Melanin-concentrating hormone-1 receptor antagonism decreases feeding by reducing meal size

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Abstract

Prior work has demonstrated that melanin-concentrating hormone-1 (MCH-1) receptor antagonism decreases food intake and body weight in obese rodents. The purpose of this study was to determine if the MCH-1 receptor antagonist-mediated hypophagia was due a decrease in meal size, meal frequency, or both. We performed a meal pattern analysis in free-feeding hyperphagic diet-induced obese (DIO) rats treated with 1, 3 or 10 mg/kg p.o. of the MCH-1 receptor antagonist T-226296 (a (−)enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-fluoro[1,1′-biphenyl]-4 carboxamide). Food intake was continuously monitored for 24 h using a BioDAQ® food intake monitoring system. A total of 10 mg/kg T-226296 significantly decreased body weight and 24-h food intake, and had no effect on locomotor activity. The decrease in food intake was due to a reduction in meal size, not meal frequency. We conclude that MCH-1 receptor antagonism with T-226296 decreases food intake in DIO rats by selectively reducing meal size, and that the reduced food intake is not due to a generalized behavioral malaise.

Introduction

Melanin-concentrating hormone (MCH) has been implicated in the control of feeding behavior and energy homeostasis. Within the central nervous system, MCH is expressed in the lateral hypothalamus and the zona incerta (Bittencourt et al., 1992). Hypothalamic MCH expression is regulated by the nutritional status of the animal, with starvation or deficient leptin signaling (Lepob/ob) increasing mRNA levels (Qu et al., 1996). Intracerebroventricular (i.c.v.) MCH administration produces hyperphagia (Qu et al., 1996) while obesity and insulin resistance result from chronic MCH administration (Della-Zuana et al., 2002, Ito et al., 2003) or MCH overexpression (Ludwig et al., 2001). Lastly, ablation of the prohormone precursor of MCH (which encodes MCH, neuropeptide EI and neuropeptide GE) results in hypophagia and leanness (Shimada et al., 1998).

In rodents, MCH acts through the MCH-1 receptor, which is a member of the G-protein coupled receptor family (Saito et al., 1999). Messenger RNA for MCH-1 receptor has been identified in several brain regions including those associated with olfaction, the hippocampus, amygdala, the shell of the nucleus accumbens, and the ventromedial, dorsomedial and arcuate nuclei of the hypothalamus (Chambers et al., 1999, Lembo et al., 1999, Saito et al., 1999, Saito et al., 2001). MCH-1 receptor expression has also been observed in several brainstem nuclei, including the locus coeruleus, hypoglossal, motor trigeminal and dorsal motor vagus (Saito et al., 2001). Immunohistochemical analysis has demonstrated that MCH-1 receptor protein is present in the dorsomedial and ventromedial nuclei of the hypothalamus (Chambers et al., 1999). The receptor distribution is consistent with the actions of MCH on feeding behavior and energy homeostasis. Genetic ablation of the MCH-1 receptor produced leanness and resistance to diet-induced obesity (Chen et al., 2002, Marsh et al., 2002), similar to the MCH deficient mice. Unlike the MCH deficient mice, however, MCH-1 receptor deficient mice are hyperphagic and the leanness is due to a hyperactive and hypermetabolic phenotype (Chen et al., 2002, Marsh et al., 2002). Recently, a second MCH receptor has been identified in non-rodent species (MCH-2 receptor) (An et al., 2001, Sailer et al., 2001, Wang et al., 2001); however, the physiological role of this receptor has not been determined.

Diet-induced obesity (DIO) in rodents has been used as an animal model to investigate the interaction between the environment and genetic background. One such model extensively used is the outbred Sprague–Dawley rat. When outbred Sprague–Dawley rats are placed on an energy dense, high fat diet, there is a wide distribution in body weight gain ranging from animals that becomes very obese (DIO) to others that remain as lean as animals fed a lower fat diet (diet-resistant (DR)) (Archer et al., 2003, Chang et al., 1990, Levin et al., 1983, Sclafani and Springer, 1976). The physiologic aspects of the diet-induced obesity in this model replicate many of the features observed with the human obesity syndrome: a polygenic mode of inheritance (Levin et al., 1997, Levin and Sullivan, 1987), a persistence of the phenotype once it is established (Levin et al., 1989), and dysregulated glucose homeostasis (Chang et al., 1990). These features have made the Sprague–Dawley DIO model an attractive tool for investigating human obesity.

Prior work in Sprague–Dawley DIO rats has shown that hyperphagia and increased energy efficiency often accompany the persistent obesity produced by long-term, high-fat feeding (Levin et al., 1985), and that the hyperphagia is due to an increase in meal size, not meal frequency (Farley et al., 2003). Recent reports have shown that pharmacological blockade of MCH-1 receptor in lean rodents abolishes MCH-induced feeding (Takekawa et al., 2002), and promotes hypophagia and weight loss in rodents (Borowsky et al., 2002, Haynes et al., 2001, Lewis et al., 2002), consistent with its role in energy homeostasis. Although the hypophagia produced in rodents is robust and has been replicated with three different chemical entities, it is not known if this action is mediated through a reduction in meal size, meal frequency, or both. This study aimed to use 24-h meal pattern analysis to determine how MCH-1 receptor blockade affects meal size and frequency in a model of rat diet-induced obesity.

Section snippets

Animals

150 male Sprague–Dawley rats (Charles River Laboratories, Wilmington, MA) were weaned onto a semipurified diet containing 45% of calories as fat with an energy density of 4.7 kcal g−1 (D12451, Research Diets, New Brunswick, NJ). Animals had ad libitum access to food and water and were housed individually in hanging wire caging at 22 °C in a 12/12-h light/dark cycle. Weekly body weight measurements and animal husbandry were performed by Charles River Laboratories for 13 weeks. At approximately

Plasma concentrations of T-226296

The plasma concentrations of T-226296 6 h after oral dosing were 70.4±3.6, 369.4±25.1 and 1273.7±72.8 nM for the 1, 3 and 10 mg/kg treated groups, respectively. At 24 h after dosing, plasma concentrations were 0, 68.7±30.2 and 535.8±96.2 nM for the 1, 3 and 10 mg/kg treated groups, respectively. Brain penetrability of T-226296 has been reported to be good (Takekawa et al., 2002); however, we did not measure brain concentrations in this study.

Food intake and body weight

The initial body weight of the rats used in this

Discussion

We show that acute oral administration of the MCH-1 receptor antagonist T-226296 in free-feeding male DIO rats produces a dose-related decrease in 24 h food intake and body weight, consistent with prior reports evaluating MCH-1 receptor antagonists (Borowsky et al., 2002, Haynes et al., 2001, Lewis et al., 2002, Takekawa et al., 2002). The novel finding of this study was that the decrease in food intake observed with MCH-1 receptor antagonism is due to a reduction in meal size, not meal

Acknowledgements

We thank Cymbelene Nardo and Hong Mei for technical assistance in the measurement of plasma T-226296.

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