NPY and stress 30 years later: the peripheral view

Abstract

Almost 30 years ago, neuropeptide Y (NPY) was discovered as a sympathetic co-transmitter and one of the most evolutionarily conserved peptides abundantly present all over the body. Soon afterward, NPY's multiple receptors were characterized and cloned, and the peptide's role in stress was first documented. NPY has proven to be pivotal for maintaining many stress responses. Most notably, NPY is known for activating long-lasting vasoconstriction in many vascular beds, including coronary arteries. More recently, NPY was found to play a role in stress-induced accretion of adipose tissue which many times can lead to detrimental metabolic changes. It is however due to its prominent actions in the brain, one of which is its powerful ability to stimulate appetite as well as its anxiolytic activities that NPY became a peptide of importance in neuroscience. In contrast, its actions in the rest of the body, including its role as a stress mediator, remained, surprisingly underappreciated and not well understood. Our research has focused on that other, "peripheral" side of NPY. In this review, we will discuss those actions of NPY on the cardiovascular system and metabolism, as they relate to adaptation to stress, and attempt to both distinguish NPY's effects from and integrate them with the effects of the classical stress mediators, glucocorticoids, and catecholamines. To limit the bias of someone (ZZ) who has viewed the world of stress through the eyes of NPY for over 20 years, fresh insight (DH) has been solicited to more objectively assess NPY's contributions to stress-related diseases and the body's ability to adapt to stress.

Fig. 1

Sources and actions of NPY in the brain and the periphery. Pools 1–6 delineate peripheral and central regions within the body where NPY is found. In the 1st pool, the brain, NPY and its receptors are expressed post-synaptically (Y₁, Y₅) and pre-synaptically (Y₂) in many stress-sensitive regions (the hypothalamus and hippocampus) where the peptide exerts potent orexigenic and anxiolytic activities. In the periphery, pools 2nd–6th, there are neuronal (2nd Pool) and non-neuronal sources of expression of NPY (3rd–6th Pools). In the cardiovascular system (secreted from the sympathetic nerves and platelets—2nd Pool), NPY mediates stress-induced vasoconstriction, vascular hyperplasia, and atherosclerosis via its Y₁ receptor. In the immune cells (3rd Pool), NPY is inducible and can mediate either pro- or anti-inflammatory actions through its Y₁ receptor on macrophages. In the autocrine/paracrine systems of the endothelial cells (4th Pool), NPY, converted by DPPIV to NPY_3–36, a Y₂ receptor-selective agonist, promotes angiogenesis and vascularization of ischemic and non-ischemic tissues. NPY when up-regulated in transgenic mice increases the basal level of capillary fibers in the hind limb, whereas Y2rKO mice show a decreased number of capillary fibers as compared to WT (4th Pool). NPY, DPPIV, and Y2Rs are also inducible in adipocytes (5th Pool) where they mediate stress-and-diet-induced adipogenesis and obesity. Finally, both NPY and PYY are expressed in the gastrointestinal system, but it is the gut PYY (6th Pool) when converted to PYY_3–36 by DPPIV, which is known to induce satiety by acting on the hypothalamic presynaptic Y₂ receptor to suppress food intake

Fig. 2

Schematic representation of the interactions between the neurotransmitters released following sympathetic activation and their actions both pre- and post-synaptically. Part a depicts how activation of the sympathetic nervous system (SNS) by glucocorticoids (GC), High Fat Sugar Diet (HFS), Nerve Growth Factor (NGF) or stress results in increased NPY mRNA expression in the nerve terminal. Part a also shows that activation of the SNS induces the release of three neurotransmitters: ATP, NE, and NPY. Each neurotransmitter is capable of having both pre- a and post-synaptic b effects. Pre-synaptically (a), NPY can inhibit the release of NE, ATP and itself. Both NE and ATP are also capable of inhibiting NPY’s release as well their own release. Post-synaptically (b) each neurotransmitter is capable of potentiating each other’s effects. Part c shows the relationship between sympathetic activation and the relative release of ATP, NE, and NPY. Part d describes the relationship between plasma NPY levels and multiple pathological states during varying degrees of sympathetic nerve activity