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Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556
3To whom correspondence and reprint requests should be addressed.
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ABSTRACT |
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 TOP ABSTRACT Zinc deficiencyFuture directions and priorities...REFERENCES |
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KEY WORDS: • zinc deficiency • anorexia • food intake • neuropeptide Y • galanin • leptin
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Zinc deficiency |
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TOPABSTRACTZinc deficiencyFuture directions and priorities...REFERENCES |
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). Symptoms reported to accompany
zinc deficiency included dwarfism, hypogonadism and poor appetite. In
these studies, similarities were noted between zinc-deficient human
subjects and known characteristics of zinc-deficient animals.
Although zinc deficiency has been studied in many different species,
including rats, pigs, chicks, lambs, monkeys and guinea pigs, studies
in the rat have provided most of the experimental data regarding zinc
deficiency and changes in food intake. The young growing rat is very
responsive to the consumption of a zinc-deficient diet. Within 3–5
d, food intake is first observed to decrease. This decrease in appetite
is the first visible sign of zinc deficiency, and it occurs well in
advance of any other symptoms associated with zinc deficiency. The
reduction in growth associated with zinc deficiency is largely caused
by the reduction in intake due to this deficiency. This is demonstrated
as pair-fed control rats that are provided a reduced amount of
zinc-adequate diet equivalent to the amount consumed by similar
zinc-deficient rats reduce or cease growth in an essentially
similar fashion, as do the deficient rats. Although there are usually
slight differences in food efficiency, with pair-fed rats having a
slightly greater efficiency compared with zinc-deficient rats, this
difference is usually very slight.
Among many, there are two classic studies we mention that provide an
excellent summary of the early findings regarding the effect of zinc
deficiency on food intake (Chesters and Quarterman, 1970
, Chesters and Will, 1973
). These findings
include the reduction in intake during zinc deficiency, identification
of a 3–4 d cycle of variable intake (described in detail by
Tamaki et al. 1995
), force-feeding zinc-deficient
rats is detrimental to their health, reduction in the protein content
(or content of essential amino acids) in the experimental diet can
affect levels of intake, zinc supplementation rapidly restores normal
levels of intake in rats and zinc-deficient rats eat fewer times
during the day, but when they do eat, they consume similar-sized
meals compared with control rats. A connection between zinc deficiency
and dietary protein or amino acid levels may exist; however, a complete
theory describing how zinc deficiency and protein metabolism are
related is still lacking.
Anorexia and zinc deficiency in humans.
Although it is clear that zinc deficiency produces a specific and
profound anorexia in experimental animals, the connection between zinc
deficiency and human anorexia is less certain. This connection is
difficult to advance as a predictive or initiating factor in the
development of human anorexias such as anorexia nervosa
(AN)4
typically observed in teenagers and in the
anorexia associated with failure-to-thrive syndrome of older people.
However, in human populations characterized as zinc deficient, such as
the Middle Eastern populations characterized by Prasad et al. (1963
) and populations of American children identified by
Hambidge et al. (1972
), a correlation has been
established among zinc status, growth and appetite. It has been
suggested that zinc deficiency contributes to the symptoms of AN. Many
of the features of zinc deficiency are observed in AN patients,
including the anorexia, poor growth or weight loss, skin abnormalities,
amenorrhea and depression. The use of zinc supplementation in the
treatment of AN was advocated by Bakan (1979
,
1984
). Clinical studies indicated that approximately
half of all AN patients tested are zinc deficient (Casper et al. 1980
, Humphries et al. 1989
, Nishi 1980
) and that absorption of dietary zinc is diminished during
AN (Dinsmore et al. 1985
). The dietary (Bakan et al. 1993
) and activity (Casper et al. 1991
)
patterns of AN patients may increase their susceptibility to zinc
deficiency. During recovery from AN, sufficient zinc must be available
to support growth if normal body weight is to be restored. In open
trials, zinc supplementation has been shown to improve weight gain in
AN patients (Bryce-Smith and Simpson 1984
, Esca et al. 1979
, Humphries et al. 1990
,
Safai-Kutti 1990
, Yamaguchi et al. 1992
).
