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Schering-Plough Research Institute and Department of Central Nervous System and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Melanocortins play a critical role in appetite and body weight regulation, because manipulations of this pathway can lead to the development of obesity in several animal models. The purpose of this study was to use a melanocortin receptor agonist and antagonist to evaluate the involvement of melanocortins in feeding, energy metabolism, and body weight regulation in lean and obese Zucker rats. Central administration of a melanocortin receptor antagonist (SHU9119) elevated food intake and body weight of lean Zucker rats but had little effect in obese Zucker rats. In contrast, the melanocortin receptor agonist MTII reduced food intake in both lean and obese rats but was more potent in the obese Zucker rats. These data indicate the existence of functional melanocortin receptors in both lean and obese Zucker rats but suggest that obese Zucker rats have reduced endogenous melanocortin tone. In addition to its effects on food intake, MTII infusion elevated oxygen consumption and decreased respiratory quotient dose dependently during the light cycle. Our data suggest that a melanocortin receptor agonist can induce weight loss by increasing energy expenditure and promoting body fat utilization in addition to its inhibitory effects on food intake in both obese and lean Zucker rats.
obesity; indirect calorimetry; oxygen consumption; respiratory quotient; agonist; antagonist
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE GENETICALLY OBESE
ZUCKER rat (Leprfa/Leprfa) has been used
extensively as an animal model to study factors associated with dysfunctional energy balance (6) and type II diabetes
(37). Adult obese Zucker rats exhibit overt obesity,
hyperphagia, hypercholesterolemia, hyperlipidemia, and hyperglycemia as
an autosomal recessive trait (6). The Leprfa
mutation that is responsible for obesity in the Zucker rat is a
missense mutation (Gln269
Pro) in the gene encoding the
leptin receptor (23). Leptin is an adipocyte-derived
hormone whose serum level is directly proportional to body-fat mass
(8). Leptin decreases energy intake and increases energy
expenditure via activation of leptin receptors in the hypothalamus
(30). The long isoform of the leptin receptor with the
(Gln269Pro) mutation leads to reduced leptin binding
affinity and defective leptin signaling through the JAK-STAT pathway in
vitro (11). Unlike the Koletsky obese rats, which have a
null mutation of all leptin receptors, Zucker obese
(Leprfa/Leprfa) rats have inconsistent in vivo
responses to exogenous intracerebroventricular (icv) administration of
leptin (45).
Recent evidence suggests that the hypothalamic melanocortin system is directly influenced by leptin to regulate food intake and body weight. Leptin activates neuropeptide Y (NPY)/agouti-related peptide (AGRP)-containing neurons and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-containing neurons of the ventromedial and ventrolateral arcuate nucleus, respectively (4, 9, 12), via activation of the long isoform of the leptin receptor that is expressed in these neurons. Central infusion of leptin stimulates expression of the POMC gene while reducing the expression of the AGRP gene in the arcuate nucleus (31, 39, 40). Furthermore, animals with deficiencies in leptin or leptin-signaling pathways have elevated AGRP mRNA but reduced POMC mRNA in the arcuate nucleus (26, 43, 46).
POMC- and AGRP-containing neurons have been demonstrated to regulate
energy homeostasis through modulation of melanocortin receptors
(10, 42, 44). There are five melanocortin receptors (MC1-MC5), three of which
(MC3-MC5) have been shown to be expressed in the brain (28, 32, 33). 
-Melanocyte-stimulating
hormone (-MSH), a POMC gene product, stimulates central
MC4 receptors to reduce food intake and weight gain
(2, 29), whereas AGRP inhibits central MC4
and/or MC3 receptors to increase food intake and weight
gain (17, 47).
Several studies show evidence that the degree of
MC4-receptor activation was determined by the balance of
-MSH and AGRP neurotransmission, which plays a key role in the
maintenance of energy balance in vivo. For example, deletion of the
MC4 receptors in mice leads to hyperphagia,
hyperinsulinemia, hyperglycemia, and delayed-onset obesity
(21). Mice with ectopic expression of agouti protein, which is homologous to AGRP and antagonizes the central MC4
receptors and the peripheral MC1 receptors, develop
hyperphagia, hyperinsulinemia and obesity (29, 34). In
addition, a selective MC4-receptor agonist (Ro27-3225)
reduces food intake and weight gain in rodents without producing any
nonspecific aversive effect (5). Furthermore, mutations of
the MC4 receptor and genetic defects in the POMC gene are
associated with marked obesity in humans (19, 20, 27, 41).
