Elsevier

Physiology & Behavior

Volume 77, Issues 2–3, November 2002, Pages 411-416
Physiology & Behavior

Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition

https://doi.org/10.1016/S0031-9384(02)00883-1Get rights and content

Abstract

Central melanocortin (MC) receptor agonists inhibit food intake and may be downstream mediators of the effects of central leptin, which (1) reduces food intake by selectively decreasing meal size and (2) augments the feeding-inhibitory effects of gastrointestinal food stimuli. Central administration of the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its effects on meal pattern and potential interactions with gastrointestinal controls of food intake remain unclear. We examined meal patterns and intake in male Sprague–Dawley rats following central intracerebroventricular administration of MTII (0.01–1.0 nmol) in two situations: (1) during daytime 60-min scheduled access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5% glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads and MTII reduced subsequent glucose intake. However, no dose of MTII augmented the reductions in food intake produced by duodenal glucose alone. During overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced food intake, meal size, meal duration, and body weight, and increased the satiety ratio (duration of intermeal interval/preceding meal size) but did not change meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces food intake by a selective reduction in meal size and not meal frequency, and (2) suggest that MTII increases the feeding-inhibitory potency of negative feedback signals critical to the control of meal size during spontaneous chow access, but not scheduled access to palatable liquid nutrient solutions.

Introduction

Melanocortin (MC) signaling in the central nervous system has been implicated in the control of energy homeostasis and food intake in multiple mammalian species, including primates [1]. Central administration of the pro-opiomelanocortin (POMC) gene product, α-melanocyte stimulating hormone (α-MSH), an endogenous MC-4R agonist, or the synthetic MC-3/4R agonist, MTII, reduces body weight and food intake [2], [3], [4]. Conversely, blockade of central MCR with the endogenous MC-4R antagonist, AGRP, or the synthetic MC-3/4R antagonist, SHU9119, increases body weight and produces hyperphagia [1], [2], [3], [4], [5], [6].

Central MCs have been proposed as downstream mediators of the effects of leptin, an adiposity hormone that acts in the brain to reduce food intake and body weight [7]. Hypothalamic POMC nuclei express leptin receptors [8], and leptin induces c-fos expression in and depolarizes hypothalamic arcuate nucleus POMC neurons [9], [10]. Fasting reduces circulating leptin and hypothalamic POMC mRNA expression, while leptin administration in nondeprived and fasted rats increases POMC mRNA [11], [12]. In behavioral studies, subthreshold doses of SHU9119 or AGRP that fail to increase feeding when given alone block the inhibition of feeding produced by central leptin [13], [14]. Targeted transgenic disruption of the MC-4R produces obesity in mice [15], and MC-4R-deficient mice do not reduce their food intake in response to intracerebroventricular leptin injections [16].

Leptin has been demonstrated to affect food intake by selectively reducing meal size without changing meal frequency [17], [18]. This effect has been interpreted to suggest that leptin reduces food intake by interacting with the neural mechanisms that mediate postoral negative feedback controls of ingestion during a meal. In support of this view, a dose of leptin that has no effect on intake when given alone significantly enhances the feeding suppression produced by exogenous administration of the gut satiety peptide, cholecystokinin (CCK), or a gastric nutrient preload [19], [20], [21].

Gastric nutrient preloads stimulate multiple postoral sites involved in the negative feedback control of ingestion, including the duodenum, where nutrient infusions potently reduce food intake [22]. To determine whether central MCR agonists might reduce feeding by modulating the potency of postoral negative feedback signals, we evaluated the effect of central MTII administration on the feeding inhibition produced by duodenal glucose preloads. We also examined the effects of MTII on nocturnal spontaneous meal pattern to determine if, like leptin, central MC-4R agonists reduce food intake by reducing meal size.

Section snippets

Methods

Male Sprague–Dawley rats (Charles River), weighing between 300 and 325 g at the start of experiments and individually housed at 12:12 h light–dark cycle, served as subjects. Rats were anesthesized with a mixture of pentobarbital (8.9 μg/ml) and chloral hydrate (42.5 μg/ml) (3 ml/kg ip) and implanted with duodenal catheters and third intracerebral ventricle (3ICV) cannulas. The duodenal catheter was implanted as previously described [23]. The end of the catheter was routed subcutaneously to the

Data analysis

Glucose test intakes on nontest days (intraduodenal saline infusion only) were averaged for each animal, and test day difference scores were calculated by subtracting intakes under each of the four treatment conditions from the average intake in the intraduodenal saline alone condition. Difference scores were analyzed with repeated-measures factorial ANOVA for the factors of intraduodenal infusion and intracerebroventricular infusion. Planned t comparisons using the mean square error term from

Baseline control intake

During training, neither intraduodenal saline infusions alone nor intracerebroventricular ACSF alone significantly altered subsequent glucose intake, overnight pellet consumption, meal size, meal frequency, intermeal interval, or meal duration compared to no infusion control conditions in any of the three MTII dose groups (Ps>.1). Sixty-minute glucose intake (range 12.8–15.4 ml), 12-h pellet intake (range 23.4–28.4 g), and pellet meal size (range 2.8–3.3 g) did not differ across the three MTII

Discussion

Intracerebroventricular MTII (0.1 and 1 nmol) reduced intake in two test situations: (1) during a scheduled 1-h daytime access to glucose solution, measured 2 h after MTII injection, and (2) during overnight spontaneous pellet intake, where ingestion was still reduced 19 h after injection. These effective time points and doses are consistent with several recent findings [3], [25], and the MTII-elicited reduction of glucose intake extends the findings of MTII-induced decreases in dark phase food

Acknowledgements

This work was supported by NIH DK47208. The authors wish to thank Drs. Nori Geary and Gerry Smith for their helpful comments and discussion.

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