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Imperial College School of Medicine Endocrine Unit, Hammersmith Hospital, London, United Kingdom W12 0NN
Address all correspondence and requests for reprints to: Prof. S. R. Bloom, ICSM Endocrine Unit, Hammersmith Hospital, Du Cane Road, London, United Kingdom W12 0HS. E-mail: sbloom{at}rpms.ac.uk
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Abstract |
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Introduction |
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We have recently reported that hypothalamic GLP-1 is a physiological satiety factor (3). In rats, intracerebroventricular (icv) GLP-1 administration reduces early dark phase feeding (3, 10, 11), fast-induced feeding (3, 12), feeding in a food restriction schedule (13), and the hyperphagia seen in the obese Zucker rat (11, 14). Intracerebroventricular administration of exendin-(9–39) has been shown to triple food intake in satiated Wistar rats (3) and to increase feeding in satiated obese Zucker rats (14). In humans, iv GLP-1 has been recently shown to promote satiety and suppress energy intake (15).
Neuropeptide Y (NPY) is the most potent stimulant of feeding yet described. It has an established role in the control of food intake (16, 17, 18, 19, 20, 21). Increased NPY messenger RNA (mRNA) (22) and peptide content (23) are found in the PVN of fasted animals, and central immunoneutralization of NPY reduces feeding (19, 20). Repeated CNS administration of NPY causes marked sustained hyperphagia, leading to obesity (24). Exendin-(9–39) when coadministered with NPY further enhances food intake (3) and significantly increases the maximum food intake obtained with NPY alone (our unpublished observations). The decrease in food intake after leptin administration (25) has been shown to result in part from interaction with other CNS peptides, including NPY (21, 26, 27). We have reported that exendin-(9–39) given at the onset of the dark phase prevents the anorectic and weight-reducing effects of icv leptin (28). We also demonstrated that the GLP-1 neurons, originating in the nucleus of the tractus solitarius and terminating in the hypothalamus, express mRNA for the long isoform leptin receptor (OB-Rb) (28). Using c-fos immunocytochemistry, it has been shown that icv GLP-1 activates hypothalamic neurons in the PVN and that this is blocked by coadministration of exendin-(9–39) (3, 29). GLP-1 has also been shown to activate hypothalamic CRH-containing neurons (29). Data from previous studies would therefore suggest that GLP-1 is a component of the complex hypothalamic circuits controlling food intake. An icv infusion of GLP-1 in Long-Evans rats reduced the consumption of a liquid diet similarly to that in icv vehicle (11), but the effect of repeated inhibition of GLP-1 receptors has not been studied. We here assess the effects of repeated CNS administration of GLP-1 or exendin-(9–39) on both food intake and body weight in rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals and surgery
Adult male Wistar rats (250–300 g) were maintained in
individual cages under controlled temperature (21–23 C) and light (on
at 0900 h, off at 2000 h) with ad libitum access
to food (RM1 diet, SDS Ltd., Witham, UK) and water.
Rats were anesthetized with xylazine (20 mg/kg; Rompun, Bayer, Suffolk, UK) and ketamine (100 mg/kg; Ketalar, Parke-Davis, Pontypool, UK). Permanent 22-gauge stainless steel cannulas (Plastics One, Inc., Roanoke, VA) were stereotactically placed 0.8 mm posterior to the bregma on the midline and implanted 6.5 mm below the outer surface of the skull into the third cerebral ventricle. The incisor bar was set at 3 mm below the interaural line. After surgery, a small wire stylet was inserted into each cannula to prevent blockage. All animals were allowed at least 7 days to recover after surgery. After this, human angiotensin II (Sigma Chemical Co., Poole, UK) (150 ng/rat) was injected icv to confirm the correct position of the cannula. Only animals (>90%) that showed a sustained drinking response within 2 min of injection were studied. The animals were handled daily before the study, and icv injections of saline were administered to acclimatize them to the study procedure. We have previously shown that icv injections of saline or GLP-1 do not stimulate ACTH secretion after acclimatization to the injection procedure for 4 days (30), suggesting that the rats were acclimatized to the procedure after 4 days. These studies were performed in conditions otherwise identical to those of the present studies, in the same biological services unit.