These studies support the contention that the MC4 receptor
plays an important role in weight regulation in animals and humans. In
contrast, central administration of 
-MSH, an MC3 agonist, did not alter food intake or weight gain (1).
However, mice with MC3-receptor deletion develop mild
obesity with elevated fat deposition (7). These data
suggest that MC3 may be a factor regulating nutrient
partitioning in mice.
The present study compares the central effects of a melanocortin receptor agonist and antagonist on feeding and energy expenditure regulation in lean vs. obese Zucker rats. Although several studies have reported effects of the melanocortin system on feeding behavior (14, 25, 36), the effects on energy metabolism have not been explored in detail. Our data demonstrate that central administration of a melanocortin receptor agonist (MTII) promotes weight loss in both lean and obese Zucker rats by affecting both food intake and energy metabolism. These data also demonstrate that obese Zucker rats have significantly reduced endogenous melanocortin tone that may contribute to the obese/diabetic syndrome of these animals.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Age-matched male Leprfa/Leprfa and lean (+/+ or +/Leprfa) Zucker rats (Charles River, MA), were housed individually and maintained in a temperature- and light-controlled environment on a 12:12-h light-dark cycle (lights on at 4:00 AM). Animals had free access to food and water. All studies were conducted in an American Association for Accreditation of Laboratory Animal Care accredited facility following protocols approved by the Schering-Plough Research Institute's Animal Care and Use Committee. The procedures were performed in accordance with the principles and guidelines established by the National Institutes of Health for the care and use of laboratory animals.
Surgery. A single 22-gauge stainless steel guide cannula (Plastics One, Roanoke, VA) was chronically implanted into the lateral ventricle of rats under ketamine-xylazine (100:10 mg/kg ip) anesthesia using the following coordinates: 1.0 mm posterior to bregma, 1.5 mm lateral to midline, and 3.6 mm ventral to dura (22). The cannula was secured to the surface of the skull with jeweler's screws and dental cement, and a 28-gauge obturator was inserted into the cannula to maintain patency. After a 3-wk recovery period, all animals were tested for cannula placement by central infusion of 0.3 nmol of NPY. Only animals demonstrating a prompt and robust feeding effect (>2.0-g intake within 60 min of infusion) were retained for the study.
Peptide and injections.
MTII {Ac-Nle4-c[Asp5, D-Phe7,
Lys10]-MSH10(4-10)NH2}
and SHU9119 Ac-Nle4-c[Asp5,
D-Nal(2)7,
Lys10]-MSH-(4-10)-NH2}
were obtained from Phoenix Pharmaceuticals (Belmont, CA). Sterile
saline (0.9% NaCl) or MT-II/SHU9119 in saline was infused icv in a
total volume of 2.5 µl over 1 min using a Bioanalytical Systems Bee
Syringe Pump (West Lafayette, IN). The 28-gauge infusion cannulus
(Plastics One) projected to 4.6 mm below the surface of the skull. The
infusion cannulus were left in place for an additional minute following
the infusion.
Indirect calorimetry.
Oxygen consumption (
O2) and carbon
dioxide production (CO2) were monitored
every 15 min (settle time: 155 s; measure time: 45 s) for
22 h with the use of an indirect calorimeter (Oxymax, Columbus
Instruments, Columbus, OH). Measurements were taken in an airtight
Oxymax chamber (10.5 l) with an air flow rate of 2.75 l/min.
Respiratory quotient (RQ) was calculated as the molar ratio of
CO2 to
O2. Water and food were available ad
libitum in the calorimeter chamber. Percent energy fuel derived from
carbohydrate or fat oxidation was determined from
O2 and
CO2 using the methods of Elia and
Livesey (13).
Animal activity monitor. Physical activities of the rats were monitored by an infrared photocell beam-interruption method (Opto-varimex-minor, Columbus Instruments, Columbus, OH). The monitor interfaced with a computer and recorded the horizontal, vertical, and ambulatory activities every 15 min.
Experimental design.
