Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

Abstract

Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db/db mouse, or at the peptide level, as in ob/ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka-Long-Evans-Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an overactive NPY system (increased mRNA expression in the ARC associated with an upregulation of the receptors) is characteristic of rats or rodent strains sensitive to dietary-induced obesity. Finally, NPY appears to play an important role in body weight and feeding regulation, and while it does not constitute the only target for drug treatment of obesity, it may nevertheless provide a useful target in conjunction with others.

Figure 1

The hypothalamic neuropeptide Y (NPY) system. Names of the areas involved in the system are indicated in italics: ARC, arcuate nucleus; PVN, paraventricular nucleus; LH, lateral hypothalamus; VMN, ventromedial nucleus; DMN, dorsomedial nucleus. The location of specific receptors is shown. The different receptors are identified once in an area by a sign and the receptor name tied to this sign (e.g. black triangle for MC4-R, black explosion for insulin, diamond for glucocorticoids, etc.). In the other nuclei, their presence is indicated by signs only. Ob-Rb, long form of the leptin receptor; MC4-R, type 4 melanocortin receptor; GHS-R, growth hormone secretagogue (ghrelin) receptor; INS-R, insulin receptor; GC-R, glucocorticoid receptor. The names of the neuronal populations connected to NPY neurons in the ARC are given in small capitals: POMC, proopiomelanocortin; CART, cocaine and amphetamine-related peptide; DYN, dynorphin; GAL, galanin; CRH, corticotropin-releasing hormone; MCH, melanin concentrating hormone; OX, orexins; TRH, thyrotropin-releasing hormone. Agouti-related peptide (AgRP) is co-localized with NPY (for more details, see Beck 2005).

Figure 2

Schematic of neuropeptide Y (NPY) regulation of food intake and body weight in relation to main hormones and macronutrients. Glucopenia includes hypoglycemia and cellular glucoprivation. Long-term and short-term regulation by macronutrients are indicated by thick and thin arrows, respectively.