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Divisions of Reproductive Biology (F.H.K., A.S., J.L.C.) and Neuroscience (F.H.K., K.L.G., A.S., M.S.S., J.L.C.), Oregon Regional Primate Research Center, and Department of Physiology and Pharmacology, Oregon Health Sciences University (M.S.S., J.L.C.), Beaverton, Oregon 97006
Address all correspondence and requests for reprints to: Frank Koegler, Ph.D., Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006. E-mail: koeglerf{at}ohsu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH analog, NDP-MSH ([Nle4,
D-Phe7]MSH), and the endogenous MSH
receptor antagonist, agouti-related protein, on feeding behavior in
adult male rhesus macaques. Infusion of NDP-MSH into the lateral
cerebral ventricle dose dependently suppressed intake of a normally
scheduled meal without affecting nonfeeding behaviors. Conversely,
infusion of agouti-related protein stimulated food intake during the
scheduled afternoon meal. In addition to these physiological
experiments, the effect of fasting on hypothalamic POMC gene expression
was assessed by in situ hybridization. Missing a single
meal or fasting for 48 h caused a similar reduction in POMC gene
expression in the arcuate nucleus. These results demonstrate that in
the primate, central melanocortin receptors can acutely regulate food
intake and suggest that the central melanocortinergic system is a
physiological regulator of energy balance in primate species. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH, which is a
cleavage product of the precursor peptide, POMC. POMC is synthesized
primarily in the arcuate nucleus of the hypothalamus (1),
and nerve fibers and terminals immunoreactive for POMC or its cleavage
products are found throughout the midbrain and within areas of the
hypothalamus, including the paraventricular nucleus (PVN)
(1). POMC gene expression in mice and rats is highly
regulated by metabolic states, including food deprivation, overfeeding,
and obesity. In rats, dietary restriction and fasting cause a reduction
in hypothalamic POMC messenger RNA (mRNA) (2, 3), whereas
overfeeding increases hypothalamic POMC mRNA (4). This
suggests that with regard to energy balance, activation of POMC has a
predominately inhibitory effect on food intake. Indeed, mice with a
mutation of the POMC gene become obese (5), and some
children with early-onset obesity have mutations in the POMC gene
(6).
Many of the effects of POMC on energy balance appear to be
mediated by MSH, which is known to profoundly affect feeding
behaviors in the rodent. In the mouse and rat, stimulation of the
central receptors for MSH, (MC3-R and MC4-R) is known to suppress
feeding behavior, whereas antagonism of central MC-Rs with synthetic
ligands, such as SHU9119 and Ro27–4680, stimulates feeding in rodents
(7, 8, 9). In addition, genetic modification of the MC4-R in
mice, leading to a loss of receptor function, results in an obese
phenotype (10), as does a null mutation of the MC3-R
(11, 12).
Interestingly, the effects of MSH are counterbalanced by the
endogenous antagonist, agouti-related protein (AGRP) (13).
AGRP antagonizes MSH at MC3-R and MC4-R (14) and
results in the stimulation of feeding in rodents (15).
Genetic overexpression of AGRP in mice leads to obesity, with a
phenotype identical to that in MC4-R knockout animals
(16), and the AGRP gene in the mouse is up-regulated by
fasting (17). These results suggest that in rodents AGRP
is a physiological modulator of energy balance and feeding behaviors.