In a randomized, double-blind, placebo-controlled trial, a daily
supplement of 14 mg zinc from zinc gluconate was found to double the
rate of body mass increase (P < 0.03) compared with
patients receiving the placebo control (Birmingham et al. 1994
). AN is a complex disorder, with contributions coming from
psychological aspects, nutritional deficiencies and genetic
predisposition perhaps due to defective gene products involved in the
appetite regulation system. Two points are important to recognize with
respect to anorexia in humans. First, the contribution to anorexia from
a variety of nutrient deficiencies is likely an accelerating or
exacerbating factor. Although zinc deficiency is very likely involved,
we suggest that other nutrient deficiencies may be playing an important
role in the development of or intensification of anorexia. Most
notably, thiamin may be implicated. Similar to zinc, thiamin deficiency
produces a specific and intense anorexia in experimental animals (see, e.g., Rains et al. 1997
). An extended period of
voluntary food restriction for any reason must increase the risk of
developing marginal or substantial deficiencies for zinc, thiamin and
other nutrients. Second, it appears that the connection between zinc
deficiency and anorexia in humans may be largely unappreciated or
underestimated. Although many clinicians with an interest in nutrition
appreciate the connection between nutrient deficiencies and anorexia
(Bakan 1984
, Birmingham et al. 1994
,
Humphries et al. 1989
, 1990
,
McClain et al. 1992
), many others may not consider
nutrient deficiencies as a important factor in eating disorders. A
recent review highlighted recent progress in the understanding and
treatment of AN and bulimia nervosa (Walsh and Devlin 1998
). Although Walsh and Devlin (1998)
discussed the possibility that there may be a genetic component to AN,
we disagree that there is a lack of an appropriate model to study
anorexia. Rodent models using exercise-induced anorexia
(Ararich et al. 1995
, Dwyer and Boakes 1997
) are an option in addition to the nutrient deficiency
model described in this review. The recent explosion in the
identification of molecular factors involved in obesity and body weight
regulation will, we hope, provide insight pertinent to anorexia. Taken
together, the contributions of nutrient deficiencies and genetics to
the initiation and progression of anorexia in humans will be better
understood because of these discoveries.
Appetite regulation.
The appetite regulation system consists of both peripheral and central
systems. Feedback from the periphery to the brain involves neural
feedback, e.g., by the vagus nerve, as well as blood-borne factors,
including both metabolites and hormones, which can affect brain
function. We have chosen to focus on the central effects of zinc
deficiency within the appetite regulation system. This focus is not
intended to discount the contribution of the periphery to zinc
deficiency–induced anorexia. Indeed, many investigators have shown the
effects of zinc deficiency on the physiology of the intestine, adipose
and other tissues that may ultimately provide a signal to the brain
that is transduced to anorexia (see, e.g., Taneja and Arya 1992
). However, a broad hypothesis guiding our research is that
regardless of whether the primary lesions of zinc deficiency are
peripheral or central, the signals to reduce intake are ultimately
integrated or coordinated by central mechanisms. This has been the
rationale for the research from our laboratory that focuses on central
effects during zinc deficiency.
In the 1970s, it was determined by Wurtman, Fernstrom and colleagues
that dietary concentrations of tyrosine and tryptophan could affect the
synthesis and concentrations of the neurotransmitters norepinephrine
and serotonin. In turn, the diet-affected central concentrations of
these neurotransmitters could affect the relative appetite/satiety
state of an individual (Fernstrom et al. 1973
,
Fernstrom and Wurtman 1972
, 1974
,
Gibson and Wurtman 1976
, Wurtman et al. 1974
, 1978). These findings spurred nutrition
researchers to connect zinc deficiency, dietary amino acid intake and
anorexia (discussed later). In 1980 it was reported that norepinephrine
had a profound influence on feeding behavior within specific sites in
the hypothalamus. Leibowitz and Brown (1980
) reported
that the predominantly inhibitory neurotransmitter norepinephrine had a
strong stimulatory effect on food intake. When exogenous norepinephrine
was delivered to the paraventricular nucleus (PVN) of the hypothalamus,
short-term food intake increased.
Later in the 1980s, neuropeptides were also discovered to have a
profound impact on feeding behavior. In 1982, neuropeptide Y (NPY) was
first isolated from neural tissue within the porcine intestine
(Tatemoto et al. 1982
). Soon after, NPY was found to
have significant stimulatory effect on food intake (Clark et al. 1984
). Although NPY may be synthesized by all neurons within
the body, it is synthesized at very high levels within cell bodies
derived in the arcuate nucleus of the hypothalamus. A high percentage
of these neurons project to the PVN of the hypothalamus. Within the
PVN, exogenously administered NPY has been demonstrated to stimulate
appetite to a greater degree than any other agent yet tested, when
considered on a molar basis (Paez and Myers 1991
).
