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Division of Endocrinology and Metabolic Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom W12 0NN
Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Division of Endocrinology and Metabolic Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London, United Kingdom W12 0NN. E-mail: sbloom{at}rpms.ac.uk
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Abstract |
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Introduction |
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Recently, a role for MCH in the central regulation of feeding behavior has been suggested. Qu et al. (10) found MCH messenger RNA (mRNA) levels to be increased in the hypothalamus of genetically obese ob/ob mice compared to those in wild-type and ob/+ controls. Expression was further enhanced in all groups of mice in the fasted state. Intracerebroventricular (icv) injection of 5 µg MCH was reported to increase feeding in Long-Evans rats. This dose was studied on four separate occasions at different stages of the dark phase, and a variable increase in food intake was found that was only consistently significant when measured 4 h after injection. A final experiment using 30 µg MCH showed no further increase above the control level compared to that in the 5-µg dose studies. Paradoxically, Presse et al. reported anorectic effects of icv MCH in male Wistar rats (11), with a reduction in food intake seen from 2–24 h after injection of 1–100 ng MCH at the beginning of the dark phase. They further demonstrated that fasting rats for 24–48 h caused a 3-fold increase in hypothalamic MCH mRNA levels.
The interaction between NEI and MCH remains unclear. Intracerebroventricular injection of MCH has been shown to affect the hypothalamic-pituitary-adrenal axis, although with conflicting results (12, 13). Bluet Pajot et al. (13) reported a decrease in plasma ACTH after icv MCH that was antagonized by prior administration of NEI. Although using a different experimental protocol an increase in ACTH with MCH was found by Jezova et al. (12), the action of NEI was not examined. A possible function in water homeostasis has been suggested by studies characterizing hypothalamic MCH gene expression and peptide immunoreactivity in response to osmotic stresses (14, 15). This has been supported by central infusion studies in sheep, which demonstrate that both MCH and NEI have a natriuretic and a diuretic effect (16).
Our aim was to characterize the in vivo roles of MCH and NEI in the control of food intake in the rat. MCH was injected at nanogram and microgram doses at the beginning of the light and dark phases. The effects of chronic exposure to MCH on food intake and body weight were investigated by repeated injections over 8 days.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals
Adult male Wistar rats (250–300 g) were maintained in
individual cages under controlled temperature (21–23 C) and light (13
h of light, 11 h of darkness), with continuous access to chow
blocks (RM1 diet, SDS, Witham, UK) and water. The animal procedures
undertaken were all approved by the British Home Office Animals
Scientific Procedures Act 1986 (Project License 90/00316).
Intracerebroventricular cannulation and injections
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,
Roanoke, VA) were stereotactically placed 0.8 mm posterior to the
bregma in the midline and implanted 6.5 mm below the outer surface of
the skull into the third cerebral ventricle. After surgery, a small
wire plug was inserted into each cannula to prevent blockage, and
animals were allowed to recover for 7 days. All animals received an icv
injection of human angiotensin II (Sigma, Poole, UK; 150 ng/rat), and
those that showed a sustained drinking response within 2 min were used
in the study. They were handled daily for 5 days before each study to
minimize nonspecific stress. All compounds were dissolved in 0.9%
saline, and each study involved an injection of 10 µl peptide or
saline. Substances were administered by a stainless steel injector,
placed in and projecting 1 mm below the tip of the cannulas. The
injector was connected by polythene tubing (id, 0.5 mm; od, 1 mm) to a
Hamilton syringe (Reno, NV) in a pump set to dispense 10 µl
solution/min. After injection, animals were returned to cages
containing preweighed chow and observed. The placement of the cannulas
was verified at the end of the studies by the injection of 10 µl dye,
removal of the brain, and visual examination of coronal brain
slices.
Effect of MCH on feeding
A dose-response study was performed with satiated animals at the
beginning of the light phase using six groups on a single occasion
(seven rats per group for all doses other than the highest dose when
n = 4). Animals were injected with either saline or 150 ng, 500
ng, 1.5 µg, 5 µg, or 15 µg MCH. Immediately after injection,
animals were returned to their home cages, which contained a known
amount of rat chow. Two, 4, and 24 h after each injection, the
remaining food was carefully collected and weighed using an ATP
Instrumentation GW 600 balance (ATP Instrumentations, Ltd.,
Ashby-De-la-Zouch, Leicestershire, UK) recording to the nearest
0.1 g. These time points were chosen after performing preliminary
studies to observe the duration of effect of MCH.
As nanogram doses had previously been shown to decrease food intake at the beginning of the dark phase (11), when rats begin their feeding period, four groups of animals (seven to nine rats per group) were studied at this time point. They were injected with either saline or 10 ng, 100 ng, or 5 µg MCH. Food intake was measured 2 and 4 h after each injection.
Effects of chronic administration of MCH on food intake and body
weight
Two groups of rats (n = 23 and 25) were studied over an
8-day period and received 5 µg MCH or saline, icv, twice daily, at
the beginning and 6 h after the onset of the light phase. They
were weighed daily and 2-h food intake was measured after each
injection. On day 9, animal groups were crossed over such that the
saline group received 5 µg MCH, and the MCH group received saline at
the beginning of the light phase.
Effect of NEI on MCH-induced feeding
Initially, the effect of NEI alone on feeding was assessed. Five
groups of satiated animals (six or seven rats per group) were studied
on a single occasion at the beginning of the light phase. They were
injected with either saline or 0.3, 0.9, 3, or 9 µg NEI (equimolar
amounts to those chosen for MCH). Food intake was measured 2 h
after each injection.