Age-matched male lean and obese Zucker rats were used in the study. In
the MTII study, the obese and lean Zucker rats were 604 ± 5 and
410 ± 17 g, respectively. In the SHU9119 study, the obese
and lean Zucker rats were 751 ± 5 and 504 ± 15 g,
respectively. Each subject was adapted to the experimental conditions
by being placed in a calorimeter chamber for 3 days before testing and continuously monitored in the same calorimeter chamber during the
experiment. icv-Cannulated obese and lean Zucker rats were infused with
MTII/saline at 1000 or SHU9119/saline at 1500. The nocturnal cycle
extended from 1600 to 0400. The effects of either saline, SHU9119
(0.1-1 nmol), or MTII (0.01-0.1 nmol) icv infusion on feeding
and body weight were monitored 23 h after the icv infusion. O2 and
CO2 were recorded every 15 min for
22 h.
Statistical analysis. Results are given as means ± SE. All statistical analyses were performed with JMP software (version 3.1.6) from SAS Institute. For each endpoint, a mixed model of ANOVA was performed. Two-factor ANOVA was used to assess significant interaction between drug effect and the obese phenotype. If there was significant interaction between drug effect and the obese phenotype, the drug effect on each phenotype was analyzed independently by one-way ANOVA. Dunnett's adjustment was used to account for multiple comparisons with the type 1 error rate of 0.05 partitioned into equal amounts for comparisons within each animal type. Statistical significance (P < 0.05) of a comparison was assessed by comparing the difference in least-squares means with the appropriate estimate of variability from the ANOVA. The dose that reduced daily food intake to 50% (ID50) data were analyzed by linear regression analysis of log drug doses and drug responses by Excel 97.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of MTII and SHU9119 on food intake.
Obese Zucker rats had significantly higher daily food intake than the
lean Zucker rats (Fig. 1, A
and B). However, when the food intake was normalized to the
metabolic body size (body weight0.75), both lean and obese
Zucker rats had similar food consumption per metabolic body mass
(42.5 ± 3.7 and 42.1 + 3.8 g/kg0.75 for lean and
obese rats, respectively). icv Administration of the melanocortin
receptor agonist MTII (0.01-0.1 nmol) significantly reduced daily
food intake of both obese and lean Zucker rats. A significant
interaction between MTII doses and phenotypes was identified by
two-factor ANOVA. The ID50 dose of MTII in obese Zucker
rats was 0.028 nmol (logID50 = 
1.56 ± 0.03 nmol), which was significantly lower than that of the lean Zucker rats
(0.1 nmol, logID50 = 0.92 ± 0.20 nmol). In
contrast, icv administration of the melanocortin receptor antagonist
SHU9119 (1 nmol) caused a 49% increase in daily food intake in the
lean Zucker rats but reduced the daily food intake of obese Zucker rats
to the level of lean Zucker rats (Fig. 1B).
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Effects of MTII and SHU9119 on energy metabolism.
Whole body energy metabolism was continuously monitored using an
open-circuit calorimeter after icv administration of MTII or SHU9119.
The daily averaged O2 of the obese
Zucker rats was significantly lower than that of the lean Zucker rats
(Fig. 2). icv
Administration of MTII dose dependently elevated average
O2 for 3 h in the obese Zucker rats
but not in the lean Zucker rats (Fig. 2, A and
B). The transient increase in
O2 of the obese Zucker rats correlated
well with the increase in 3-h total activity recorded concomitantly
(Fig. 2C). Six hours after MTII or saline infusion,
MTII-treated obese Zucker rats had O2
similar to the saline-treated obese Zucker rats (Fig. 2B).
Therefore, the 22-h average O2 of both
lean and obese Zucker rats treated with various doses of MTII was not
statistically different from their saline controls (Table
1). To dissociate the effect of MTII on
food intake from its effects on energy metabolism, we pair fed the obese Zucker rats with the same amount of food consumed during the MTII
(0.1 nmol) experiment. The pair-fed lean and obese Zucker rats both had
significantly lower O2 than the
MTII-treated rats (Table 1). After icv administration of SHU9119
(0.1-1 nmol) to obese or lean Zucker rats (Table 1), we did not
observe any significant change in O2
despite significant elevation of food intake of lean Zucker rats with
0.1 nmol of SHU9119. However, there was a trend for SHU9119-treated
lean and obese rats to reduce O2 during
the dark cycle.
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O2 rate, we
also monitored the RQ after icv infusion of MTII or SHU9119 in the lean
and obese Zucker rats. The obese Zucker rats had a significantly higher 22-h RQ than the lean Zucker rats (Fig.
