Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition
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.
References (32)
- et al.
Melanocortin mediated inhibition of feeding behavior in rats
Neuropeptides
(1998) - et al.
Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area
Neuron
(1999) - et al.
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
Cell
(1997) - et al.
Leptin amplifies the feeding inhibition and neural activation arising from a gastric nutrient preload
Physiol. Behav.
(2001) - et al.
TongueTwister: an integrated program for analyzing lickometer data
Physiol. Behav.
(1996) - et al.
Integration of NPY, AGRP and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat
Neuron
(1999) - et al.
Central melanocortin receptors mediate changes in food intake in the rhesus macaque
Endocrinology
(2001) - et al.
Effect of intracerebroventricular alpha-MSH on food intake; adiposity; c-Fos induction; and neuropeptide expression
Am. J. Physiol., Regul. Integr. Comp. Physiol.
(2000) - et al.
Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight
J. Neurosci.
(1998) - et al.
A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo
Endocrinology
(1998)