Supporting this concept is the finding that AGRP is colocalized with
another potent orexigenic neuropeptide, neuropeptide Y, in arcuate
nucleus neurons in the rat (17, 18, 19). AGRP is also
expressed in the monkey and human hypothalamus (19, 20);
however, it is not known to what degree AGRP or the melanocortins
regulate feeding in primate species. Although obesity in certain human
populations has been linked to mutations in POMC genes
(6), there has been no examination of the role that MSH
or AGRP plays in the control of food intake in primate species. Thus,
the present experiments were designed to evaluate the role of the
central melanocortin system in the regulation of food intake in the
primate. Specifically, we report that centrally administered
melanocortin receptor ligands [NDP-MSH and AGRP-(83–132)] can
modulate normally scheduled meals in the monkey, and that missing even
a single scheduled meal decreases POMC gene expression in the monkey
hypothalamus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Instrumentation. All animals used in the feeding studies had a chronically implanted iv catheter and a chronically implanted intracerebroventricular cannula. Intravenous catheters were implanted into either the subclavian or femoral vein and traversed sc to an exit site on the back, using previously published methods (21). Stainless steel intracerebroventricular (icv) cannulas were targeted at one of the lateral cerebral ventricles and implanted using previously described methods (22). During implantation of central cannulas, an x-ray-opaque liquid (Omnipaque, Nycomed, Princeton, NJ) injection into the cannula allowed immediate radiographic confirmation of proper cannula placement in the ventricle. The icv cannula was connected to SILASTIC brand silicone tubing (Dow Corning Corp., Midland, MI), which traversed sc to an exit site in the midscapular region of the back. Monkeys wore a short-sleeved nylon jacket to protect the catheters. From the back of the jacket, catheters were threaded through a stainless steel tether to the top of the cage, where they were connected to a stainless steel swivel. The swivel/tether system allowed monkeys a free range of movement within the cage. To maintain patency, a continuous infusion of artificial cerebrospinal fluid (20 µl/h, icv) or heparinized saline (4000 U/liter; 3 ml/h, iv) was pumped through the catheters. Animals were generally maintained with dual catheters systems for a period of several months. Patency of central cannulas and timing of central drug infusions was determined via icv infusion of morphine and measurement of a morphine-induced release of plasma PRL (22). Blood samples for measurement of plasma PRL were collected remotely in freely moving animals via the iv catheter system.
Drug infusion protocol. For experiments, the tubing leading to the icv cannula was filled sequentially with a 5-µl air bubble, 30 µl 1% BSA (to decrease binding of peptides to the walls of the SILASTIC brand tubing), a second 5-µl air bubble, a 20-µl drug solution, followed by a third 5-µl air bubble (total injection volume of 65 µl). The air bubbles prevented mixing of solutions during the infusion and served as a visual guide to track the initial transit of solutions. The BSA, drug solution, and corresponding air bubbles were manually injected into the SILASTIC brand tubing leading to the icv cannula at a connector near the top of the cage over a 60-sec period. After injection, the icv tubing was reconnected to the artificial cerebrospinal fluid-filled tubing connected to the automatic infusion pump. A programmable electronic switch controlled the infusion pump to deliver 65 µl of solution during 5 min once every 30 min, which generated pulses of solution into the lateral ventricle. The number of pulses needed before the drug solution traversed the length of the catheter to the ventricle was calculated at least 1 week before feeding tests by measuring the time and number of pulses necessary for a similarly performed icv morphine injection to stimulate release of PRL (22). Based on the length of the icv catheters, the total volume delivered from the start to end of pulses was between 390 and 520 µl (six to eight pulses) over 3–4 h. Intracerebroventricular infusions were timed so that the drug entered the ventricle at 1500 h, simultaneously with meal presentation.
Drugs. The degradation-resistant MSH analog, NDP-MSH
([Nle4,
D-Phe7]MSH), was purchased from
Phoenix Pharmaceuticals, Inc. (Mountain View, CA).
[Nle126]AGRP-(83–132)NH2
was synthesized by Nicholas Ling (Neurocrine Biosciences, Inc., San
Diego, CA) and was provided by Roger Cone (Vollum Institute for
Advanced Biomedical Research, Oregon Health Sciences University,
Portland, OR). This fragment of AGRP peptide is known to be
biologically active (15). Solutions were made on the day
of each experiment from lyophilized peptide and sterile artificial
cerebrospinal fluid. The injection volume of drug solution was always
20 µl. NDP-MSH was given in doses of 0, 1, 2, and 4 nmol. AGRP was
given in doses of 0, 1, 5, and 10 nmol. For any given animal, the AGRP
experiments were performed at least 1 month after testing with NDP-MSH
was completed. Doses of both drugs were given in ascending order
because it was not known whether the compounds would have any
deleterious side-effects when administered to monkeys. Note that on
each drug testing day at least one animal received the control
treatment. Experimental days were separated by at least 3 nontesting
days to allow a drug washout period. Feeding behavior was monitored
during each posttest period, and subsequent tests were not performed
until feeding patterns normalized.
