Elsevier

Physiology & Behavior

Volume 70, Issue 5, 15 September 2000, Pages 533-536
Physiology & Behavior

Attenuation of the anorectic effects of cholecystokinin and bombesin by the specific amylin antagonist AC 253

https://doi.org/10.1016/S0031-9384(00)00302-4Get rights and content

Abstract

Previous studies provided evidence for an interaction between the satiety effects of cholecystokinin (CCK), bombesin (BBS), and amylin. Amylin released in response to CCK (or BBS) was supposed to mediate part of CCK's (or BBS's) anorectic effect since the amylin and calcitonin gene-related peptide (CGRP) antagonist CGRP 8–37 attenuated their anorectic action. Due to the low specificity of CGRP 8–37 for amylin vs. CGRP binding sites, the aim of the present study was to test whether the specific amylin antagonist AC 253 also influenced the anorectic effects of CCK and BBS. Injections took place at dark onset in 24-h food-deprived rats. At a dose that attenuated the anorectic effect of amylin (5 μg/kg), the amylin antagonist AC 253 (500 μg/kg) significantly attenuated the anorectic effects of CCK and BBS (0.5 μg/kg). It can therefore be concluded that amylin, rather than CGRP, mediates part of the anorectic effects of CCK and BBS.

Introduction

Satiety peptides appear to be involved in the control of the size of individual meals. These peptides, e.g., cholecystokinin (CCK) [12], bombesin (BBS) [21], and amylin [36] are released in response to feeding and reduce food intake at least in part by reducing meal size [12], [17], [21], [29]. While CCK's and BBS's anorectic effects have been known for a long time, the role of amylin, a pancreatic beta-cell hormone first isolated in 1986 [34], as a satiety peptide has been recognized in recent years only [4], [14], [23], [25]. Apart from being a satiety peptide, there is evidence that amylin may also act as a long-term regulator of feeding [1], [7], [30].

Numerous studies have established the central nervous system as the site of the short-term satiety action of peripherally administered amylin [13], [19], [24], [28]. Amylin seems to act directly on neurons in the area postrema/nucleus of the solitary tract (AP/NTS) region to bring about its anorectic effect. In contrast, at least part of the anorectic effects of CCK and BBS is mediated by abdominal vagal or non-vagal afferents that project to the AP/NTS region [12], [21]. There is evidence, however, that both peptides also partly exert their anorectic action by a direct central effect [6], [10].

Previous studies have shown that the amylin and calcitonin gene-related peptide (CGRP) receptor antagonist CGRP 8–37 attenuates the anorectic effects of CCK and BBS [16], [18]. Since this was observed in non-diabetic, but not in streptozotocin-diabetic rats [18] whose secretory capacity for amylin and insulin is markedly reduced [26], we concluded that part of CCK's and BBS's anorectic effects is due to their propensity to release amylin from the pancreas [16], [18]. Partial mediation of CCK's and BBS's effects by CGRP rather than amylin could however not be excluded because CGRP 8–37 acts as an antagonist at both amylin and CGRP binding sites [5], [35], and CGRP's anorectic effect seems to be similar to that of amylin after peripheral administration [13], [19], [22], [24]. Further, streptozotocin-treatment may also lead to a depletion of CGRP in sensory nerves [31] and, at least temporarily, to a decrease of the plasma CGRP levels [32].

The present study therefore aimed at clarifying whether the attenuation of CCK's and BBS's anorectic effects by CGRP 8–37 was in fact due to a blockade of the action of endogenous amylin rather than that of endogenous CGRP. We therefore co-administered CCK or BBS with the specific amylin antagonist AC 253 since in contrast to CGRP 8–37, AC 253 is about 400-fold selective for amylin vs. CGRP binding sites [2], [37].

Section snippets

Animals and housing conditions

Three groups of adult male Sprague–Dawley rats (OFA, BRL, Füllinsdorf, Switzerland; body weight 350–400 g) were used in the experiments. Each experiment was performed using a different group of rats (n=24 in each group). The rats were individually housed in specially designed Plexiglass cages with wire bottoms. A small tunnel (length: 15 cm; diameter: 6.5 cm) provided access to spillage-resistant feeding cups [17]. Rats had ad libitum access to water and food (powdered medium-fat diet [MF]

Experiment 1: Influence of AC 253 (500 μg/kg) on the anorectic effect of amylin (5 μg/kg) in 24-h food-deprived rats (Fig. 1)

We first tested the influence of the specific amylin antagonist AC 253 on the anorectic effect of amylin under test conditions similar to previous studies showing that CGRP 8–37 and the amylin antagonist AC 187 attenuated amylin's anorectic action [6], [20], [33] (AC 187 and AC 253 are practically equipotent and have a similar specificity profile [2]).

While a preliminary experiment had shown that AC 253 leaves basal food intake unaffected under the present experimental conditions, AC 253

Discussion

Previous studies had shown that the amylin and CGRP receptor antagonist CGRP 8–37, which blocks the anorectic action of amylin and CGRP [16], [18], attenuated the anorectic effects of CCK and BBS [16], [18]. We now show a similar effect with the specific amylin receptor antagonist AC 253.

While AC 253 reduced the anorectic effect of amylin, the dose of AC 253 used in the present study had no effect on food intake on its own under the present experimental conditions. The latter finding agrees

Acknowledgements

The supply of AC 253 by Amylin Pharmaceuticals (San Diego, CA, USA) and the financial support of the Swiss National Research Foundation (grant # 3100-045 583.95/1) are gratefully acknowledged.

References (37)

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