Review
KO's and organisation of peptidergic feeding behavior mechanisms

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Abstract

Feeding behavior results from complex interactions arising between numerous neuromediators, including classical neurotransmitters and neuropeptides present in hypothalamic networks. One way to unravel these complex mechanisms is to examine animal models with a deletion of genes coding for the different neuropeptides involved in the regulation of feeding. The aim of this review is to focus on feeding and body weight regulation in mice lacking neuropeptide Y (NPY), melanocortins (POMC), corticotropin-releasing hormone, melanin-concentrating hormone, or bombesin-like peptides respectively. The phenotypes, which relate to the deletion of gene coding for the peptides, rarely include changes in body weight and food intake, indicating therefore the existence of redundant mechanisms to compensate for the loss of the peptide. The phenotype is much more marked when the gene deletion is targeted towards the functioning of the peptidergic machinery, e.g. the receptors and especially the POMC and NPY receptors, as well as one subtype of bombesin receptor (BRS-3). These knockout models are also interesting when examining the role of environmental and social factors in the determination of feeding behavior. They have granted us better knowledge of all these integrated and complex mechanisms. Moreover, they are also valuable tools for pharmacological studies when specific antagonists are lacking. From the information obtained by the study of knockouts, it is possible to determine certain targets for selective drugs that could be efficient for the pharmacological treatment of obesity. However, at the present state of our knowledge, it seems necessary to target several peptides in order to get good results with weight loss. It will also be imperative to associate these multitherapies with changes in eating and behavioral habits, in order to obtain complete effectiveness and long-lasting results.

Introduction

For two d ecades now, research on the mechanisms for the regulation of feeding behavior has increased exponentially. This is partly due to the overwhelming increase in the prevalence of obesity in the developed and developing countries [1], [2], [3]. This epidemic has become a real health problem, as well as an economic problem, which will still be developing in the third millennium. The positive energy balance necessary to induce overweight is related to both increase in energy intake and decrease in energy expenditure. The more sedentary lifestyle, in combination with the progress in communication and transportation, is one of the reasons for this phenomenon, but changes in feeding behavior due to the large availability of rich food also contributes to it. Environmental cues also affect the choice of food and the level of ingested energy. A diminution of overweight can be obtained through good control of qualitative and quantitative aspects of ingestion.

The determination of the factors that contribute to the establishment of eating has therefore been the goals of research in this area. The promotion of good nutritional practices through learning and education appears not to be sufficient in our western societies of abundance. Pharmacological treatments are helpful in many situations, e.g. mild to severe obesity, as well as in the life of ordinary slightly overweight people who consider that it is an easy way to loose some weight and have not decided to modify their behavior. This attitude might reflect unconscious mechanisms aimed to spare energy stores. Drugs must therefore be targeted to specific and important steps of the complex mechanisms involved in the regulation of feeding behavior and body weight. These mechanisms of control are mainly active in the central nervous system, and particularly in the hypothalamus.

Sixty years ago, feeding was thought to be regulated through two hypothalamic areas: the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH). This was described as the ‘dual feeding center’ hypothesis. The LH was considered to be a ‘feeding’ center, since its electrolytic lesion and electric stimulation induced anorexia and food intake, respectively. The VMH was considered to be a ‘satiety’ center since its lesion induced overeating and obesity [4], [5], [6]. More recently, other hypothalamic nuclei have also been involved in the regulation of feeding: the paraventricular (PVN) nucleus [7], the dorsomedial (DMN) nucleus [8] and the suprachiasmatic (SCN) nucleus [9]. The latter was shown to modulate feeding rhythms. The PVN, with its connections with the arcuate (ARC) nucleus was thought to play a major role [10]. It is therefore more usual and more adequate now to consider networks comprising all of these areas and to envisage an exchange of information between these areas in order to explain the regulation of feeding (Fig. 1, Fig. 2). These hypothalamic networks also integrate either metabolic or cognitive information coming from the periphery through connections either with the hindbrain or with the limbic system. Metabolic information, provided through important hormones such as insulin and leptin, can also be directly integrated at the hypothalamic level merely by the presence of specific receptors located on different neuronal populations present in the arcuate nucleus [11], [12], [13]. All this information leads to a specific neuromediator profile adapted to each situation (fast/refed, macronutrient choice and availability, etc.). This is possible, given the numerous neuromediators which have been discovered during the last 20 years.