Food intake recordings. Drugs were infused to coincide with the presentation of the normally scheduled 1500 h meal. The number of uneaten biscuits was recorded (±0.25 biscuit) after 15, 30, 45, 60, 90, 120, and 180 min and overnight by an observer blind to the treatment.
Behavioral analysis by video. Because NDP-MSH was
hypothesized to decrease feeding, it was important to rule out
nonspecific causes for reduced food intake, such as sickness or
malaise. Video recordings were made to evaluate effects of NDP-MSH on
general behavior. Video cameras placed in front of cages on tripods
were used to record behavior onto super-VHS tapes. A person blinded
with regard to drug treatment used a computer that was interfaced to a
super-VHS player, and The Observer software (Noldus Information
Technology, Sterling, VA) scored a variety of feeding and nonfeeding
behaviors for each animal (Table 1
).
Behavior was analyzed for the first 20 min of feeding tests with
NDP-MSH, the period during which suppression of food intake began.
Behavior after animals received the highest dose of NDP-MSH (4 nmol)
was compared with behavior on the day of a control experiment when
animals received icv vehicle infusions.
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Perfusion. Animals were sedated with ketamine HCl (10 mg/kg, im) at approximately 1230 h on the day of death and then deeply anesthetized with sodium pentobarbital (>30 mg/kg, iv). The chest cavity was opened, and each animal was perfused transcardially with 0.9% NaCl containing 2% sodium nitrite (800–1000 ml) to flush blood from the vascular system, followed by 4% paraformaldehyde in 0.1 M sodium phosphate buffer solution (pH 7.4; 3–3.5 liters). The brains were removed, and hypothalamic tissue blocks were cut and immersed in the same fixative for 2 h at 4 C. The tissue blocks were then immersed in 10% glycerol solution for 24 h at 4 C and in a 20% glycerol solution for an additional 72 h at 4 C. The tissue was then frozen and stored at -80 C until it was sectioned.
In situ hybridization. The hypothalamus was sectioned at a thickness of 25 µm on a coronal plane using a freezing microtome. Sections were collected as a 1 in 4 series. Sections were stored in cryoprotectant (30% sucrose and 30% polyethylene glycol, buffered with NaPO4, pH 7.2) at -20 C until processed for in situ hybridization. For in situ hybridization, one series of sections was mounted on slides (SuperFrost Plus, Fisher Scientific, Pittsburgh, PA) in ribonuclease-free potassium phosphate buffer (pH 7.4) and dried overnight. The sections were then postfixed in 4% paraformaldehyde (pH 7.4 in 0.1 M NaPO4), rinsed in phosphate buffer, incubated with proteinase K (10 µg/ml) for 30 min at 37 C, and treated with 0.25% acetic anhydride in 0.1 M triethanolamine (pH 8.0). The sections were washed in 2 x SSC (20 x stock solution: 17.5% sodium chloride and 8.8% sodium citrate), dehydrated through a graded series of alcohols, delipidated in chloroform, rehydrated through a second series of alcohols, and air-dried.
A monkey-specific POMC complementary RNA probe was transcribed from a
1115-bp complementary DNA clone in a pGEM4 vector [provided by R.
A. Steiner (23)] with 40% of the UTP labeled with
35S (NEN Life Science Products,
Boston, MA). The specific activity of the probe ranged from 6–8
x 108 dpm/µg. A saturating concentration of
0.3 µg/ml·kb of the probe was used, diluted in hybridization buffer
(62.5% formamide, 12.5% dextran sulfate, 375 mM NaCl, 10
mM Tris, 1 mM EDTA, 1.25 x Denhardt’s
solution, and 10 mM dithiothreitol). The sections were
hybridized with the POMC probe overnight (
16 h) in a moist chamber
at 55 C. After incubation, the slides were washed in 4 x SSC and
ribonuclease A at 37 C, and in 0.1 x SSC at 60 C. Slides were
then dehydrated through a graded series of alcohols, dried, then dipped
in Kodak NBT2 emulsion (Eastman Kodak Co.,
Rochester, NY) diluted 1:1 in 600 mM ammonium acetate,
placed in light-tight boxes containing desiccant, and stored at 4 C for
3 weeks. The slides were developed and counterstained with cresyl
violet and the distribution of the silver grains was analyzed by
darkfield microscopy.