3A). After
icv infusion of MTII (0.01-0.1 nmol), the RQ of both lean and
obese Zucker rats declined in a dose-dependent manner with a
significant interaction between MTII doses and the obese phenotypes in
two-factor ANOVA analysis (Fig. 3A). The obese Zucker rats
were more sensitive to the MTII-induced reduction of RQ than the lean
Zucker rats, with a minimal effective dose of 0.03 and 0.1 nmol for the
obese and lean rats, respectively (Fig. 3A). Analysis of
energy fuel usage showed that MTII decreased the proportion of expended
energy derived from carbohydrate and increased the proportion derived from fat in both lean and obese Zucker rats (Fig. 3, B and
C). Moreover, icv administration of SHU9119 (1 nmol)
significantly increased RQ of lean Zucker rats but decreased the RQ of
the obese Zucker rats (Fig. 4).
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Effects of MTII and SHU9119 on weight gain.
A single icv infusion of MTII (0.01-0.1 nmol) to both the lean and
obese Zucker rats resulted in a dose-dependent reduction of 24-h weight
gain (Fig. 5A). Body weight
was significantly reduced in lean and obese Zucker rats after icv
infusion of MTII (0.1 nmol) by 3.2 ± 0.3% and 4.4 ± 0.4%
reduction, respectively. icv Infusion of SHU9119 (0.1-1 nmol)
increased weight gain dose dependently in both lean and obese Zucker
rats (2-factor ANOVA, P < 0.01). Body weight was
increased in lean and obese Zucker rats after icv infusion of SHU9119
(0.1 nmol) by 2.3 ± 0.8% (P < 0.05) and 0.54 ± 0.17% (P = 0.053), respectively (Fig.
5B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we have demonstrated that acute icv administration
of MTII, a melanocortin receptor agonist, induced weight loss in both
obese and lean Zucker rats by reducing food intake, increasing
O2 and promoting the usage of fat as
energy substrate. Obese Zucker rats were more sensitive to the effects
of MTII than lean Zucker rats. These data not only indicate that both
lean and obese Zucker rats have functional melanocortin receptors, but
they also suggest that the effects of melanocortin receptor activation
by MTII on energy homeostasis may be independent of the leptin
receptor. We also demonstrated that inhibition of melanocortin receptors by SHU9119 selectively increased weight gain, food intake, and RQ of the lean Zucker rats. However, SHU9119 normalized food intake
and RQ of obese Zucker rats to the level of lean Zucker rats. The
observation that obese Zucker rats are more sensitive to the effects of
MTII and less sensitive to the effects of SHU9119 suggests that obese
Zucker rats have less endogenous melanocortin tone than lean Zucker
rats. Thus reduction of melanocortin tone may contribute to the
development of the obese phenotype in the obese Zucker rats.
The differential sensitivity between lean and obese Zucker rats to MTII
and SHU9119 could be due to differences in the expression of the
melanocortin receptor(s) or variation in the production of the
endogenous agonist (-MSH) or endogenous antagonist (AGRP). Recent
evidence has shown that obese Zucker rats have an increased density of
MC4 receptors in various hypothalamic regions (dorsomedial hypothalamic nucleus, ventromedial hypothalamic nucleus, arcuate nucleus of hypothalamus, and medial eminence) crucial to feeding and
energy regulation compared with lean Zucker rats (16). In addition, obese Zucker rats have less -MSH peptide in the PVN than
lean Zucker rats (24). These data suggest that reduced endogenous melanocortin agonist production and elevated MC4
receptor levels in the obese Zucker rats may contribute to the increase in sensitivity to the MTII and the decrease in sensitivity to SHU9119
in these animals.
Direct administration of MTII to the paraventricular nucleus of the
hypothalamus has been shown to increase
O2 of lean mice (10). In
this study, we have shown that icv administration of MTII not only
reduced energy intake but also affected energy expenditure and energy
substrate usage in both lean and obese Zucker rats. By
monitoring CO2 and by an indirect
calorimetric method, we have shown that MTII significantly reduced the
RQ of both lean and obese Zucker rats. These data suggest that
activation of melanocortin receptors promotes the use of fat as the
preferred energy substrate while reducing carbohydrate usage
(13). Despite the drastic 83% and 50% reductions in
energy intake induced by MTII (0.1 nmol icv) in obese and lean Zucker
rats, the 22-h averaged O2 in both obese
and lean Zucker rats was not significantly different from the saline
control group. The MTII (0.1 nmol icv)-treated rats had a significantly
higher O2 rate than pair-fed rats, suggesting that MTII had direct effects on energy expenditure.
