Elsevier

Nutrition

Volume 16, Issue 10, October 2000, Pages 916-923
Nutrition

Ingestive behavior and obesity
Neuropeptides and obesity

https://doi.org/10.1016/S0899-9007(00)00410-XGet rights and content

Abstract

This review focuses on the expression, content, and release of neuropeptides and on their role in the development of obesity in animal models with single-gene mutations. The balance between neuropeptides that contribute to the control of feeding behavior is profoundly and variously altered in these models, supporting the concept of the existence of several types of obesity. The hypothalamic neuropeptide Y (NPY) and the pro-opiomelanocortin (POMC) systems are the networks most studied in relation to energy intake. Both receive information about the nutritional status and the level of energy storage through insulin and leptin signaling mediated by specific receptors located on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the receptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide itself (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpression and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. For the POMC system, there is a complex interaction between the tonic inhibition of food intake exerted by α-melanocyte-stimulating hormone (α-MSH) and the Agouti-related protein at the level of the type 4 melanocortin receptor. The latter peptide is coexpressed with NPY in the ARC. Corticotropin-releasing factor (CRF) is the link between food intake and environmental factors. It not only inhibits food intake and prevents weight gain, likely through hypothalamic effects, but also activates the hypothalamo-pituitary axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pituitary axis system remain to be more clearly defined (comodulators, connections between limbic system and ARC, cellular location, and type of receptors, etc.). The pathways used by all of these neuromodulators include numerous brain areas, but some interest has returned to the classic ones such as the ventromedial and lateral hypothalamic areas because of the recent discovery of some peptides (orexins and melanin-concentrating hormone for the lateral hypothalamus) and receptors (CRF type 2 in the ventromedial hypothalamus). All of these pathways are redundant and function in a coordinated manner and sometimes by the novel expression of a peptide in an unusual area. The importance of such a phenomenon in obesity remains to be determined. Even if single-gene mutations are exceptions in human obesity, the study of genetic animal models of obesity has greatly contributed to the understanding of the regulation of feeding behavior and will allow researchers to develop new drug treatments for obesity that have to be associated with drastic changes in lifestyle (feeding, work habits, and physical activity) for a complete efficiency.

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.

References (170)

  • M. Lavau et al.

    Inguinal fat pad weight plotted versus body weight as a method of genotype identification in 16-day-old Zucker rats

    J Lipid Res

    (1982)
  • T.J. Kowalski et al.

    Neuropeptide Y overexpression in the preweanling Zucker (Fa/fa) rat

    Physiol Behav

    (1999)
  • H.D. Mc Carthy et al.

    Hypothalamic neuropeptide-Y receptor characteristics and NPY-induced feeding responses in lean and obese Zucker rats

    Life Sci

    (1991)
  • P.S. Widdowson

    Regionally-selective down-regulation of NPY receptor subtypes in the obese Zucker rat. Relationship to the Y5 ‘feeding’ receptor

    Brain Res

    (1997)
  • A. Stricker-Krongrad et al.

    Increased threshold concentrations of neuropeptide Y for a stimulatory effect on food intake in obese Zucker rats—changes in the microstructure of the feeding behavior

    Brain Res

    (1994)
  • B. Beck et al.

    Putative neuropeptide Y antagonist failed to decrease overeating in obese Zucker rats

    Neurosci Lett

    (1994)
  • D.J. Brief et al.

    Intraventricular neuropeptide Y injections stimulate food intake in lean, but not obese Zucker rats

    Physiol Behav

    (1992)
  • C.L. Marin Bivens et al.

    Intraventricular injection of neuropeptide Y antisera curbs weight gain and feeding, and increases the display of sexual behaviors in obese Zucker female rats

    Regul Peptides

    (1998)
  • B. Beck et al.

    Unexpected regulation of hypothalamic neuropeptide-Y by food deprivation and refeeding in the Zucker rat

    Life Sci

    (1992)
  • A. Sahu et al.

    Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus

    Peptides

    (1988)
  • B. Beck et al.

    Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status

    Brain Res

    (1990)
  • U. Pesonen et al.

    Hypothalamic neuropeptide expression after food restriction in Zucker rats—evidence of persistent neuropeptide-Y gene activation

    Mol Brain Res

    (1992)
  • S. Dryden et al.

    Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats

    Brain Res

    (1995)
  • M. Jhanwar-Uniyal et al.

