The orexigenic effect of melanin-concentrating hormone (MCH) is influenced by sex and stage of the estrous cycle☆
Introduction
Melanin-concentrating hormone (MCH) is a 19-amino acid peptide that is synthesized in the mammalian lateral hypothalamus (LH) and zona incerta (ZI) [1]. In rodents, MCH exerts its varied actions through the MCH-1 receptor, a G protein-coupled receptor that is widely expressed throughout the central nervous system [2]. First identified for its role in regulating the aggregation of melanin pigment in teleost fish [3], more recent studies involving rodents implicate MCH in the control of food intake and the regulation of fluid and energy balance. For example, acute hypothalamic or ventricular (i.c.v.) administration of MCH increases food intake [4], [5], [6], [7], and chronic treatment with an MCH-1 receptor agonist or transgenic overexpression of MCH promotes hyperphagia, weight gain, and lipogenesis [8], [9]. In addition to its potent orexigenic effect, MCH has been reported to stimulate water intake, independent of food intake, in male rats [4], [10]. Finally, i.c.v. infusion of MCH decreases core body temperature [11], [12], and targeted deletion of the genes encoding either pre-pro MCH or the MCH-1 receptor stimulates locomotor activity, metabolic energy expenditure, and thermogenesis [13], [14], [15].
At present, only two studies have investigated whether the orexigenic effect of MCH is mediated by an increase in meal size, meal number, or both. Because food intake is the product of meal size and meal number [16], this represents an important initial step in characterizing the mechanism by which MCH influences ingestive behavior in the rat. In one study involving diet-induced obese rats, the hypophagia induced by T-226296, a selective MCH-1 receptor antagonist, was mediated by a decrease in meal size, not meal number [17]. This suggests that endogenous MCH influences feeding by selectively affecting the controls of meal size. However, in a more recent study, acute administration of MCH increased food intake primarily via an increase in the number of meals consumed by lean, male rats [10]. Thus, additional studies are necessary to reconcile the discrepant findings regarding meal number.
Also requiring additional research is the notion that the behavioral response to MCH may differ in male and female rats. While the majority of rodent studies investigating the behavioral effects of MCH have been conducted in male rats, a recent study involving female rats provided the first evidence that the orexigenic and dipsogenic effects of MCH may be sexually dimorphic. In this study, the hyperphagia induced by acute i.c.v. administration of MCH was decreased by estradiol treatment in ovariectomized (OVX) rats [18]. Unlike that observed in male rats [4], [10], MCH failed to stimulate water intake, independent of food intake, in either oil- or estradiol-treated OVX rats [18].
The primary aim of this study was to investigate whether the behavioral response to MCH is reduced in female rats, relative to male rats. To investigate this hypothesis, the effects of MCH on food and water intakes, meal patterns, and locomotor activity were examined in male and female rats. To further characterize the impact of estradiol on the behavioral effects of MCH, female rats were OVX and treated with a physiological regimen of estradiol or oil vehicle replacement. In a second experiment, ovarian-intact rats were studied at different stages of the estrous cycle in order to examine the influence of endogenous estradiol on the orexigenic effect of MCH.
Section snippets
Animals and housing
Twenty-three female and seven male Long-Evans rats (Charles River Breeding Laboratory, Raleigh, NC), weighing 225–250 g at study onset, were housed individually in custom-designed cages. In Experiment 1, the cages were connected to running wheels (Wahmann; 35 cm in diameter) and equipped with feeding niches that provided access to spill-resistant food cups mounted on weight-sensitive load beams. Infrared beams, located on either side of the feeding niches and centered above the feeding cups,
Experiment 1
During the first 2 h following drug treatment, MCH influenced dark-phase food and water intakes, F(2,40) = 21.37 and 9.62, respectively, Ps < 0.05 (Fig. 1A,B). At this time, both doses of MCH increased food intake in oil-treated OVX and male rats, Ps < 0.05 (Fig. 1A). In contrast, only the largest dose of MCH increased food intake in EB-treated OVX rats, P < 0.05. During this same 2-h interval, both doses of MCH increased water intake in male rats, Ps < 0.05 (Fig. 1B). Although there was a tendency for
Discussion
A major goal of the present study was to determine whether the behavioral effects of MCH are sexually dimorphic. In support of this hypothesis, the increase in food intake, meal size, and water intake following MCH treatment was attenuated in female rats (i.e., EB-treated OVX rats), relative to male rats. Interestingly, MCH-induced a short-term decrease in wheel running that, unlike its effect on ingestive behavior, was similar in male and female rats. A secondary goal of the present study was
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This work was supported by a grant from the NIH (MH-63932) and an NIH Joint Neuroscience Predoctoral Training Grant (NIH, NIDCR, NIGMS, NIMH, NINDS, NINR).