Ingestive behavior and obesityNeuropeptides and obesity☆
Introduction
Obesity has become a real health problem and an economic problem in developed countries. The prevalence of this condition has rapidly expanded during the past 20 y and has increased from 12% to 18% between 1991 and 1998 in the general U.S. population.1 Moreover, Mokdad et al. considered these values underestimates.1 The same phenomenon has occurred in Europe, apparently with the same rate of increase but starting from a lower level.2 As a consequence, numerous investigations have tried to determine the multiple factors at the origin of the positive energy balance between energy intake and energy expenditure. Attention was first focused on the nutritional aspects and in particular on the use and storage of ingested food. These factors remain pertinent, but upstream regulatory factors such as ingestive behavior and stress are also being considered. Research in this area has focused on the central nervous system. The first attempts were to find the brain areas involved in the regulation of feeding behavior through electrolytic lesions or excitatory methods. After the discovery of a satiety center (ventromedial hypothalamic nucleus, VMN) and a feeding center (lateral hypothalamus, LH) in the early 1940s, several new areas located mainly in the hypothalamus were detected. The hypothalamic arcuate (ARC), paraventricular (PVN), dorsomedial (DMN), and suprachiasmatic nuclei are among the most important. They form with the VMN and LH complex networks for the regulation of energy intake and expenditure. Numerous neuromodulators are present in the areas including the classic neurotransmitters serotonin, catecholamines, and γ-aminobutyric acid. The first effective drugs (fenfluramine, sibutramine) developed to inhibit food intake and limit weight gain acted on the metabolism of these transmitters. More recently and in an exponential manner in the past 10 y, more and more experiments have investigated the role of the neuropeptides present in these areas. This new class of neuromodulators includes peptides that inhibit or stimulate feeding behavior.3 Corticotropin-releasing factor (CRF), cholecystokinin (CCK), neurotensin, cocaine- and amphetamine-regulated transcript, α-melanocyte-stimulating hormone (α-MSH), and vasopressin are anorexigenic,3, 4, 5, 6 whereas neuropeptide Y (NPY), galanin, Agouti-related protein (AgRP), melanin-concentrating hormone (MCH), and the orexins stimulate food intake.7, 8, 9, 10 Their physiology has been recently reviewed.11 Their role in the development of obesity has been determined through the study of many obesity models, not only lesion and diet models but also genetic models.
Obesity clearly has an important genetic basis, with estimates of heritability ranging from 30% to 70%. Several autosomal dominant (yellow Agouti) and recessive (fa, ob, db, tub, fat) obesity mutations have been described. Some have been studied for decades and can be considered “classic.” The Zucker fatty fa/fa rat, the ob/ob mouse, and the db/db mouse belong to this category. Others have been examined more recently and include the Tubby mouse, the Agouti mouse, the Mahogany mouse, the Fat/Fat mouse, and the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Some of these strains are characterized by coat color. Similar single-gene mutations are very rare in humans (fewer than 10 have been mapped12), but these genetic models are very useful to determine the part played by the protein when it is absent or inactive due to the mutation. These models contribute to the understanding of the etiology of obesity. This review focuses on the role of the most important neuropeptides and on recent developments concerning their expression and function in the brain in these genetic models.
Section snippets
The Zucker fa/fa rat
The Zucker fa/fa rat is the model used most widely for the study of obesity. It has several characterics in common with human obesity such as hyperphagia, hypertriacylglycerolemia, and hyperinsulinemia.13, 14 All metabolic changes are present very early (3 to 5 wk of age) in the life of these animals.15 Its mouse homolog is the db/db mouse.16 In 1994, the manner in which mutation of the fa gene causes obesity was determined. The Zucker fa/fa rat has a mutated leptin receptor17, 18, 19, 20;
The yellow Agouti mouse
The yellow Agouti Ay mouse is the most studied “color” model of obesity. The product of the Agouti gene interacts with α-MSH at the level of type 1 melanocortin receptors to determine the coat color of the animals. The Agouti gene is expressed throughout the body of the animals. In the hypothalamus, its product, AgRP, interacts with α-MSH at the level of MC4-R. This interaction leads to the development of obesity associated with moderate hyperphagia and decreased thermogenesis.134 Feeding
Conclusion
This review of the neuropeptidergic variations in several genetic models of obesity emphasizes the complexity of the central mechanisms that regulate feeding behavior. The different neuropeptide profiles found in the brain of these models support the concept of the existence of different types of obesity and thus suggest the use of a multitargeted treatment to decrease weight in obese subjects. Two main systems are implicated: the NPY system and the POMC system. Both receive information from
Acknowledgements
The author thanks Dr. A. Burlet, Dr. A. Stricker-Krongrad, Dr. J.P. Max, Dr. R. Kozak, Dr. J.M. Mercer, and Mr. S. Richy for their active collaboration and constructive discussion in several experiments presented in this review. The author also thanks the technical staff (F. Bergerot, F. Giannangeli, and B. Fernette) and Mrs. L. Poirson and C. Habert for preparing the manuscript.
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2018, BoneCitation Excerpt :An arc-shaped hypothalamic region, located at the bottom of 3rd ventricle, above the medial eminence – the ARC – harbors two populations of neurons, identified on the basis of the dominant neuromediator they synthesize and secrete upon activation: the “anabolic” Agouti Related Peptide (AgRP)/Neuropeptide Y (NPY) and the “catabolic” Proopiomelanocortin (POMC)/Cocaine- and amphetamine-regulated transcript (CART) neurons, which counterbalance body weight (Fig. 1). AgRP neuropeptide expression is restricted to the ARC, while POMC is also expressed in a brainstem area, called Nucleus Tractus Solitarius (NTS) [56,73,74]. CART and NPY are concentrated in the hypothalamus, but show a broad distribution pattern in both the central and peripheral nervous systems [56,73].
Gas-phase structural characterization of neuropeptides Y Y1 receptor antagonists using mass spectrometry: Orbitrap vs triple quadrupole
2018, Journal of Pharmaceutical and Biomedical Analysis
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These works were supported by grant MRT 92G0341 from the Ministère de la Recherche et de la Technologie and by grants from the Institut Benjamin Delessert, Paris.