Interestingly, it was also found that the administration of NPY to the
PVN specifically stimulated carbohydrate intake when rats were allowed
to freely select from a three-choice macronutrient diet system
(Stanley et al. 1985
). Some investigators have also
suggested that the results demonstrating an effect of NPY on
macronutrient preference may be influenced by the past history or
dietary preferences of rats chosen for study (Welch et al. 1994
). Even specifics of the diet ingredients used in
macronutrient choice studies may influence the results obtained
(Glass et al. 1997
). Because of its very potent effect
on food intake, NPY has been investigated very vigorously at many
laboratories. Targets of research have included the effects of NPY, the
development of agonists and antagonists of NPY and the identification
and study of NPY receptors. The development of an NPY antagonist with
an appetite-modulating activity is of interest to pharmaceutical
concerns. Consistent with the complex nature of the appetite regulation
system, NPY has proved to be a difficult target to study. First, it has
been found that there are a family of NPY receptors, and it is still
unclear whether a single NPY receptor or a subset of a few receptors
mediate the appetite-generating effect of NPY (Gerald et al. 1996
). Second, the NPY knockout mouse regulates food intake in
a relatively normal fashion (Erickson et al. 1996a
).
This has led some to suggest that the large set of physiological
studies investigating the effect of NPY on food intake may need to be
reconsidered (Palmiter 1998
). A possible explanation for
normal appetite in the NPY knockout mouse is that NPY action may be
accommodated for by other neuropeptides during development. The paradox
between physiological data and the NPY knockout results is of great
interest and is likely to be further investigated.
Other hypothalamic neuropeptides with a stimulatory effect on appetite
have been studied; these peptides include galanin and ß-endorphin,
which produce their stimulatory effect on appetite within the PVN of
the hypothalamus. In addition, galanin has been of interest because of
a proposed role in stimulating the preference for the consumption of
dietary fat (Temple et al. 1988
). There are a growing
number of factors to consider in the hypothalamic regulation of food
intake; most recently, these new factors include cocaine- and
amphetamine-related transcript (Kristensen et al. 1998
) and orexin-A and -B (Sakarai et al. 1998
). These newly identified factors are regulated with food
intake, have been shown to regulate food intake when exogenously
administered to the hypothalamus and appear to have a site of action
within the lateral hypothalamus. This site of action contrasts with
NPY, galanin, ß-endorphin and pro-opiomelanocortin, which have a
site of action within the PVN. Other important hypothalamic
neuropeptides recognized as a part of the hypothalamic regulatory
system include corticotropin-releasing hormone, which may be an
important antagonist of NPY in the PVN, as well as
melanocyte-stimulating hormone (
-MSH) and melanocortin receptors
such as MC4-R. Readers are referred to the minireview of Flier and Maratos-Flier (1998
) for an excellent overview that
integrates how the most recently discovered factors fit into a proposed
hypothalamic regulatory system.
Along with the sizable numbers of hypothalamic factors identified in
recent years, the discovery of leptin (Zhang et al. 1994
) from the obese (Ob) mutant mouse
(Ingalls et al. 1950
) has proved to be of importance if
appetite regulation in the hypothalamus is to be completely understood.
Leptin is a peptide that is produced by adipose tissue and is involved
in appetite regulation and body weight maintenance via the regulation
of hypothalamic factors. Apparently, leptin travels through the
bloodstream, is transported across the blood-brain barrier and
produces effects in the brain after binding to specific leptin
receptors located in the hypothalamus (Tartaglia et al. 1995
). Leptin was found to change NPY levels in the
hypothalamus. High levels of leptin, presumably reflecting high or
adequate levels of body fat, were found to down-regulate
hypothalamic NPY mRNA and NPY levels, which in turn suggests a decrease
in appetite in response to the signal of adequate body energy reserves
(Erickson et al. 1996b
). Similarly, low levels of leptin
relate to higher NPY levels, likely stimulating intake to restore
energy reserves. However, as the NPY knockout mouse responds to leptin
injections with satiety, there must be other targets for leptin in the
hypothalamus in addition to NPY. It was subsequently shown that
galanin, melanocyte-concentrating hormone, neurotensin and
pro-opiomelanocortin are regulated by leptin in addition to NPY
(Sahu 1998
). Dysregulation of leptin during zinc
deficiency has the potential to affect both central and peripheral
physiology, in that leptin receptors have been identified within
reproductive tissues of the body (Zamorano et al. 1997
).