Numerous factors can influence the energy expenditure of an animal.
Basal metabolic rate, body temperature, physical activity, and
diet-induced thermogenesis all contribute to the regulation of energy
expenditure (13). Central administration of -MSH or
MTII has been shown to induce transient hyperthermia in rats (35,
38). It is also known that icv infusion of MTII produces sympathoexcitation in the brown fat, renal, and lumbar regions (18). Monitoring physical activity by infrared-photocell
sensors, we have observed a simultaneous augmentation of physical
activity in the obese Zucker rats during the first 3 h after MTII
infusion. These data are consistent with the excessive grooming
behavior in rodents after central activation of MC4
receptors that was previously reported (3, 15). This
activity-associated thermogenesis of obese Zucker rats probably was the
predominant thermogenic source after MTII infusion. However, we cannot
completely rule out the involvement of brown fat thermogenesis on
energy expenditure after MTII infusion in obese Zucker rats, because
brown fat is the major organ contributing to nonshivering thermogenesis
in rodents. Hence, increases in physical activity, body temperature, and brown fat thermogenesis all may underlie the effect of MTII on
energy expenditure.
RQ is an indication of the proportion of energy expenditure derived from fat and carbohydrate oxidation (13). In addition, the lipogenesis processes from both carbohydrate and protein require gas exchanges. The RQ of glucose and protein conversion into fat are 5.56 and 1.12, respectively. Therefore, when lipogenesis contributes to a significant part of the overall gas exchange, the RQ can reach higher than 1. The obese Zucker rats had a significantly higher RQ than lean Zucker rats, indicating a relatively low fat oxidation rate or a high rate of lipogenesis (13). It has been demonstrated that high 24-h RQ is one of the risk factors for body weight gain in the Pima Indians (48). Activation of melanocortin receptors by MTII reduced body weight by stimulating fat usage while decreasing carbohydrate usage in both lean and obese Zucker rats. However, inhibition of melanocortin receptors by SHU9119 increased weight gain by reducing fat usage and increasing carbohydrate usage specifically in the lean rats.
In conclusion, the hypothalamic melanocortin system plays a key role in the regulation of body weight, food intake, and energy metabolism. Central administration of the melanocortin receptor antagonist SHU9119 increases weight gain by elevating food intake and promoting fat deposition, especially in the lean Zucker rats. The weight loss induced by central infusion of MTII in both lean and obese Zucker rats is mediated by reducing food intake, lowering RQ, and elevating metabolic rate.
Perspectives
Obesity is a disorder of energy balance, arising from a chronic disequilibrium between energy intake and energy expenditure. Thus the optimal treatment for obesity would be one that both suppresses food intake and increases energy expenditure. Energy intake and energy expenditure are closely regulated processes, as reflected in the relative stability of body weight in the presence of large daily fluctuations in caloric intake. Energy balance is controlled by a complex system of metabolic pathways, integrated at the level of the central nervous system by a series of neurotransmitter signals. The central melanocortin system has been demonstrated to act downstream of leptin in the regulation of energy balance. We have demonstrated that obese and lean Zucker rats display differential sensitivities to exogenous melanocortin receptor agonists and antagonists. The apparent reduction in endogenous melanocortin tone in the obese rats that can be inferred from these data may contribute to the energy imbalance in these obese rats. Administration of melanocortin receptor agonist MTII not only reduces food intake and weight gain in both lean and obese Zucker rats but also elevates energy expenditure and fat usage in the obese Zucker rats. As mentioned above, this represents an ideal profile for an antiobesity agent. These data indicate that the obese rats have the potential to respond well to melanocortin agonists and suggest that the hypothalamic melanocortin system may be a potential target for pharmacological intervention in the treatment of obesity.| |
ACKNOWLEDGEMENTS |
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We thank Drs. B. Salisbury and M. Rudinski for fruitful discussions and careful reading of the manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. J. Hwa, CNS/CV Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033-0530 (E-mail: joyce.hwa{at}spcorp.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 December 2000; accepted in final form 20 March 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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