Boucle régulatrice entre le neuropeptide Y et la leptine et son altération chez le rongeur obèse.

Abstract

La découverte du neuropeptide Y et de la leptine, respectivement stimulateur et inhibiteur de la prise alimentaire, a confirmé l’existence d’une boucle régulatrice reliant le système nerveux central à la périphérie. L’équilibre de leur action respective semble être modulé par les glucocorticoïdes. D’autres modulateurs de la prise alimentaire font probablement partie intégrante de cette boucle, en particulier la corticolibérine, inhibitrice de la prise alimentaire et stimulatrice de l’axe hypothalamo-hypophyso-surrénalien. Les relations fonctionnelles entre les différents effecteurs de ce système de boucle sont altérées chez les animaux obèses. Chez l’homme, l’obésité est associée à des concentrations élevées de leptine circulante et à une résistance à l’action de la leptine dans laquelle les glucocorticoïdes pourraient être impliqués. La production de puissants agonistes de la leptine ou d’antagonistes du neuropeptide Y pourrait constituer une approche thérapeutique intéressante dans le traitement de l’obésité.

The concept of interrelationships between the central nervous system and the periphery aimed at maintaining normal body weight homeostasis has been recently strengthened by two discoveries: a hypothalamic neuropeptide, neuropeptide Y (NPY), synthesized in the arcuate nucleus of the hypothalamus, the axons of which project to the paraventricular nucleus, and a peripheral hormone, leptin, synthesized by the adipose tissue. Neuropeptide Y and leptin are major actors in the loop system linking the brain and the periphery to regulate body weight in the rat, as NPY is a potent stimulator of food intake and leptin an inhibitor of food intake. The data presented here will soon be expanded, when the hormono-metabolic effects of other hypothalamic peptides involved in the regulation of food intake and potential targets of leptin such as galanin, MCH (melanin-concentrating hormone), CRH (corticotropin-releasing hormone), GLP-1 (glucagon-like peptide-1) and alpha-MSH (alpha-melanocyte-stimulating hormone) are identified. When NPY levels increase in the hypothalamus of normal rats, they stimulate feeding; they produce hormone-metabolic changes channeling nutrients preferentially toward lipogenesis and storage in adipose tissue and away from their utilization by the muscular mass; and, finally, they promote the secretion of leptin. Elevated plasma leptin levels exert a negativie feedback on the hypothalamus, reducing neuropeptide Y levels by acting on the long form hypothalamic leptin receptors. This loop system is well-functioning in the normal rat, but is altered in (genetically) obese rodents in which hypothalamic neuropeptide Y levels are increased. Rodent obesity syndromes are characterized by hyperphagia, hormonal alterations, increased lipogenesis in adipose tissue and fat accretion, as well as by a state of insulin-resistance. They are also characterized by high leptin levels which cannot exert a negative feedback on the hypothalamus due to structural alteration of hypothalamic leptin receptors, such that hypothalamic NPY levels remain continuously elevated. Glucocorticoids play a modulatory role within this loop system linking the brain and the periphery, favoring neuropeptide Y effects and limiting those of leptin, thereby suggesting that stressful situations could contribute to overweight. [References: 58]