Freezing and thawing of GLP-1 in solution results in inactivation of the compound (our unpublished observations). Thus, all compounds were dissolved in saline immediately before injection. In each study an injection of 10 µl peptide(s) or saline was administered via a stainless steel injector, placed in and projecting 0.5 mm below the tip of the cannula. The injector was connected by polythene tubing (id, 0.5 mm; od, 1 mm) to a Hamilton syringe (Reno, NV) in a syringe pump (model 11, Harvard Apparatus, Kent, UK) set to dispense 10 µl solution/min.
In vivo feeding studies
Animals were acclimatized to the experimental procedures by
exposure to the appropriate feeding schedule, daily handling, weighing,
and sham injections before the start of the study. Body weight was
measured daily throughout and on the day after the final injection.
Study 1: effects of icv GLP-1 on food intake and body weight. A single icv injection of GLP-1 has been shown to reduce food intake for 2 h in fasted rats when injections are given in daylight hours (3), but there is subsequent compensation so that the total 24-h food intake is unaffected by icv GLP-1 (11). To prevent such compensation, rats were schedule fed for 4 h each day. Before experimentation, total daily food intake was normal in animals acclimatized to the feeding schedule. Thus, animals were schedule fed in two periods from 0900–1100 h and from 1700–1900 h. Schedule feeding commenced 10 days before the study, which allowed sufficient acclimatization time for the animals to return to a normal daily food intake. The animals were acclimatized to the injection procedure by icv injection of saline at the start of the first feeding period for 4 days before the start of the study. At the end of this 4-day period, food intake and body weight had stabilized, and the rats were randomly divided into three groups. Animals were injected icv with either 3 nmol GLP-1 (n = 7) or saline (n = 6), or were not injected (n = 8), at 0900 h for 6 days. This dose of GLP-1 was used because we have previously established that 3 nmol GLP-1, icv, is effective at reducing 2-h food intake (3). Food intake during both 2-h periods was measured as previously described (31), and the total food intake for each study day was calculated.
Study 2: effects of icv exendin-(9–39) on food intake and body weight. Effect of icv exendin-(9–39) alone (study 2a): It has previously been shown that exendin-(9–39) is long acting and completely prevents GLP-1-induced suppression of feeding when administered 5 h before GLP-1 (28). However, a single icv injection of exendin-(9–39) to ad libitum-fed rats does not affect total food intake when measured over a 24-h period (our unpublished observation). Therefore, animals were schedule fed, having access to food for 6 h/day between 0900–1500 h. To acclimatize the rats, schedule feeding commenced 10 days before the study. For 4 days before the study, saline was administered icv at the start of the 6-h feeding period to acclimatize the animals to the injection procedure. At the end of this 4-day period, food intake and body weight had stabilized, and the rats were randomized into two groups. An icv injection of either 30 nmol exendin-(9–39) (n = 21) or saline (n = 23) was administered daily at 0900 h for 3 days, and 6-h food intake was monitored.
Effect of icv exendin-(9–39) with NPY (study 2b): Animals were fed ad libitum throughout and were randomized into two groups. An icv injection of 2.4 nmol NPY was administered to one group (n = 25). An icv injection of 2.4 nmol NPY and 30 nmol exendin-(9–39) was administered to the second group (n = 19). Injections were administered twice daily, at 0900 and 1700 h, for 8 days. Two-hour food intake after each injection and 24-h food intake were recorded daily.
Statistical analysis
The food intake and body weight data from all of the chronic
studies were compared by repeated measures ANOVA. Mean food intake for
the duration of each study was compared by Student’s t
test. Body weight data from the final day of each study were analyzed
by Student’s t test. Significance was taken as the 5%
level.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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]. The mean total daily
food intake was significantly reduced by GLP-1 compared
with that of saline-injected controls (12.5 ± 0.6 vs.
18.6 ± 0.8 g; P < 0.001).
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]. By the end of the study, animals that had received icv
GLP-1 had lost weight compared with those in the icv
saline group (-16 ± 5 vs. +5 ± 6 g;
P < 0.02). There was no difference in either food
intake or body weight between the saline control group and the
cannulated noninjected control group over the course of the study (Fig. 1).
Study 2: effects of icv exendin-(9–39) on food intake and body
weight
Effect of icv exendin-(9–39) alone (study 2a). Daily icv
administration of exendin-(9–39) for 3 days increased food intake
compared with that in saline-injected controls [F(1, 42) = 6.57;
P < 0.02; Fig. 2a].
Mean daily food intake was significantly increased by exendin-(9–39)
(21.9 ± 0.5 vs. 19.5 ± 0.4 g;
P < 0.001) compared with that of saline-injected
controls.
