The role of hypothalamic peptides in the regulation of appetite

The National Health and Nutrition Examination Survey for 1999/2002 in the USA indicated that about 65% of adults aged 20 years and older are either overweight or obese, and are at risk of associated diseases such as diabetes, coronary heart disease, hypertension, stroke and depression. The trend is worldwide: in the U.K, about 55% of adults are overweight or obese, and about 40% in France. Research on appetite has progressed rapidly in the last ten years, but there is still little understanding of how appetite-related signals are processed in the brain. Understanding the mechanisms of appetite regulation has thus become a major goal for neuroscientists, clinicians, and pharmaceutical companies. Classically, appetite is regulated by an alternation between 'hunger' signals and 'satiety' signals that inform the brain about the metabolic status of the individual. During feeding, distension of the stomach induces the release of 'satiety peptides' and the activation of 'satiety centres' in an area of the brain called the hypothalamus. The ventromedial nucleus of the hypothalamus (VMH) is an important satiety centre; when it is damaged, animals eat voraciously and become obese. In the last five years, the VMH has become a major focus of research on satiety regulation. However, there is still very little known about the electrical properties of VMH neurons, about what type of satiety signals they receive, or about how they process these signals. One of the most potent appetite inhibitor in the brain is the peptide alpha-melanocyte-stimulating hormone (a-MSH). Human genetics studies have shown that variations in the receptor through which a-MSH acts are the most common established monogenetic link with human obesity. Injections of a-MSH potently reduces appetite, and this effect is exerted by its actions in the hypothalamus. In the hypothalamus, a-MSH interacts with another appetite-inhibitor peptide, oxytocin. Oxytocin neurons have receptors for a-MSH and a-MSH induces the release of oxytocin in in vitro preparations. In these studies, we will investigate the mechanisms of regulation of satiety in the brain. We believe that a-MSH that is released in the brain during feeding, in turn induces the release of oxytocin, which then acts on the VMH to modulate satiety. Our most general objective is to understand better how peptides released in the brain can generate coherent changes in behaviour. More specifically, we aim to understand better the mechanisms of appetite regulation in the brain. Precisely, we will test the hypothesis that regulation of satiety is modulated by the VMH which is the final target for the interaction between a-MSH and oxytocin. This project will involve experiments on anaesthetised rats to a) record the electrical activity of VMH neurons and characterise their properties, b) stimulate the release of oxytocin in the hypothalamus and record its effects on VMH neurons, and c) stimulate a-MSH release in the hypothalamus and measure its consequences for oxytocin release. The project will contribute to our fundamental understanding of the regulation of feeding behaviour in the brain, and might thus lead to the development of more effective treatments for obesity.

This proposal addresses the role of the hypothalamus in the regulation of appetite. a-melanocyte stimulating hormone (a-MSH) is produced in neurons of the arcuate nucleus that innervate many brain areas, acting at MC3 and MC4 receptors, and support is sought for a postdoctoral appointment for 3 years. a-MSH injected i.c.v. potently inhibits food intake, and mutations of MC4R lead to obesity in animals and humans. However, exactly where and how a-MSH acts in regulating appetite is not clear; we propose to test the hypothesis that the appetite-inhibiting actions of a-MSH involve intrahypothalamic release of oxytocin, which modulates satiety-mediating neurons in the ventromedial hypothalamus (VMH). The VMH is a major satiety centre, and expresses abundant oxytocin receptors, oxytocin, like a-MSH, is a potent inhibitor of appetite, and central (dendritic) release of oxytocin is evoked by direct actions of a-MSH on magnocellular oxytocin neurons. The proposed experiments will involve electrophysiological studies of single neurons in the VMH in anaesthetised rats; there have been very few studies of the appetite-regulating regions of the hypothalamus by electrophysiological experiments in vivo, and these experiments are important to understand how peripheral signals relating to appetite are integrated by the hypothalamic control centres. The experiments also involve measurements of peptide release by microdialysis in vivo, and will contribute to a better understanding of the physiological regulation of dendritic neuropeptide release, and address the controversial question of whether diffusional transmission of peptides is a major mediator of communication between neurones.