic and reliable suppression of
food intake (an anorectic response) when subsequently switched
to an isoleucine imbalanced diet (12). Food intake, corrected for
spillage, was recorded on the 10th day of receiving the basal diet.
The rats were then switched to the IAAD [(11), Table 1] and food
TABLE 1
COMPOSITION OF DIETS USED IN THE EXPERIMENT
Isoleucine Diets % of Diet by Weight
Ingredients Basal lmbalanced
Dispensable amino acid mixture 8.08 8.08
Indispensable amino acid mixture 3.65 3.65
Imbalanced amino acid mixture 9.86
Vitamin mixture 1.00 1.00
Salt mixture 5.00 5.00
Corn oil 5.00 5.00
Sucrose 25,72 22.43
Cornstarch 51.45 44.88
Choline chloride 0.10 0.10
Total 100.00 100.00
For details of diets see references cited in (11); amino acids from
Ajinomoto U.S.A., Inc.
consumption was recorded daily for 7 additional days. Body
weights were recorded throughout the study. The rats were then
killed with an overdose of pentobarbital and completeness of
TLD and HAPV denervations determined by glyoxylic acid
histofluorescence method (2). Completeness of HVX was verified
using a dissecting microscope (45 × ).
Only those animals completely denervated were included in
statistical analyses. Data were analyzed by one-way ANOVA and
two-way ANOVA for repeated measurements, Duncan's multiple
range test, and Student's t-test.
RESULTS
Three rats died shortly after surgery, and histology on two
HAPV and three TLD showed the presence of catecholamine
neurons. These rats were eliminated from the study, which left:
SHAM, n= 10; HVX, n= 10; HAPV, n= 11; and TLD, n = 11.
The body weights of the groups were similar at the time of
surgery [SHAM, 227.9+ 6.7 g vs. HVX, 231.5 4-5.6 g, NS;
HAPV, 234.6 4- 4.0 g, NS; TLD, 231.9 4- 3.6 g, NS, F(3, 41) =
0.03, NS] and when started on the IAAD [SHAM, 260.4 4- 6.6 g
vs. HVX, 257.4 4- 5.7 g, NS; HAPV, 264.4 4- 5.0 g, NS; TLD,
251.6 4- 5.3 g, NS, F(3, 41) = 0.95, NS]. The consumption of the
basal diet the day before switching to the IAAD was similar
among the groups [SHAM, 23.2 4- 0.9 g; HVX, 21.3 4- 0.6 g;
HAPV, 22.7 4- 1.2 g; TLD, 23.0 4- 1.2 g, F(3, 41)= 0.62, NS].
After presentation of the IAAD the intake of the IAAD was
expressed as a percentage of that rats' basal intake (Fig. 1) and
ILl
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130%
120%
110%
100% I
90%
80%
70%
60%
50%
40%
30%
T , ~ --o-- SHAM
~, . ,/'~E, / T T/ --A-- HART
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1 ±
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1 2 3 4 5 7
DAYS
FIG. 1. Food intake (grams) after switching from imbalanced amino acid diet. Significant (* p < 0.05, ** p < 0.01) differences from SHAM: HVX, days
3 and 4; HAPV, days 2-5; TLD, days 2-5.
LIVER DENERVATIONS AND IMBALANCED AMINO ACID DIET 927
O9
O9
O
._1
I---
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-10
-15
-20
-25
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1 2 3 4 5 6 7
DAYS
FIG. 2. Body weight change (gms) after switching from basal diet to
imbalanced amino acid diet. All experimental groups significantly (**p
< 0.01) different from SHAM group on days 3-7. All other group
comparisons were not significant.
the groups compared. There was a significant group effect, F(3,
38) = 4.60, p < 0.01, and time effect, F(6, 228) = 84.62, p <
0.001, whereas the interaction was not significant, F(18, 266)=
0.77, NS. Further analyses revealed that the food consumption of
all the experimental groups was significantly (p < 0.05-0.01)
enhanced over the SHAM group on days 2-6 for HVX and on
days 2-5 for HAPV and TLD. None of the experimental groups
differed from each other on any day. In general body weight
changes (Fig. 2) reflected the food intakes, in which there was a
significant group effect, F(3, 38) = 6.28, p < 0.01, time effect,
F(6, 228) = 44.01, p < 0.001, and interaction, F(18,228) = 2.90,
p < 0.001. Post hoc comparisons among the group means indi-
cated that the body weight of the SHAM group was significantly
(p < 0.01) more attenuated than each of the experimental groups
on days 3-7, whereas the body weight changes in each of the
experimental groups were similar.