    Diurnal rhythm of neuropeptide Y–like immunoreactivity in the suprachiasmatic, arcuate and paraventricular nuclei and other hypothalamic sites

    Brain Res

    (1990)
  • E.E. Becker et al.

    Meal patterns in the genetically obese Zucker rat

    Physiol Behav

    (1977)
  • A.B. Alingh Prins et al.

    Daily rhythms of feeding in the genetically obese and lean Zucker rats

    Physiol Behav

    (1986)
  • B.K. Smith et al.

    Chronic cerebroventricular galanin does not induce sustained hyperphagia or obesity

    Peptides

    (1994)
  • S.E. Kyrkouli et al.

    Stimulation of feeding by galanin—anatomical localization and behavioral specificity of this peptides effects in the brain

    Peptides

    (1990)
  • J.G. Mercer et al.

    Regulation of galanin gene expression in the hypothalamic paraventricular nucleus of the obese Zucker rat by manipulation of dietary macronutrients

    Mol Brain Res

    (1996)
  • B. Beck et al.

    Galanin in the hypothalamus of fed and fasted lean and obese Zucker rats

    Brain Res

    (1993)
  • D.S. Roane et al.

    Decreased [3H]-naloxone binding and elevated dynorphin-A(1–8) content in Zucker rat brain

    Physiol Behav

    (1988)
  • D. Feifel et al.

    Central somatostatin—a re-examination of its effects on feeding

    Brain Res

    (1990)
  • S.Q. Giraudo et al.

    Somatostatin and growth hormone-releasing factor release from Zucker rat hypothalamic tissue

    Brain Res Bull

    (1992)
  • B. Beck et al.

    Neurotensin in microdissected brain nuclei and in the pituitary of the lean and obese Zucker rats

    Neuropeptides

    (1989)
  • B. Beck et al.

    Hyperphagia in obesity is associated with a central peptidergic dysregulation in rats

    J Nutr

    (1990)
  • B. Beck et al.

    Early modification of neuropeptide-Y but not of neurotensin in the suprachiasmatic nucleus of the obese Zucker rat

    Neurosci Lett

    (1992)
  • B. Beck et al.

    Neurotensin decreases with fasting in the ventromedian nucleus of obese Zucker rats

    Metabolism

    (1995)
  • C.L. McLaughlin et al.

    Decreased sensitivity of obese Zucker rats to the putative satiety agent cholecystokinin

    Physiol Behav

    (1980)
  • A.J. Strohmayer et al.

    Devazepide increases food intake in male but not female Zucker rats

    Physiol Behav

    (1996)
  • C.L. McLaughlin et al.

    Effects of CCK antibodies on food intake and weight gain in Zucker rats

    Physiol Behav

    (1985)
  • C.A. Maggio et al.

    Diet composition alters the satiety effect of cholecystokinin in lean and obese Zucker rats

    Physiol Behav

    (1988)
  • J.A. Finkelstein et al.

    Levels of gastrin-cholecystokinin-like immunoreactivity in the brains of genetically obese and non-obese rats

    Peptides

    (1981)
  • C.L. McLaughlin et al.

    Changes in brain CCK concentrations with peripheral CCK injections in Zucker rats

    Physiol Behav

    (1986)
  • S.C. Heinrichs et al.

    Corticotropin-Releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide-Y

    Brain Res

    (1993)
  • F. Menzaghi et al.

    Functional impairment of hypothalamic corticotropin-releasing factor neurons with immunotargeted toxins enhances food intake induced by neuropeptide-Y

    Brain Res

    (1993)
  • K. Arase et al.

    Effects of corticotropin releasing factor on genetically obese (fatty) rats

    Physiol Behav

    (1989)
  • M. Fukushima et al.

    Immunoreactive corticotropin-releasing hormone levels in the hypothalamus of female Wistar fatty rats

    Neurosci Lett

    (1992)
  • S. Nakaishi et al.

    Immunoreactive corticotropin-releasing hormone levels in discrete hypothalamic nuclei of genetically obese Zucker rats

    Neurosci Lett

    (1993)
  • A.H. Mokdad et al.

    The spread of the obesity epidemic in the United States, 1991–1998

    JAMA

    (1999)
  • K. KromeyerHauschild et al.

    Prevalence of overweight and obesity among school children in Jena (Germany)

    Int J Obesity

    (1999)
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      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].

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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.

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