Besides the classical neurotransmitters (serotonin, catecholamines, GABA), there is now a large number of neuropeptides involved in the regulation [14] and the list is still growing. The most-recently discovered peptides, with a role in the control of feeding behavior, are the cocaine and amphetamine-regulated transcript (CART), the melanin-concentrating hormone (MCH), the glucagon-like peptide 1 (GLP-1) and 2 (GLP-2), the Agouti-related protein (AgRP) and the orexins [15], [16], [17], [18], [19], [20]. They participate in the fine tuning of feeding behavior in association with ‘older’ peptides either stimulating intake (neuropeptide Y (NPY), galanin (GAL)) or inhibiting it (corticotropin-releasing hormone (CRH), cholecystokinin (CCK), neurotensin (NT), bombesin etc. [21], [22], [23], [24], [25], [26]).

To unravel these complex mechanisms, researchers use three different approaches. The first one involves injecting the peptide into the brain and looking at its stimulatory or inhibitory effects on food intake [27] in association with the determination of the brain areas affected by these injections. This is followed by the measurement of peptide content, mRNA expression and release in various physiological situations associated with food intake changes. The second one consists of blocking the action of these peptides by using antagonists acting on specific receptors [28], or antisense oligonucleotides in order to block the endogenous synthesis of the peptide [29], [30]. The third one consists of the examination of animal models where the physiological effects of endogenous peptides are either blocked or stimulated. These models include some strains of rats and mice with a spontaneous single mutation at the gene level. The most studied are the ob/ob mouse which has a defect at the level of production of an active leptin peptide and the db/db mouse and Zucker fa/fa which have a defect at the leptin receptor level. The yellow mouse, with impairment at the melanocortin system levels, and the agouti mouse are also frequently used in obesity research. The consequences of these mutations for feeding behavior and body weight regulation have been recently reviewed [31]. Other animal models result from the manipulation of the genome by researchers, leading to the production of strains with specific genes knocked out or overexpressed. The mouse has been widely used for such manipulations because of the considerable knowledge of its genome. Its genome also has a quite good structural homology with the human genome [32]. The technology for making transgenics and gene targeted deletions or substitutions is well-established for the mouse. However, the mouse may not be the optimal animal model for measuring food intake. Larger animals like rats are more adequate for this purpose. Nonetheless, these current mice models allowed us to make significant progress in the determination of central feeding mechanisms. The aim of this review is to focus on the advances brought about by these knockout and transgenic models.

Section snippets

Knocking out orexigenic neuropeptides

As previously mentioned, the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus constitute two key areas for the regulation of feeding. The arcuate nucleus is the main hypothalamic site with an important population of neurons synthesizing a very potent orexigenic peptide, NPY [33]. These neurons send their projections to the PVN to form a pure peptidergic pathway [34]. Various experiments measuring peptide content and release have shown that this pathway is very important for

Conclusions and perspectives

Research on brain neuropeptides involved in the regulation of feeding behavior has been boosted over the two last decades, and the discovery of new peptides has been accelerated since a few years. This review on knockout models which will probably loose a significant part of its exhaustivity when it is published, brings some discouraging feelings, but also some hopes. One particularly disappointing but intriguing element is the absence of a marked phenotype attached to the deletion of the gene

Acknowledgements

The author thanks Ms Lydie Poirson and Ms Françoise Bergerot for their help in the preparation of this review. Some experiments presented in this review were supported by a grant of Ministère de la Recherche et de la Technologie MRT 92G0341.

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