Cardiovascular effects of melanin-concentrating hormone

Abstract

Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid neuropeptide exclusively synthesized in the lateral hypothalamic area (LHA) and the zona incerta (ZI) that has been implicated in the regulation of energy balance. Despite what is known about the orexigenic effect of MCH, whether MCH has distinct cardiovascular and metabolic effects has yet to be determined. Thus, our goal here was to characterize the concurrent cardiovascular, metabolic, and behavioral responses of male rats to chronic intracerebroventricular (icv) infusion of MCH. Male Long–Evans rats were instrumented with telemetry transmitters for measurement of heart rate (HR) and housed in room calorimeters for assessment of food intake and oxygen consumption (VO₂) at standard lab ambient temperature (23 °C) in order to examine physiological responses to chronic infusion of MCH (8 μg/d and 16 μg/d). Our findings provide the first evidence that chronic administration of MCH induces bradycardia and reduced mean arterial pressure, while it did not affect VO₂. A second experiment was performed in which the physiological responses to an acute icv infusion of MCH were observed. The results of experiment 2 indicate that MCH leads to a low HR that is maintained during the first 2 h post-infusion, the time period during which MCH acutely stimulated feeding. Collectively, these findings confirm that MCH may be an important modulator of sympathetic nervous system activity and thus may play a critical role in coordinating normal responses to negative energy balance.

Introduction

Genetic studies provide strong support for a physiological role for the hypothalamic neuropeptide, melanin-concentrating hormone (MCH), in regulating energy homeostasis. For instance, targeted deletion of MCH and/or MCH receptor 1 (MCHR1; one of the two known types of MCH receptors), leads to a lean phenotype that is resistant to diet-induced obesity, has increased energy expenditure and enhanced thermogenesis [4], [8], [12], [25]. Mice lacking MCH are lean due to hypophagia and increased metabolic rate [8], [25], while mice lacking MCHR1 are hyperphagic, hyperactive, have enhanced energy expenditure, and gain less weight than wild-types on a high-fat diet [4], [12]. Correspondingly, transgenic over-expression of MCH stimulates feeding and increases susceptibility to obesity and insulin resistance [11]. As would be expected, antagonism of MCHR1 produces hypophagia and decreased body weight in obese rodents [9]. Thus, MCHR1 antagonists appear to offer a viable means by which to treat human obesity and metabolic syndrome [10], [22]. All of this evidence supports the notion that MCH plays an important role in regulating energy expenditure, in addition to producing a stimulatory effect on food intake.

In general, MCH infusion studies aimed at better understanding the functional significance of MCH have produced results that are far less compelling than those obtained from studies involving mutant mice. Acute central ventricular infusion of MCH stimulates feeding [17], [20], an effect that also occurs when MCH is injected directly into the hypothalamic arcuate and paraventricular nuclei [1], [20]. Similarly, increased food intake and body weight has been observed in rats given chronic continuous intracerebroventricular (icv) infusion of either MCH [6], [24] or an agonist for MCHR1 [6], [24]. However, alternative findings exist with regard to the ability of MCH to produce a sustained increase in food intake and body weight. For example, repeated daily injections of MCH in rats did not increase 24 h food intake or produce obesity [20]. Although an acute infusion of MCH initially produced hyperphagia, tolerance to the feeding effect of MCH occurred after 5 d and no further increase in food intake was then observed [20]. Furthermore, an acute infusion of MCH was found to stimulate food intake in sheep, but chronic infusion of MCH failed to do so [29]. Further studies are necessary in order to elucidate the ability of chronic MCH to induce obesity and/or hyperphagia.

Finally, since MCH is largely expressed in the zona incerta and the lateral hypothalamic area [3], [27], the latter of which being an area which also plays a role in autonomic nervous system (ANS) regulation, it seems plausible that MCH modulates ANS activity. Much circumstantial evidence exists that implicates MCH as having a role in modulating ANS activity, particularly by means of decreasing energy expenditure. For instance, blocking MCH expression appeared to augment the increase in sympathetic activity that occurs in cold-exposed rats (T_a ≈ 4 °C), as demonstrated by an increase in uncoupling protein-1 (UCP-1) expression [16]. Additionally, ob/ob mice lacking MCH demonstrate an increase in body temperature and UCP-1 expression in BAT, compared to control ob/ob mice [23]. In contrast, chronic infusion of MCH has been shown to decrease body temperature and UCP-1 expression in BAT [7]. Furthermore, sympathetic projections to BAT have been traced to MCH-containing cells in the LHA [14]. There are just two known studies to date that have directly addressed the role of MCH in modulating cardiovascular activity [2], [15]. Among the findings of these studies, mice lacking MCHR1 exhibit tachycardia, which is completely reversible by adrenergic receptor blockade [2]. MCHR1^−/− mice exhibit a distinct delay in the onset of bradycardia and body temperature downregulation in response to fasting [2]. This evidence supports the possibility of enhanced sympathetic tone and/or reduced vagal tone in MCHR1^−/− mice, implicating MCH as being a potential tonic suppressor of sympathetic activity. However, chronic MCH infusion in sheep has been found to have no effect on heart rate and mean arterial pressure [15]. Clearly, the extent to which MCH mediates cardiovascular activity requires further investigation. Thus, the primary goal of this study was to examine and characterize the concurrent cardiovascular, metabolic, and behavioral responses of male rats to chronic icv infusion of MCH.