This connection may ultimately help us to understand the role of zinc
deficiency in reproductive dysfunction.
Zinc deficiency and the regulation of food intake.
Beginning in the early 1970s, a large number of studies investigated a
possible link between dietary protein or amino acid intake and the
anorexia that accompanies zinc deficiency. In early studies
(Chesters and Quarterman 1970
, Griffith and Alexander 1972
), it was shown that lower protein diets appeared
to reduce the magnitude of cycling associated with zinc deficiency,
mainly by increasing intake during the day of minimal intake within the
cycle. However, Griffith and Alexander (1972
) also
reported that the patterns of plasma amino acid concentrations are
changed by zinc deficiency, regardless of dietary protein level. It was
later reported that concentrations of norepinephrine in an extract
derived from whole brain were higher in extracts prepared from
zinc-deficient than in those from zinc-adequate rats
(Wallwork et al. 1982
). Others (Reeves and O’Dell, 1981a
, 1981b
) reported no differences
in catecholamine levels in whole brain, although samples representing
only the hypothalamus were reported as different. Within the brain,
Reeves and O’Dell (1981a
, 1981b
) found
no differences in brain levels of tyrosine, tryptophan, catecholamines
or serotonin. In contrast, Wallwork and Sandstead (1983
)
reported an inverse relationship between tyrosine levels and food
intake in zinc-deficient rats. In their study, they found no
correlation between tryptophan levels and food intake. In their report
of 1984, Reeves and O’Dell proposed a relationship between zinc
deficiency and catecholamines that suppresses food intake.
Kasarkis et al. (1986
) also reported increases in
norepinephrine concentrations in rats fed a zinc-deficient diet for
10 d but not after 4 d of diet treatment. It is unclear from
their report whether food intake was already different at day 4,
because food intake was reported cumulatively from days 0–4 and 5–10.
Kasarkis et al. (1986
) also presented data that
inversely correlated concentrations of plasma zinc with changes in food
intake. In their review of 1989, O’Dell and Reeves concluded that
changes in intake occurred either as a direct result of changing plasma
zinc concentrations or indirectly through other agents, including
catecholamines, peptides and amino acids.
One important limitation to many of the studies mentioned was that concentrations of brain metabolites, such as amino acids or catecholamines, were determined as a concentration obtained from a homogenate of excised tissue obtained after animals were killed. When considering the effect of catecholamines, for example, it is important to consider active secretion from tissue in addition to total tissue content. If a cellular defect due to zinc deficiency resulted in an impairment of the secretory process, for example, the methods previously described would be unable to detect this result. In fact, if the process of secretion was impaired, it is possible that neurons might attempt to compensate for a reduced effect of catecholamine secretion by increasing the cellular synthesis of these factors. Tissue homogenate would then incorrectly reflect catecholamine effect during zinc deficiency. In these earlier studies, the contribution of receptors to cellular physiology is largely ignored.
An important series of studies was published in 1984 (Essatara et al. 1984a
, 1984b
, 1984c
) in
which techniques more appropriate to neurobiological studies were used.
Although one of these reports is a more traditional, descriptive study
characterizing food intake (Essatara et al. 1984c
), the
two reports used live rats, and their response to exogenously
administered compounds was determined. In Essatara et al. (1984a
), the effect of exogenously administered dynorphin was
tested in zinc-deficient and zinc-adequate rats. Dynorphin is a
opioid peptide that induces spontaneous feeding in the rat after
intracerebroventricular infusion. Zinc-adequate rats responded with
a dose-dependent increase in spontaneous feeding after the infusion
of 1 and 10 µg of dynorphin into the right ventricle of the rat
brain. Zinc-deficient rats were unable to respond to the infusion
of 1 µg of dynorphin and responded to the infusion of 10 µg
dynorphin less robustly than zinc-adequate rats. As a measure of
opiate peptide receptor sites, naloxone binding was quantified. It was
found there was a higher binding capability for naloxone in membranes
isolated from brain tissue derived from zinc-deficient rats. In
Essatara et al. (1984b
), the effect of central
administration of norepinephrine, the 
-aminobutyric acid agonist
muscimol and dopamine agonist bromergocryptine was evaluated in
zinc-deficient and control rats. All three compounds were either
less effective or unable to produce any stimulatory effect on feeding
in zinc-deficient rats. From both studies, Essatara and colleagues
suggested that the diminished response of zinc-deficient rats may
be due to reduced responsiveness of receptors in the brains of
zinc-deficient rats. Although only a very general mechanism is
proposed to explain their results, these studies are very important
because they demonstrate that mechanistic studies can be performed on
animals in vivo to investigate the effects of a nutrient deficiency on
normal physiology.