DISCUSSION
Liver denervations, both total and partial, have repeatedly
been shown not to affect the ad lib intake of rats given a variety
of diets including: chow, milk diet, 15% fructose-water solution
plus chow, 30% sucrose-water solution plus chow, 32% sucrose-
chow diet, 5% glucose-water solution plus chow, or a 33%
Crisco-chow diet (2,4-6). Also similar between liver denervated
and sham-operated rats were meal patterns of chow intake and
first meal size postdenervation of an oil and chow choice, first
meal of a 15% fructose-water solution, or first meal of a com-
plete liquid diet (2,4). Furthermore, liver-denervated rats respond
like controls when given a variety of diets including both high-
and low-protein diets (2,4,6). Subsequent weight gains of the
liver-denervated and sham-operated rats were similar in all the
above cases.
Nevertheless, the present study demonstrates that partial or
TLD in rats does affect their intake of an IAAD. On the first day
of exposure to the IAAD all the experimental groups ate more
than the sham-operated group; however, a significant difference
was not reached until the next day. The results for the TLD group
are complementary to and in accord with our previous results (3).
There appear to be at least three phases in the rat's response
an to IAAD: 1) recognition by the rat that the diet is imbalanced,
2) following recognition a conditioned taste aversions develops,
and 3) in the absence of dietary choices the animal adapts to the
IAAD over a course of days (11). The anterior piriform cortex
appears to be the primary chemosensor, in that it recognizes the
amino acid deficiency that is induced in the brain shortly after
ingestion of an IAAD. The increased levels of the amino acids
added to the diet that cause the imbalance are not seen in the
brain, but they do cause competition at the blood-brain barrier
(29). Thus, the effect in some, but not all brain areas, is a rapid
drop in the concentration of the dietary limiting amino acid (11).
Our most recent data with C-Fos (Wang et al., in press) suggests
that the signal caused by the amino acid deficiency in the
piriform cortex (within 2 h of presentation of the IAAD) is
transmitted to the infralimbic cortex "autonomic motor cortex"
and then to the dorsomedial hypothalamic nucleus at 2 h and then
to the central nucleus of the amygdala by 3 h. In the present
study, transection of the nerves to/from the liver did not influ-
ence the rat's early recognition that the diet was imbalanced. The
early recognition that the diet is imbalanced may take place and
be processed at the above-mentioned central sites, whereas liver
denervation enhanced the rat's later adaptation to the IAAD.
Notably, the IAAD consumption of the HVX, HAPV, and
TLD groups was similar throughout the study. A cursory inspec-
tion of the results would suggest that loss of afferent/efferent
fibers travelling with either the mainly parasympathetic HVB or
the mixed sympathetic/parasympathetic branch on the hepatic
artery could account for the attenuating the hypophagia normally
seen in intact rats ingesting an IAAD. Although this might be
true, one also has to consider the pathways by which the neurons
travel and the surgery technique. Berthoud and colleagues (8)
have recently reported that the HVB afferents were not found in
association with liver parenchymal cells, but rather innervated the
biliary system. They further noted that two-thirds of the afferents
bypass the liver and course over the hepatic portal vein on their
way to innervate the hepatic portal vein, pancreas, stomach,
pylorus, or the duodenum. Hepatic vagal branch efferents were
also not found in the liver parenchyma (but see enzyme studies
below) and tended to follow the afferents. If the HVB fibers
(afferent/efferent) are important for the rat's response to the
IAAD and travel either to the portal vein or by way of the portal
vein to the pancreas, stomach, or duodenum, then both the HVX
and HAPV surgeries in the present study should have removed
these HVB neurons. This could account for the fact that the food
intake responses following HVX or HAPV were the same and
not additive in rats that received TLD.
It should be noted that in a previous study using TLD, when
compared to sham-operated rats, the denervated group did not
show a significant increase in consumption of IAAD until the
second day of diet exposure. However, in the present study on
the first day of IAAD exposure there was a trend for the
denervated rats to consume more of the IAAD than the control
animals. This could be due either to decreased recognition that
the diet was an IAAD or a subsequent enhanced ingestion of the
IAAD. Similarly, Bellinger et al. recently reported (7) that rats
with the anterior vagal trunk transected above the HVB, but not
distal to the HVB (see below), and presented with the same
IAAD used in the present study, were consuming significantly
more of the diet, as early as 9 h after diet introduction, than
sham-operated rats. This time course is similar to that seen with
total subdiaphragmatic vagotomy (32). This again suggests that
liver denervation is not influencing the initial recognition (i.e.,
prior to 9 h of diet exposure) of the IAAD, but rather is
enhancing the normal adaptation to the IAAD that occurs in
intact rats. In this same study, severing the posterior vagal trunk
resulted in no early increase in consumption of the IAAD.
Interestingly, in another study Wiggins et al. (34) showed when
the anterior trunk was severed below the HVB the rats showed no
928 BELLINGER ET AL.
early enhanced ingestion of the IAAD. This indicates that the loss
of the HVB is important for attenuating the IAAD hypophagia.
Because the attenuation was seen somewhat earlier after cutting
the anterior trunk above the HVB than after HVB transection
alone, it does not preclude that the loss of afferent/efferent
anterior vagal fibers below the HVB (i.e., right gastric and
accessory coeliac branches) may act synergistically with the loss
of HVB fibers to potentiate the early increase in consumption of
an IAAD.
