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.

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

“…In addition to its well known roles in stimulating appetite and weight gain, NPY plays a prominent role in glucose homeostasis. An increase in NPY expression in the arcuate and dorsomedial nuclei is characteristic of several models of insulin resistance, for example Lep ob/ob and agouti (A y ) mice, Otsuka Long-Evans Tokushima fatty rats, and tubby mice (Guan et al, 1998;Beck, 2006). Moreover, similar to the effect of intracerebroventricular resistin in the current study, central administration of NPY during a hyperinsulinemic clamp increased glucose production without altering peripheral glucose uptake (Marks and Waite, 1997;van den Hoek et al, 2004).…”

Possible Involvement of Hypothalamic Nucleobindin-2 in Hyperphagic Feeding in Tsumura Suzuki Obese Diabetes Mice

“…[35][36][37][38][39] Many model animals of type 2 diabetes such as db/db and ob/ob mice demonstrate marked increases in NPY mRNA and peptide in the hypothalamus. 40) The genetic removal of NPY partially restored hyperphagic feeding, obesity, hyperglycemia and hyperinsulinemia in ob/ob mice. 10) Therefore, the up-regulation of hypothalamic NPY signaling is associated with hyperphagic feeding under the T2DM state.…”

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

“…Thus, NPY acts as a critical gatekeeper for the excitatory inputs that drive sympathoexcitation, suggesting that suppressed NPY inhibition must occur in parallel to increased POMC excitation with obesity. Indeed, obesity decreases hypothalamic NPY content (6). However, whether hypothalamic NPY contributes to obesity-induced increases in SNA has not been investigated.…”