Neuropeptides and obesity

This review focuses on the expression, content, and release of neuropeptide s and on their role in the development of obesity in animal models with sin gle-gene mutations. The balance between neuropeptides that contribute to th e 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 r eceive information about the nutritional status and the level of energy sto rage through insulin and leptin signaling mediated by specific receptors lo cated on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the r eceptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide it self (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpr ession and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. Fo r the POMC system, there is a complex interaction between the tonic inhibit ion of food intake exerted by alpha -melanocyte-stimulating hormone (alpha -MSH) and the Agouti-related protein at the level of the type 4 melanocorti n receptor. The latter peptide is coexpressed with NPY in the ARC. Corticot ropin-releasing factor (CRF) is the link between food intake and environmen tal factors. It not only inhibits food intake and prevents weight gain, lik ely through hypothalamic effects, but also activates the hypothalamopituita ry axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pit uitary axis system remain to be more clearly defined (comodulators, connect ions between limbic system and ARC, cellular location, and type of receptor s, etc.). The pathways used by all of these neuromodulators include numerou s brain areas, but some interest has returned to the classic ones such as t he ventromedial and lateral hypothalamic areas because of the recent discov ery of some peptides (orexins and melanin-concentrating hormone for the lat eral hypothalamus) and receptors (CRF type 2 in the ventromedial hypothalam us). All of these pathways are redundant and function in a coordinated mann er and sometimes by the novel expression of a peptide in an unusual area. T he importance of such a phenomenon in obesity remains to be determined. Eve n if single-gene mutations are exceptions in human obesity, the study of ge netic animal models of obesity has greatly contributed to the understanding of the regulation of feeding behavior and will allow researchers to develo p new drug treatments for obesity that have to be associated with drastic c hanges in lifestyle (feeding, work habits, and physical activity) for a com plete efficiency. Nutrition 2000;16:916-923. (C) Elsevier Science Inc. 2000 .