Statistical analyses
A main effect of drug treatment on food intake was determined
using two-way repeated measures ANOVA with factors of dose and time.
Individual post-hoc comparisons between doses at a
particular time point were made with t tests, adjusted for
multiple comparisons using the Bonferroni correction (familywise error
rate = 0.05). Linear regression analyses were used to assess the
dose-response relationship between AGRP dose and food intake at a given
time point. Video analysis of feeding-related behaviors with normally
distributed data were analyzed using paired t tests. Several
behavioral categories did not have normally distributed data and were
tested for drug effects with the Wilcoxon signed rank nonparametric
test (crouching, grooming, stereotypy). Food intake data are presented
as the mean number of biscuits ± SEM.
Behavioral data collected by video analysis are presented as the mean
duration in seconds ± SEM.
In situ hybridization experimental slides were analyzed for silver grain density using Optimus Imaging software (Videk Corp., Rochester, NY). An individual brain section was captured by a CCD camera (Cohu High Performance CCD Camera, San Diego, CA) and displayed on a computer monitor. Background (nonspecific) labeling, defined by the level of labeling in the lateral hypothalamus [a region devoid of neuropeptide Y (NPY) cells], was eliminated by setting a sampling threshold within the Optimus system. The threshold value was kept constant for all sections and brains. In general, probe labeling in the lateral hypothalamus (nonspecific) was less than 5% of labeling in the arcuate nucleus. The silver grain density in (representing [35S]POMC cRNA labeling) was measured in arbitrary units using a sampling box that encompassed the entire region of interest. This sampling box was held constant for all brains analyzed. Measurements were taken bilaterally from the complete rostro-caudal extent of the arcuate nucleus (ranging from 15–25 sections, resulting in a total of 30–50 sample readings/brain) as determined by histological analysis of the sections. Some sections were not sampled due to tears and folds or excessively high background labeling in the region of interest. However, to best represent the level of [35S]POMC cRNA probe labeling, 15 values from the peak area of expression were used to obtain the mean level of POMC labeling for each individual animal. The area displaying the peak level of [35S]POMC cRNA probe labeling was in the mid range of the arcuate nucleus and was anatomically matched for each animal. Differences between the groups were detected using a one-way ANOVA (P < 0.05) with a Newman-Keuls multiple comparison test post-hoc analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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]. Planned individual
comparisons between doses revealed that the highest dose of NDP-MSH (4
nmol) significantly suppressed intake as early as 45 min. Intake after
the overnight period was suppressed in a dose-dependent manner with the
highest dose suppressing intake up to 67% [F(3, 13) = 7.667;
P = 0.003; Fig. 1B].
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shows that behaviors
were not statistically affected by treatment. Although NDP-MSH caused a
dose-related suppression in the amount of food eaten, there were no
statistically reliable effects of 4 nmol NDP-MSH on feeding-related
behaviors as scored by videotape, although there was a trend toward a
decrease in several of these behaviors.
AGRP stimulates food intake
There was a main effect of AGRP on food intake [F(3, 9) =
7.309; P = 0.008; Fig. 2A]. Average food intake after 10 nmol
AGRP was significantly increased relative to that in controls within 45
min after the initiation of the meal. There was a statistically
significant linear relationship between AGRP dose and stimulation of
intake at 180 min [F(1, 21) = 5.468; P = 0.029;
Fig. 2B]. The average increase in food intake persisted overnight;
however, because of individual variability and adjustment for multiple
comparisons this was not statistically significant.