Just how the loss of innervation increases the intake of rats
ingesting the IAAD is uncertain. Whether this response is due to
loss of afferent or efferent fibers (or both) is also unclear. HVB
afferents have been found that respond to glucose, alanine,
leucine, and glycine (21,24,26). These afferents affect reflex
insulin and glucagon secretion with HVX enhancing the secretion
of both hormones when arginine is given to the rat IP (19,21,27).
Insulin is well known to affect protein metabolism and food
consumption.
It has been established that the response of the liver to IAAD
in rats prefed a low-protein (the BAS) diet is an initial increase in
protein synthesis (12). Synthesis is attenuated when the concen-
tration of the limiting amino acid is insufficient for further
protein formation. This time point coincides with the time of the
initial depression of food intake [see (11)]. Subsequently, the
availability of the limiting amino acid is substantially decreased
in the brain, because of the severely decreased concentration of
the limiting amino acid in the plasma and an increase in competi-
tor amino acids at the blood-brain barrier (29). As mentioned
above liver denervation did not affect the early recognition that
the diet was imbalanced. However, the early increase in ingestion
of the IAAD by the denervated rats may depend on adaptation of
the catabolic enzymes [increases in enzyme activity (10)], along
with altered feeding patterns that decrease the continued influx of
the imbalanced mix of amino acids (12).
As previously noted (3), if continued protein synthesis was
not stimulated or of a normal magnitude in the liver of the
denervated animals in response to the influx of the amino acids in
the imbalanced mix, the dramatic reduction of the limiting amino
acid would not be as great and the imbalanced feeding response
would be blunted. This is possible following hepatic denervation
[but see (8)] because the hypothalamus, via autonomic innerva-
tion to the liver, has been implicated in protein and DNA
synthesis (i.e., parasympathetic efferents increase and sympa-
thetic efferents decrease both protein and DNA synthesis)
(16,17,33,35). Autonomic efferents to the liver have also been
shown to affect the activity of hepatic enzymes including: trypto-
phan pyrrolase, tyrosine transaminase, aspartate transcarbamoy-
lase, and thymidine kinase (9,16,20,25,31).
Hepatic vagal afferents have also been implicated in taste
perception (18,30) and subsequent diet selection in the rat. Sweet
and protein taste perceptions cause enhancement of both hepatic
and pancreatic parasympathetic efferent activity with sweet taste
perception and also result in decreased activity in the splanchnic
nerves to the liver, pancreas, and adrenals (22,23). Thus, it is
possible that autonomic afferent input from the liver could play
some role in the learned responses to the IAAD diets. Hepatic
glucoreceptors have also been implicated in the reflex secretion
of pancreatic and adrenal hormones, which could have indirectly
promoted the consumption of the IAAD. Taken as a whole, the
present results indicate that loss of innervation that courses to,
from, or through the liver-portal vein region causes an increased
ingestion in rats presented with an IAAD. The full physiological
mechanisms that resulted in the attenuation of the hypophagia
normally seen after ingestion an IAAD remain to be elucidated.
Finally, from a practical point of view the ability of generalist
feeders to compose a diet from natural foods, that meets their
nutritional needs, is an important adaptation when they forage
foods that may be deficient or imbalanced in some nutrients.
Recognition of the deficiency or imbalance can lead to a search
for other food types. Adaptive mechanisms also serve to prevent
the ingestion of excess amino acids. From a clinical view defi-
ciencies and imbalances may occur when people take amino acid
supplements in the hope that they will improve their health, body
composition, memory, strength, etc. Moreover, unless their diet
selection is knowledgeably made individuals on vegetarian diets
may also suffer from imbalances or deficiencies. Accordingly,
the IAAD has been used to study the responses to plasma amino
acid deficiencies in omnivores, particularly in rodents and birds
[reviewed in (11)]. Whether these responses are mediated cen-
trally or peripherally (or both) has been a matter of interest over
the years. The present data do suggest a role for the hepatic vagal
branch (this name may be a misnomer, because this branch also
reaches the portal vein, pancreas, stomach, and small intestine as
well as the liver) in the adaptation to an IAAD that occurs in the
absence of food choices. Clearly, maintenance of essential amino
acid precursors for protein synthesis is an important homeostatic
mechanism, and would be expected to be subserved by multiple
systems, such as periphery-brain interactions. These interactions
will provide an important focus for future studies.
ACKNOWLEDGEMENTS
The authors wish to thank Mrs. Connie Tillberg, Mr. Gerald Hill,
Mrs. Brenda Anderson, Mr. George Dula, and Mr. Dan Wong for
technical assistance, and Mrs. Teresa Thompson for typing the manuscript.
Supported in part by NIH DK42274 to D.W.G., and Baylor University
and Baylor College of Dentistry Research Funds.
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