Four groups of satiated animals (seven or eight rats per group) were studied at the beginning of the light phase and injected with saline, 5 µg MCH, 3 µg NEI (an equimolar amount to MCH), or a combination of the two peptides.
Statistical analysis
Food intake (grams) is expressed as the mean ±
SEM on graphs and in the text is referred to as the percent
increase compared with the control value. Results obtained after
increasing doses of MCH were analyzed by ANOVA followed by Dunnett’s
test for pairwise comparison. Unpaired two sample Student’s
t test was used to compare 2-h food intake in the chronic
studies and in the acute study with MCH and NEI. P <
0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The lowest
effective dose was 1.5 µg, with an increase in food intake of
325 ± 7% [P < 0.05 compared with the saline
group (0.9 ± 0.4 g)]. A dose of 5 µg produced an effect
of 425 ± 9% (P < 0.001 vs. saline),
and 15 µg produced an effect of 462 ± 30% (P
< 0.005 vs. saline). There was no significant difference
between these two groups. At the 15-µg dose, animals showed abnormal
locomotor activity, which was not elicited at any other dose.
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). The effect was, however, less than that seen at
2 h (260 ± 17%; P < 0.05, saline group
vs. 15 µg MCH). There was no difference in food intake in
any group compared to the saline group 24 h after injection (data
not shown). This indicates that the major feeding effect of MCH occurs
within the first 2 h.
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]. This increase
was no longer significant at 4 h. Lower doses of MCH did not alter
food intake at any time point studied.
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). A greater effect was consistently seen with
the early light phase injection when the rats were fully satiated (Fig. 4a). There was an overall average increase in food intake of 197
± 9% vs. the control value. Body weights showed no
difference on days 1–5 in the MCH group vs. the saline
group (291 ± 5 vs. 286 ± 6 g on day 1;
280 ± 6 vs. 280 ± 12 g on day 5). Food
intake over 24 h was also not altered throughout the study period
in the two groups (24 ± 2 vs. 22 ± 2 g on
day 1; 23 ± 1 vs. 23 ± 2 g on day 5). No
difference was seen in response to MCH from days 6–8. At cross-over on
day 9, MCH caused a significant increase in 2-h food intake when
administered to the control group (245 ± 51% increase
vs. saline-treated animals; P < 0.05),
confirming the development of true tachyphylaxis in response to
repeated doses of MCH on the effect of food intake in these
animals.
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).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This work supports the findings by Qu et al. (10), but contradicts those of Presse et al. (11), who reported that icv MCH reduced food intake by 40–75% from 2–24 h after injection when studied at doses of 1, 10, and 100 ng at the beginning of the dark phase. The icv dark phase studies by Qu et al. used Long-Evans rats with MCH doses 50- to 300-fold higher (5 and 30 µg) than those studied by Presse et al. in Wistar rats. Our work addresses the major differences between the two previous studies by observing the effects of icv administration of MCH at different times in the light-dark phase and spanning the dose range covered by both studies. These data provide convincing evidence that icv MCH is a stimulator of feeding in both the light and dark phases. The greater effect of MCH at the beginning of the light phase compared to that in the dark phase may reflect the increase in endogenous MCH, as demonstrated by the increase in mRNA levels during the dark phase (13).
We have further examined the orexigenic effects of repeated icv administration of MCH. No increase in body weight was seen during the initial 5-day period when MCH stimulated 2-h food intake. This contrasts to the dramatic increase in body weight induced by neuropeptide Y (NPY) (17). Tolerance to the effect of MCH on food intake was seen by day 6. Again, this contrasts with NPY, which continues to stimulate feeding for as long as it is administered, in one report up to 10 days (17). Tachyphylaxis and lack of increase in body weight raise doubts of a pathophysiological role for central MCH in the development of obesity.
Recent studies with galanin by Smith et al. (18) also demonstrated tachyphylaxis of repeated icv galanin to feeding, which led them to propose that it may not have an important role in feeding. However, a physiological role for galanin in the control of fat intake was later demonstrated by Akabayashi et al. (19), who found peptide levels in the paraventricular nucleus to be positively correlated with fat ingestion. In addition, injection of antisense oligonucleotides to galanin mRNA into the paraventricular nucleus caused a reduction in fat intake. Therefore, an action for endogenous MCH in the central regulation of feeding remains a possibility despite our findings.
Despite recent identification of specific MCH receptors on mouse melanoma cells (20), the absence of a satisfactory radioligand has hindered research on MCH receptor structure and function. Our work demonstrating the lack of interaction between NEI and MCH on feeding is compatible with the presence of more than one receptor type mediating the central effects of MCH, as NEI interacts with its actions on both ACTH release and water homeostasis (13, 16). The presence of a separate NEI receptor mediating these effects may be another possibility.
There is now good evidence to support the role of MCH as a stimulator, but not an inhibitor, of feeding. Chronic administration shows that this stimulatory effect is maintained for 5 days before tolerance developes. The inability of MCH to maintain hyperphagia and cause obesity does not exclude an immediate physiological role in controlling feeding, but may indicate that MCH is not involved in long term body weight maintenance. Future work involving the blockade of endogenous hypothalamic MCH by the development of a specific antagonist or a monoclonal antibody and examining interactions with other peptides acting in the central control of feeding, such as NPY, glucagon-like peptide-1, and leptin, will allow clarification of the role of MCH in appetite regulation.
Received July 15, 1997.
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