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and 4]. Additional food deprivation during a
48-h fast also reduced POMC mRNA by 41%; however, the decrease was no
greater than that seen after missing a single meal.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Importantly, the reduction of food intake after treatment with NDP-MSH
did not seem to be caused by nonspecific behavioral effects of drug
treatment. Detailed video analysis showed that animals behaved normally
and did not display any signs of nausea or illness after treatment.
Based on the absence of overt abnormal behaviors after treatment and,
more importantly, the observation that AGRP stimulated intake, it is
likely that endogenous MSH and AGRP act as physiological antagonists
to modulate feeding.
The most likely site of action of NDP-MSH and AGRP after lateral
cerebroventricular infusion is the hypothalamus. Drugs are moved via
cerebrospinal fluid flow and diffusion through the interventricular
foramen and into the third ventricle rapidly (during surgeries we
observed movement of radioopaque dye from the lateral ventricle to the
third ventricle in <30 sec). Hypothalamic areas closely adjacent to
the third ventricle include the PVN, and messenger RNA for MC4-R is
high in the PVN of the hypothalamus of rats (24),
suggesting that this may be a local site of action for icv injections
of MSH and AGRP in the rodent. Detailed mapping of MC-Rs and
immunoreactive MSH in primates has not been performed; however,
immunoreactivity for POMC is found in fibers traversing and terminating
in the midline hypothalamic and thalamic structures of the monkey
(1). Likewise, AGRP fiber immunoreactivity is high in the
monkey paraventricular nucleus (19), and based on results
from rodent studies demonstrating the PVN to be the most sensitive area
responding to exogenous AGRP and NDP-MSH (25), it is
likely that the PVN is a critical structure for the effect of
melanocortins on food intake. Because AGRP-containing cells are located
only in the arcuate nucleus, the arcuate projection to the PVN is the
only known afferent source for antagonism of MSH in the PVN.
The doses of NDP-MSH and AGRP that were effective in modulating food intake in this study were in the low nanomolar range. Third ventricle infusion of AGRP in rodents increased feeding at doses as low as 10 pmol (26). The effective doses of AGRP in our study were considerably, but not unusually, higher than those used in the rodent study. A direct comparison between efficacy of AGRP in monkey vs. rodent is complicated by the inherent differences between the species and the differences in experimental protocols used in these two studies. Two major factors may have contributed to an effective reduction in drug concentration at the active site after injection in the monkey: 1) the volume of the brain and ventricular system is much larger in the primate; and 2) infusions were made into the lateral, rather than the third, ventricle, which is farther away from the presumed site of action. Another factor that may have contributed to the difference in effective doses between the rodent and primate studies is the feeding schedule. The monkeys in this study were fed a predetermined, limited amount of food at each scheduled meal time, and under control conditions food intake during the first 30 min of meals was rapid. Because of the rate of initial feeding induced by the feeding schedule, it may not have been possible to detect the stimulatory effects of low doses of AGRP due to a ceiling effect. Rodent experiments demonstrate that AGRP doses as low as 0.01 nmol can stimulate feeding during the first 2 h of the dark period (26), during which time feeding is robust; however, it has not been reported that this low dose stimulation can be detected during the initial phase of the meal or whether it is observed with a restricted feeding schedule. Finally, species differences between rhesus macaque and rodents have been reported with regard to the effects of other centrally administered peptides. Indeed, there is a difference in sensitivity to the feeding induced by NPY in monkeys and rodents, albeit in the opposite direction of that seen with AGRP (22), with the monkey showing greater sensitivity to centrally administered NPY-induced stimulation of food intake.
An important issue to consider is the potential for longer-term effects of AGRP on feeding. After a single icv treatment with 0.01 nmol, 24-h food intake in the rat is increased for up to 7 days (26). We did not detect a similar long-term effect in the monkey. It is possible that AGRP is metabolized differently in the monkey than in the rat, or that the larger brain volume of the monkey contributes to the absence of a long-term effect for the doses tested. Because the treatment order of AGRP in these monkey experiments was ascending, there could be the potential for cumulative effects of subthreshold AGRP on food intake. However, we do not believe this occurred because food intake was monitored daily between all tests, and there were no indications of lasting hyperphagia. After each dose, testing resumed only after 2 days of normalized of feeding patterns.