Our laboratory’s initial report investigating zinc deficiency and food
intake was a macronutrient selection study (Rains and Shay 1995
). This simple food intake study was motivated by the
macronutrient studies conducted to investigate the effect of centrally
administered factors on food intake. Many studies have used the
three-choice system, which allows rats to freely choose to eat from
three different food cups, each containing essentially pure
carbohydrate, protein or fat. The rat, by consuming a number of
different meals throughout the day, provides itself with a mixture of
carbohydrate, protein and fat that allows it to maintain health and to
grow at normal rates. Our Sprague-Dawley rats, when offered
three-choice diets containing adequate levels of zinc, choose a
very typical pattern of intake consisting of ~70% carbohydrate,
~15% protein and ~15% fat. When similar rats were provided the
three-macronutrient diets formulated to provide a deficient level
of zinc, the average intake of the group of zinc-deficient rats
decreased as expected. Unanticipated results showed that essentially
100% of the reduction in intake was due to reduced consumption of
carbohydrate. When zinc-deficient rats were repleted in
zinc, rats transiently increased protein intake for ~2–4
d after zinc repletion. The change in carbohydrate rather than protein
intake during zinc deficiency contrasts with the results of
Reeves and O’Dell (1981a
), who reported that rats fed a
zinc-deficient diet reduced their intake of protein when tested in
a two-choice system. In our three-choice studies, we found no
evidence of changes in protein intake during zinc deficiency; in fact,
protein was the most consistently consumed macronutrient during the
deficiency period compared with carbohydrate and fat. Because the
central administration of NPY has been shown to increase the intake of
carbohydrate, we hypothesized that the effect of NPY may be diminished
by zinc deficiency. We subsequently chose to study the regulation of
NPY during zinc deficiency.
Recently, we investigated food intake behavior of zinc-deficient
rats using a two-choice system similar to that described by
Reeves and O’Dell (1981
). We modified their design to
use egg white protein and mixtures of purified amino acids rather than
the soy protein used in their study. Interestingly, we found two major
differences between our studies and their prior work. First, we were
unable, under any conditions, to have Sprague-Dawley outbred rats
choose to eat a measurable amount of diet containing 50% protein.
Thus, after a series of pilot studies, we prepared two-choice diets
containing 10 or 30% protein (or amino acids) for rats to choose from.
Second, in four separate and complete trials, two each using egg white
protein and complete amino acid mixtures, we found no evidence that
rats can selectively decrease protein intake during zinc deficiency
(Shay et al. 1998).
Another study from our laboratory (Kennedy et al. 1998
)
reported the macronutrient preferences of individual rats. In
Rains and Shay (1995
), we expressed intakes as average
values of the zinc-deficient and zinc-adequate groups of rats.
However, during those studies, we noticed that some individual
zinc-deficient rats, but not zinc-adequate rats, developed a
very unusual preference for the consumption of fat. The studies
reported by Kennedy et al. (1998
) were dedicated to an
investigation of these changes in macronutrient selection patterns. The
preference for fat, at > 50% of total energy intake, was
observed in a subset (~25%) of zinc-deficient rats, and fat
preference was never observed in any zinc-adequate rat. However,
when this change in preference did occur, there were very significant
changes in food intake selection patterns, with some fat-preferring
zinc-deficient rats observed to consume > 90% of their total
calories from dietary fat. We subsequently identified a set of
zinc-deficient fat-preferring rats and assessed their macronutrient
intake patterns after normalizing their zinc status. We observed that
50% of the rats reversed their fat-preferring phenotype, but the
remaining rats continued preferring dietary fat for 5 wk after zinc
repletion, at which time the study was terminated. We speculated that
the results observed in these rats might suggest that periods of
nutrient deficiencies may cause permanent changes in food intake
behaviors, either due to learned responses or because of damage to
neurons caused by the nutritional deficiency itself. Whether this
speculation may be extrapolated to humans experiencing nutritional
deficiencies during a prolonged case of anorexia remains to be
demonstrated. We also noted in these studies that a few rats switched
from a carbohydrate- to a fat-preferring phenotype as soon as 1–2
d after beginning a zinc-deficiency trial. This switch in
macronutrient preference actually preceded the decrease in intake
caused by zinc deficiency, which suggests that the change in
macronutrient preference may not be linked to anorexia. These results
suggest that unusual food cravings or aversions observed in humans
might in fact be related to nutrient deficiencies. Because of the
relationship suggested by some to exist between preference for fat and
hypothalamic galanin, in the report of Kennedy et al. (1998
) we chose to measure hypothalamic galanin concentrations
in zinc-adequate rats and fat- and carbohydrate-preferring
zinc-deficient rats (discussed later).