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]. At the end of the study, animals
that had received icv exendin-(9–39) had gained weight compared with
those treated with saline (7 ± 2 vs. 2 ± 1
g; P < 0.02).
Effect of icv exendin-(9–39) with NPY (study 2b). Animals
given NPY with exendin-(9–39) had significantly higher morning and
evening 2-h food intakes for the duration of the study compared with
those given NPY with saline [F(1, 41) = 6.38; P < 0.02
and F(1, 41) = 5.43; P < 0.05, respectively]. Daily
food intake was also significantly increased in animals given
exendin-(9–39) with NPY compared with those given NPY with
saline [F(1, 41) = 12.58; P = 0.001; Fig. 3a]. Mean daily food intake was
32.6 ± 0.8 g in animals given exendin-(9–39) with NPY and
27.0 ± 0.5 g in animals given NPY with saline
(P < 0.001).
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).
Intracerebroventricular administration of exendin-(9–39) with NPY
increased body weight compared with the effect of NPY with saline
[F(1, 41) = 4.19; P < 0.05; Fig. 3c]. At the end of
the study, animals given icv exendin-(9–39) with NPY had gained
28 ± 4 g compared with 14 ± 3 g in animals given
NPY with saline (P < 0.02).
In this study, because the animals were ad libitum fed, they were not habituated to the injection procedure, and there was, therefore, some weight loss after the first icv injection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In response to daily icv administration of GLP-1, animals continued to eat less and lose weight compared with controls for the duration of the study. Furthermore, daily icv administration of exendin-(9–39) resulted in a sustained increase in food intake and body weight in two separate experimental paradigms, either alone or in combination with NPY, a potent stimulant of food intake (4, 5, 33). This contrasts with the effect on feeding with repeated icv administration of galanin (34) and melanin-concentrating hormone (35), where the stimulatory effect on food intake is rapidly attenuated. Lack of tolerance to the effects of NPY (36), CRH (37), and leptin (38, 39) allow a change in body weight to occur after repeated administration and is supportive evidence for a physiological role of these compounds in the control of body weight. This report, demonstrating changes in body weight caused by repeated stimulation and inhibition of GLP-1 and lack of tolerance, provides evidence that GLP-1 may play a physiological role in the regulation of body weight.
GLP-1 has been shown to significantly inhibit drinking and to stimulate diuresis (13). It is possible that the fall in weight in study 1 is due in part to dehydration and the reduction in food intake secondary to this. However, the increase in feeding both with and without NPY caused by exendin-(9–39) mitigates against this.
It has been suggested that GLP-1 only suppresses feeding by induction of conditioned taste aversion (40), but high doses of GLP-1 were used in that study. Tang-Christensen et al. have demonstrated, using the two-bottle taste aversion paradigm, that GLP-1 does not induce taste aversion at doses that reduce food intake (13). Similar results have recently been found when GLP-1 is administered to the PVN (41, 42, 43). The finding that icv injection of the specific GLP-1 receptor antagonist increases food intake and body weight would also suggest that endogenous GLP-1 does not normally suppress feeding by induction of conditioned taste aversion alone (40). The inhibitory effect of GLP-1, but not of CRF, on feeding is completely abolished in monosodium glutamate-lesioned rats (44). Monosodium glutamate causes extensive damage to the arcuate nucleus as well as to parts of the sensory circumventricular organs. These rats also display normal aversive responses to peripheral administration of lithium chloride and D-amphetamine (44). Blockade of an agent purely inducing conditioned taste aversion would not be expected to produce a sustained increase in feeding and an increase in body weight. Studies with cholecystokinin (CCK) have shown that it is both a satiety factor (45) and can cause conditioned taste aversion (46). Rats that do not express the CCK (A) receptor are obese despite slowed gastric emptying (47). Despite its aversive effects, therefore, CCK is thought to have an important role in the control of food intake. This may well be the case for GLP-1.
Surprisingly, targeted disruption of the GLP-1 receptor gene in mice results in a phenotype with normal body weight, although they do have abnormal glucose tolerance. It has therefore been suggested that this cloned GLP-1 receptor plays no significant role in the control of feeding (48). Studies of animals with targeted disruption of either the NPY (49) or galanin (50) genes have also shown no effect on feeding. One possible explanation for these negative findings is that gene disruption allows compensatory mechanisms to develop. Consistent with this argument is the observation that although targeted disruption of the NPY gene is not, by itself, associated with a change in food intake, when this knockout mouse is crossed with the leptin-deficient ob/ob mouse, the overeating and obesity are significantly reduced (21). Alternatively, the lack of an obese phenotype in receptor knockout animals could result from a second active receptor, and that in neurotransmitter knockouts could result from a related alternative neurotransmitter system. In this regard it is of interest that the existence of other GLP-1 receptors has been claimed (51, 52, 53, 54).