Because experimentally induced or naturally occurring interference with
melanocortin signaling, such as after targeted ablation of the MC4-R,
overexpression of agouti or AGRP, or congenital POMC mutations in
humans, causes obesity (6, 10, 16, 27, 28), it is probable
that MC-Rs have a physiological role in the long-term regulation of
body weight and the control of food intake. Indeed, long-term treatment
of rodents with MSH analogs causes a reduction in body weight
(29), and overfeeding in rats increases POMC mRNA
(4). That the MC3-R is thought to regulate energy
utilization independently of alterations in food intake is further
evidence supporting a role for the MC3-R in longer-term energy balance
(11, 12). The results presented in our study clearly
demonstrate the ability of melanocortin receptor ligands to regulate
short-term food intake, and our results examining changes in POMC mRNA
after food deprivation suggest that the short-term regulation of intake
by melanocortins is physiological. Forty-eight hours of food
deprivation in monkeys caused a marked reduction in mRNA for POMC in
the arcuate nucleus of the hypothalamus. Presumably, the availability
of POMC products, including MSH, would have also decreased in this
time frame, leading to a decrease in MSH-induced inhibition of
feeding. The reduction in POMC message in response to fasting has been
demonstrated in rodent models (2, 3); however, the
observation that the decrease in POMC message after missing a single
meal is equivalent to that seen after a 48-h fast in the monkey is a
novel and important finding. The fact that missing a single meal
suppressed POMC message as much as did a 48-h fast lends support to the
hypothesis that POMC products are important physiological regulators of
normally scheduled meals as well as important longer-term regulators of
body weight and adiposity.
Eating is a complex behavior influenced by many factors, including, but not limited to, previous experience with a particular type of food, palatability, circulating fuel levels, stomach contents, and hormones secreted from the gastrointestinal tract, the pancreas, and body fat depots. There is substantial evidence that all of these factors eventually influence hunger and satiety by modulating the activity of several key brainstem and hypothalamic neural systems that play central roles in regulating food intake, and thereby energy balance. A characteristic of the regulation of food intake is that there is a counterbalance between systems that stimulate food intake, including NPY and melanin-concentrating hormone (30, 31, 32), and systems that suppress food intake, including serotonin, leptin, and cholecystokinin (33, 34, 35). The results presented in this report provide evidence for a particularly interesting counterbalancing system in which there are endogenous ligands for a single set of receptors (MC3-R and MC4-R) that both inhibit (MSH) and stimulate (AGRP) food intake. This is the first report showing these effects of MSH and AGRP in a primate species, and the results indicate that as in rodent species (7, 9, 26, 36), these systems are likely to play an important role in the meal to meal regulation of food intake. Much progress has been made in understanding the neural systems regulating feeding behavior and body weight in both rodent and higher species. However, the regulation of feeding in humans and other primates is likely to be subject to higher order cognitive processing and psychological factors. Undoubtedly, hypothalamic and brainstem neural systems are influenced by cortical and limbic structures to allow integration of emotional and cognitive control over feeding behaviors and, ultimately, body weight. New challenges that the field is soon to face will include understanding how cortical brain systems affect the hypothalamic and brainstem feeding circuits that have been elucidated in the last several years.
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Acknowledgments |
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Footnotes |
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Received October 12, 2000.
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References |
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-melanocyte stimulating hormone in vivo. Endocrinology 139:4428–4431-melanocyte-stimulating hormone. J Clin Endocrinol Metab 85:2596–2603-melanocyte-stimulating
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)
and 1 nmol (
), 2 nmol (X), and 4 nmol (
) NDP-MSH (n = 6).
Error bars are omitted from intermediate doses for clarity.
Asterisks denote a significant difference
(P < 0.05) from the control. Pluses
denote a significant difference (P < 0.05) from
the 1-nmol dose and the control. B, Total intake of the afternoon meal,
as measured the following morning, after 0, 1, 2, and 4 nmol NDP-MSH.
), and 10 nmol (