We characterized NPY levels and responsiveness to NPY during zinc
deficiency (Lee et al. 1998
). Another report
(Selvais et al. 1997
) has also provided a great deal of
information regarding both NPY and galanin levels during zinc
deficiency. Hypothalamic galanin concentrations during zinc deficiency
were also reported in Kennedy et al. (1998
). Taken
together, these three studies provide a consistent description
regarding the regulation of NPY and galanin during zinc
deficiency–induced anorexia. With respect to NPY, Selvais et al. (1997
) reported higher levels of NPY mRNA (P
< 0.01) but not of NPY peptide levels in the hypothalamus of the
zinc-deficient rat. In the report from Lee et al. (1998
), NPY mRNA levels were ~100% higher (P
< 0.05) and NPY peptide levels were ~50% higher (P
< 0.01) during zinc deficiency. Neither study reported decreases
in NPY levels, which might be hypothesized to account for the reduced
intake observed during zinc deficiency. Differences in the strain of
rat, diet formulation, length of study and tissue dissection procedures
may account for the reported NPY peptide levels. Taken together, these
two reports suggest that an NPY "paradox" or "resistance" may
exist during zinc deficiency, in that NPY and NPY mRNA levels are
elevated yet a physiological situation characterized by low food intake
exists. There are possible several explanations for this apparent
resistance, such as impairments in the processing of pro-NPY into
active NPY, reduced secretion of NPY from neurons and an attenuation of
NPY signal transduction. There is some evidence that peptide processing
is zinc dependent (Pekary et al. 1991
). In Lee et al. (1998
), NPY-mediated food intake during zinc deficiency
was examined in vivo by delivering exogenous NPY to the PVN of
cannulated zinc-deficient and zinc-adequate rats. At doses of
0, 80 and 160 pmol NPY administered bilaterally to the PVN, we could
not detect differences in 1-h food intakes after the delivery of NPY to
zinc-deficient and zinc-adequate rats. However, in our pilot
testing, we observed that zinc-deficient rats were sensitive to
infusions of NPY of > 160 pmol. Although zinc-deficient rats
did not consume a greater amount of diet compared with
zinc-adequate controls at these higher doses, the deficient rats
appeared to be highly stressed by these doses of NPY. In light of our
results from these pilot tests, we restricted our doses of NPY to
160 pmol, whereas control rats would easily tolerate doses of
NPY up to 1000 pmol or more. In some ways, this stress response appears
to resemble the results reported by Chesters and Quarterman (1970
), who discovered that zinc-deficient rats fed normal
levels of diet by gavage did not tolerate this treatment well. The
administration of NPY and the stimulation of short-term food intake
in the zinc-deficient rat may be equivalent to the delivery of diet
by gavage.
Selvais et al. (1997
) also reported lower levels of
hypothalamic galanin mRNA (P < 0.001) but no
differences in galanin concentrations during zinc deficiency. In the
report of Kennedy et al. (1998
), galanin concentrations
in the PVN were ~120% higher (P < 0.05) in
zinc-adequate than in zinc-deficient rats. Galanin mRNA levels
were not measured. Again, differences in the design of these two
different reports may account for the differences in galanin
concentrations reported; however, it appears that there is a consistent
trend between galanin and galanin mRNA levels and appetite in these two
studies. These data support the premise that galanin is normally
regulated during zinc deficiency, in that galanin concentrations
reflect the levels of intake of zinc-deficient and
zinc-adequate rats. In contrast, NPY levels may be dysregulated by
zinc deficiency. These results suggest that other hypothalamic factors
such as corticotropin-releasing factor, which is an important
counterregulatory factor of NPY, may be playing an important role in
the hypothalamus during zinc deficiency.
