Characterization of MCH-mediated obesity in mice

Abstract

. Characterization of MCH-mediated obesity in mice. Am J Physiol Endocrinol Metab 284: E940-E945, 2003. First published January 28, 2003 10.1152 10. /ajpendo.00529.2002 hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus. Recently, we demonstrated that chronic intracerebroventricular infusion of MCH induced obesity accompanied by sustained hyperphagia in mice. Here, we analyzed the mechanism of MCH-induced obesity by comparing animals fed ad libitum with pair-fed and control animals. Chronic infusion of MCH significantly increased food intake, body weight, white adipose tissue (WAT) mass, and liver mass in ad libitum-fed mice on a moderately high-fat diet. In addition, a significant increase in lipogenic activity was observed in the WAT of the ad libitumfed group. Although body weight gain was marginal in the pair-fed group, MCH infusion clearly enhanced the lipogenic activity in liver and WAT. Plasma leptin levels were also increased in the pair-fed group. Furthermore, MCH infusion significantly reduced rectal temperatures in the pair-fed group. In support of these findings, mRNA expression of uncoupling protein-1, acyl-CoA oxidase, and carnitine palmitoyltransferase I, which are key molecules involved in thermogenesis and fatty acid oxidation, were reduced in the brown adipose tissue (BAT) of the pair-fed group, suggesting that MCH infusion might reduce BAT functions. We conclude that the activation of MCH neuronal pathways stimulated adiposity, in part resulting from increased lipogenesis in liver and WAT and reduced energy expenditure in BAT. These findings confirm that modulation of energy homeostasis by MCH may play a critical role in the development of obesity.melanin-concentrating hormone; body weight; liver weight; brown adipose tissue OBESITY IS CAUSED BY AN IMBALANCE between caloric intake and energy expenditure. The hypothalamus plays an important role in the integrated regulation of this homeostatic balance. In the past several years, a number of hypothalamic neuropeptides involved in feeding and energy homeostasis were discovered. Melanin-concentrating hormone (MCH), a cyclic neuropeptide originally isolated from salmon pituitaries (8), was recently identified as a mediator of energy homeostasis. In rodents, MCH is predominantly expressed in the lateral hypothalamic area, pivotal center of energy homeostasis (1,20). Qu et al. (15) found that MCH stimulated food intake after intracerebroventricular (ICV) administration. Furthermore, mRNA levels of MCH increased in genetic obesity models such as ob/ob, db/db, and A Y /a mice and Zucker fatty rats (5,14,15,21). These results suggest that MCH might play an important role in the regulation of energy homeostasis. In support of the potential role of MCH, prepro-MCH-deficient mice are lean and hypophagic and show a slight increase in their metabolic rate (18). Moreover, prepro-MCH overexpression in transgenic mice is marked by obesity and insulin resistance (11). However, these models do not rule out influence of the neur...

Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype

“…Both basal thermoregulation and shivering thermogenesis were improved in MCH Ϫ/Ϫ ob͞ob mice, and these animals also showed an elevation in UCP-1 expression in BAT. Interestingly, a very recent report indicates that MCH infusions can suppress UCP-1 and decrease body temperature (6). These findings suggest a role for MCH in regulating the activity of the sympathetic nervous system (SNS) as relates to energy expenditure pathways.…”

“…Initially identified as a neuropeptide up-regulated in hypothalami of ob͞ob mice (2), MCH administered intracerebroventricularly into rats causes a rapid, robust hyperphagic response. Ablation of the prepro-MCH gene leads to a lean phenotype secondary to hypophagia and increased energy expenditure (3), and chronic infusions of MCH lead to weight gain and hyperinsulinemia (6,7). Ablation of MCHR-1, the rodent receptor for MCH, also leads to leanness secondary to increased locomotor activity (11,12).…”

“…Genetic evidence for a role of MCH in energy balance was derived from a model of MCH gene ablation, which produced a lean phenotype associated with a decrease in feeding and an increase in resting energy expenditure (3), and also from a model of transgene-derived eutopic overexpression, which produced mild obesity (5). Recently, chronic infusions of MCH were shown to produce hyperphagia and obesity in mice (6) and rats (7).…”

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

“…Central administration of MCH stimulates food intake [10,20] and chronic i3vt infusion of MCH leads to hyperphagia and obesity [15]. Mice lacking MCH are hypophagic and lean [25].…”

Pmchexpression during early development is critical for normal energy homeostasis

“…Processing of Pmch results in the production of three neuropeptides: neuropeptide glycine-glutamic acid (N-GE), neuropeptide glutamic acid-isoleucine (N-EI), and MCH (41). Pmch mRNA is upregulated after fasting or leptin deficiency (32, 50); third ventricle intracerebroventricular injections of MCH increase food intake and body weight (11,19,22,28,53); Pmch knockout mice are lean due to a decreased food intake and an increased metabolic rate (31, 59); and overexpression of MCH causes obesity (35). In rodents MCH binds to melanin-concentrating hormone receptor 1 (MCH1R), a G protein-coupled receptor expressed throughout the brain (7,33,55,56).…”