Chronic MCH-1 receptor modulation alters appetite, body weight and adiposity in rats

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Abstract

Central administration of the neuropeptide melanin-concentrating hormone (MCH) stimulates feeding in rodents. We studied the effects of intracerebroventricular (i.c.v.) administration of an MCH-1 receptor agonist (Compound A) and an MCH-1 receptor antagonist (Compound B) on feeding in satiated rats. Compound B (10 μg, i.c.v.) blocked the acute orexigenic effect of Compound A (5 μg, i.c.v.). In an experiment designed to either stimulate or inhibit MCH-1 receptor signaling over an extended period, rats received continuous i.c.v. infusions of vehicle (saline), Compound A (30 μg/day), Compound B (30 or 48 μg/day) or neuropeptide Y (24 μg/day, as positive control) via implantable infusion pumps. Continuous MCH-1 receptor activation recapitulated the obese phenotype of MCH-over-expressor mice, manifest as enhanced feeding (+23%, P<0.001), caloric efficiency and body weight gain (+38%, P<0.005) over the 14-day period relative to controls. Chronic MCH-1 receptor activation also elevated plasma insulin and leptin levels significantly. Conversely, continuous MCH-1 receptor antagonism led to sustained reductions in food intake (−16%, P<0.001), body weight gain (−35%, P<0.01), and body fat gain relative to controls, without an effect on lean mass. Antagonism of the MCH-1 receptor may be an effective approach for the treatment of obesity.

Introduction

Melanin-concentrating hormone (MCH) is a nonadecapeptide with an amino acid sequence highly conserved among fish, rats and humans (Vaughan et al., 1989). MCH was first isolated from chum salmon pituitary and shown to regulate melanin pigment aggregation in melanocytes (Kawauchi et al., 1983). Neuroanatomical studies in the rat demonstrated that MCH gene expression is restricted to the lateral hypothalamic area and zona incerta with extensive fiber projections throughout the brain (Bittencourt et al., 1992). Lesions of the lateral hypothalamic area produce profound hypophagia and extreme weight loss in rodents, indicating its importance in feeding regulation Teitelbaum et al., 1969, Bernardis and Bellinger, 1996.

Many studies suggest that MCH plays a role in feeding and energy metabolism in rodents (for review, see Griffond and Baker, 2002, Boutin et al., 2002). Central administration of MCH promotes feeding in rats and mice Qu et al., 1996, Rossi et al., 1997 and antagonizes the actions of alpha-melanocyte-stimulating hormone (α-MSH), an anorexigenic melanocortin peptide Sanchez et al., 1997, Grill et al., 1998, Ludwig et al., 1998. The adipocyte hormone leptin inhibits hypothalamic MCH gene expression Shimada et al., 1998, Kokkotou et al., 2001 while fasting increases hypothalamic MCH mRNA levels in both leptin-deficient ob/ob and wild type mice Qu et al., 1996, Kokkotou et al., 2001. Importantly, prepro-MCH-deficient mice are lean, hypophagic and have an increased metabolic rate (Shimada et al., 1998) in contrast to transgenic mice over-expressing the prepro-MCH gene which develop hyperphagia and mild obesity on a high-fat diet (Ludwig et al., 2001).

Two G-protein coupled receptors for MCH have been identified, MCH-1 and MCH-2 receptors, however, only MCH-1 receptor is found in rodents Saito et al., 2000, An et al., 2001, Hill et al., 2001, Mori et al., 2001, Sailer et al., 2001, Wang et al., 2001, Tan et al., 2002. Both MCH receptors are selective for MCH and are not activated by other neuropeptide derivatives of the prepro-MCH gene, including neuropeptide E-I (NEI), neuropeptide G-E (NGE) and MCH-gene-overprinted-polypeptide (MGOP) Sailer et al., 2001, Saito et al., 1999, Chambers et al., 1999. MCH-1 receptor mRNA and protein are located in rat cerebral cortex, caudate putamen, hippocampus, amygdala, hypothalamus and thalamus Hervieu et al., 2002, Saito et al., 2001. MCH-1 receptor deficient (Mch1r−/−) mice are lean (like pre-pro-MCH deficient mice), but are hyperphagic when maintained on regular chow Chen et al., 2002, Marsh et al., 2002. Mch1r−/−mice are less susceptible to diet-induced obesity due to their hyperactivity and increased energy expenditure Chen et al., 2002, Marsh et al., 2002. In addition, the MCH-1 receptor is essential for the orexigenic effects of MCH in mice (Marsh et al., 2002).

To better understand the physiological function of the MCH-1 receptor in mammals, we utilized a potent MCH-1 receptor agonist peptide, Compound A, a truncated analog of MCH which efficiently binds to and activates MCH-1 and MCH-2 receptors (detailed in Bednarek et al., 2001, Bednarek et al., 2002a) and a selective MCH-1 receptor antagonist peptide, Compound B (Bednarek et al., 2002b). Here we characterize the acute effects of the novel MCH-1 receptor agonist and the selective MCH-1 receptor antagonist on food intake, body temperature and locomotor activity in rats. In addition, in lean rats we evaluate the effects of chronic intracerebroventricular infusions of the MCH 1 receptor agonist, Compound A, the MCH-1 receptor antagonist, Compound B, and neuropeptide Y on food intake, body weight, plasma hormone levels, body composition and on MCH, pro-opiomelanocortin (POMC), neuropeptide Y and melanocortin MC4 receptor hypothalamic gene expression.

Section snippets

Animals

Male Sprague–Dawley rats with indwelling stainless steel guide cannulas placed intracerebroventricularly (i.c.v.) into the right lateral ventricle of the brain were purchased from Charles River Laboratories (Wilmington, DE). Rats were housed singly in a temperature-and humidity-controlled room with a 12:12 light–dark cycle (4:00 p.m. EST lights off). Rats were maintained with ad libitum access to water and regular pelleted rat chow (Harlan Teklad, Madison, WI, Diet 7012, 14.8% kcal from fat)

Acute food intake effects of Compound A

In pre-fed rats, i.c.v. administration of the MCH-1 receptor agonist Compound A increased food consumption in a dose-and time-dependent manner over the 18 h duration of the study. In comparison to vehicle-treatment, the acute orexigenic effects of Compound A were most evident within the first 6 h following peptide administration (Fig. 2). The extents of the increases in food intake evoked by Compound A at 1, 5 and 15 μg were +315% (P<0.01), +409% (P<0.05) and +611% (P<0.01), respectively, at 3

Discussion

Here we show that central administration of the MCH-1 receptor agonist Compound A into the lateral ventricle of satiated rats prior to dark onset increases food intake and that this hyperphagia can be blocked pharmacologically by the MCH-1 receptor antagonist Compound B. We used a moderate high fat (MHF) diet in our studies because we determined empirically that it provided a substantially bigger window for detecting effects of the MCH-1 receptor peptides on food intake over regular, low fat

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