Zinc deficiency and leptin.
Recent studies have investigated the regulation of leptin levels during
zinc deficiency. These studies provide useful information in both the
rat (Mangian et al., 1998
, Ott and Shay, 1998
) and humans, (Mantzoros et al. 1998
,
Ryan et al. 1998
). The results of all of these studies
are entirely consistent. Circulating leptin concentrations are reduced
during zinc deficiency in the rat (Mangian et al. 1998
)
and in humans (Mantzoros et al. 1998
, Ryan et al. 1998
). This reduction appears to be due to both a decrease in
the amount of body fat present during zinc deficiency (Mangian et al. 1998
) and a decrease in the amount of leptin produced
per gram of adipose tissue (Ott and Shay, 1998
). Reduced
levels of leptin as a result of zinc deficiency support the reports of
Lee et al. (1998
) and Selvais et al. (1997
), which show increases in hypothalamic NPY. Circulating
leptin levels and hypothalamic NPY are recognized to be inversely
related (Schwartz et al. 1996
). Reductions in leptin
during zinc deficiency likely provide the basis for a new hypothesis
relating zinc deficiency to reproductive dysfunction. With the
discovery of leptin receptors in reproductive tissues (Barash et al. 1996
), a reduction in leptin levels due to zinc deficiency
may help explain why certain specific reproductive parameters, such as
serum testosterone concentrations (Om and Chung, 1996
),
are reduced by zinc deficiency. The results of Mantzoros et al. (1998
) and Ryan et al. (1998
) both demonstrate
that zinc deficiency reduces leptin concentrations in humans,
suggesting that this finding will be clinically important.
Because the secretion of leptin from adipose tissue is reduced by zinc
deficiency (Ott and Shay, 1998
) and insulin action is a
major factor stimulating the synthesis and secretion of leptin
(Barr et al. 1997
), we hypothesize that a reduction in
the effect of insulin due to zinc deficiency may be partially
responsible for the reductions in leptin. From our studies, we obtained
other data suggesting that insulin action is reduced during zinc
deficiency (Kennedy et al. 1998
). This hypothesis is not
particularly novel: many studies from the 1970s investigated the link
between zinc deficiency and insulin resistance. Recent evidence in
humans (Song et al. 1998
) and in rats (Tobia et al. 1998
) suggests that connection may be important and worth
revisiting. If found, a relationship between zinc deficiency and
insulin signal transduction pathways, or signal transduction in
general, may ultimately help explain many of the physiological
pathologies associated with zinc deficiency.
This hypothesis may relate to recent work reported by O’Dell,
MacDonald and colleagues (Browning and O’Dell 1995
,
1998
, MacDonald et al. 1998
). Broadly
speaking, one of the hypotheses advanced by this research team has been
that zinc deficiency may produce a primary defect that is related to
growth and that growth failure due to zinc deficiency may be producing
a signal ultimately transduced into anorexia. The administration of
progestins (Browning et al. 1998
) and contributions of
zinc deficiency to defects in
N-methyl-D-aspartate and insulin-like
growth factor-I signaling pathways (Browning and O’Dell 1995
, MacDonald et al. 1998
) have been
investigated. It is still unclear how growth impairment feeds back to
the hypothalamus. This might be occurring via vagal or a
blood-borne message. It also appears that it has not been clearly
demonstrated whether growth impairment is occurring before or after
anorexia begins. The questions asked by this research group are
important, and continued research will provide important answers.
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Future directions and priorities for research |
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TOPABSTRACTZinc deficiencyFuture directions and priorities...REFERENCES |
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The fact that anorexia nervosa is relatively rare makes the study of readily available populations of patients difficult at best. If progress is to be made in understanding this disorder, it should be a priority to support the identification and study of human populations, both young and old. In addition, support for the further development of animal models of anorexia, including nutrient deficiency–induced anorexia, should provide additional insight into the etiology of this poorly understood condition.
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FOOTNOTES |
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2 Supported in part by awards from ILSI, North America, Whitehall Foundation and U.S. Public Health Service Grant AG13586.
4 Abbreviations used: AN, anorexia nervosa; NPY, neuropeptide Y, PVN, paraventricular nucleus.
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REFERENCES |
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TOPABSTRACTZinc deficiencyFuture directions and priorities...REFERENCES |
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