Intracerebroventricular administration of exendin-(9–39) in combination with NPY at the start of the light phase had a consistently greater effect on 2-h food intake compared with administration at the end of the light phase, whereas there was no difference after icv administration of NPY alone at these times. There is a diurnal rhythm in feeding in ad libitum-fed rats, with most feeding occurring at night (55, 56). It has previously been shown that the effect of icv exendin-(9–39) is greater in satiated animals (3) than in fasted animals (3, 12), and that it has no effect when administered at the onset of the dark phase (28). Our results are compatible with a diurnal variation in GLP-1 activity, being low when feeding normally commences and high at the end of the feeding period. This is consistent with our original hypothesis that GLP-1 is a physiological satiety factor.
Leptin has been shown to reduce body weight after either CNS or peripheral administration (38, 39, 57). Acute administration of exendin-(9–39) has recently been shown to greatly attenuate the reduction in feeding and body weight induced by leptin (28). CNS GLP-1 neurons express OB-Rb mRNA. They thus may be a target for leptin. We have therefore proposed that the inhibition of food intake by leptin is mediated in part through the release of CNS GLP-1 (28).
In conclusion, GLP-1, which is a potent inhibitor of feeding, appears to play a physiological role in the regulation of body weight. The future development of GLP-1 agonists that act in the CNS may ultimately lead to a novel agent for the management of obesity.
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Acknowledgments |
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Footnotes |
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2 United Kingdom Medical Research Council Research Fellow.
3 Wellcome Trust Research Fellow.
4 R. D. Lawrence BDA Research Fellow.
5 United Kingdom Medical Research Council Student.
6 Wellcome Trust Prize Student.
Received June 5, 1998.
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C. M. B. Edwards, S. A. Stanley, R. Davis, A. E. Brynes, G. S. Frost, L. J. Seal, M. A. Ghatei, and S. R. Bloom Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E155 - E161. [Abstract] [Full Text] [PDF]
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Y.-H. Choi and G. H. Anderson An Interaction between Hypothalamic Glucagon-Like Peptide-1 and Macronutrient Composition Determines Food Intake in Rats J. Nutr., June 1, 2001; 131(6): 1819 - 1825. [Abstract] [Full Text]
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M. Zander, M. Taskiran, M.-B. Toft-Nielsen, S. Madsbad, and J. J. Holst Additive Glucose-Lowering Effects of Glucagon-Like Peptide-1 and Metformin in Type 2 Diabetes Diabetes Care, April 1, 2001; 24(4): 720 - 725. [Abstract] [Full Text]
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 A. INUI Transgenic study of energy homeostasis equation: implications and confounding influences FASEB J, November 1, 2000; 14(14): 2158 - 2170. [Abstract] [Full Text]
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A. Inui Transgenic Approach to the Study of Body Weight Regulation Pharmacol. Rev., March 1, 2000; 52(1): 35 - 62. [Abstract] [Full Text] [PDF]
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N. J. MacLusky, S. Cook, L. Scrocchi, J. Shin, J. Kim, F. Vaccarino, S. L. Asa, and D. J. Drucker Neuroendocrine Function and Response to Stress in Mice with Complete Disruption of Glucagon-Like Peptide-1 Receptor Signaling Endocrinology, February 1, 2000; 141(2): 752 - 762. [Abstract] [Full Text] [PDF]
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L. Baggio, F. Adatia, T. Bock, P. L. Brubaker, and D. J. Drucker Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, beta -Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice J. Biol. Chem., October 27, 2000; 275(44): 34471 - 34477. [Abstract] [Full Text] [PDF]
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J. Lovshin, J. Estall, B. Yusta, T. J. Brown, and D. J. Drucker Glucagon-like Peptide (GLP)-2 Action in the Murine Central Nervous System Is Enhanced by Elimination of GLP-1 Receptor Signaling J. Biol. Chem., June 8, 2001; 276(24): 21489 - 21499. [Abstract] [Full Text] [PDF]
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