Neuropeptide Y – Its role in human performance and extreme environments

Abstract

Neuropeptide tyrosine (neuropeptide Y or NPY) is one of the most abundant neuropeptides in the mammalian central nervous system and also widely distributed in the peripheral nervous system. Among the many mediators involved in important physiological and psychological systems, NPY in particular appears to be a multisignaling key peptide. The biological actions of NPY are vast and mediated via the Y₁, Y₂, Y₄, and Y₅ receptors, which are involved in both essential physiological and pathophysiological processes. Here, we discuss various roles of NPY in seven systems: a) regulation of energy homeostasis, b) thermoregulation, c) circadian system, d) sleep, e) nociception, f) emotional behavior, and g) the autonomic nervous system.

NPY regulates a) energy homeostasis with actions at different sites (central and peripheral), via different receptors in various neuronal tissues. Due to its prominent actions in the brain, including stimulating appetite, NPY function has gained importance. However, NPY is more than just an orexigenic peptide. Food intake and decrease in energy expenditure are exerted together by the Y₁ and Y₅ receptors. While the Y₄ receptor exerts anorexigenic effects, the Y₂ receptor has central anorexigenic and peripheral orexigenic properties. The involvement of NPY in b) thermoregulation remains unclear. Although it has been reported that cold exposure activates NPY. Increased or decreased thermogenesis has been observed as a result of NPY administration to different central sites. Central Y₁ and Y₅ receptors inhibit sympatho-adrenal transmitted thermogenesis in peripheral brown adipose tissue. NPY functions as a chemical messenger autonomous of the light-dark-cycle in the c) circadian rhythm and exerts similar phase-shifting effects to those of light. NPY leads to a shortened d) sleep onset and reduced REM latency, but its role in the circadian rhythm seems to be elusive and has not been established. NPY is implicated in e) pain perception and modulates nociception. It has been shown to cause both nociceptive and anti-nociceptive responses.

Moreover, Y receptors are thought to form heterodimers with those of galanin and glutamate to enhance their nociceptive modulatory effects. Especially the role of the Y₂ receptor within this system and all the other systems reveals opposite properties. The different effects of Y₂ receptors are dependent on their central or peripheral location.These opposing effects can be observed in other receptors as well and are likely explained by tissue-specific differences in receptor expression (number and distribution of receptors). Differences in cell type-specific second messenger coupling also play a role. Therefore, centrally located receptors can have a completely different function than peripherally located receptors. The regulation of f) emotional behavior through NPY and its receptors is biphasic. The Y₁ and Y₅ receptor are anxiolytic, whereas the Y₂ and Y₄ receptors lead to anxiety- and depression-like behavior. Moreover, the Y₂ receptor enhances dopamine mediated anxious behavior but can also reverse the dopamine effects. Comparison of several studies showed that NPY mainly exerts anxiolytic, anti-depressant effects, and is implicated in memory processing. Moreover, it seems to be the ‘peptide of success.’ Polymorphisms in NPY genes may predispose different kinds of human affective disorders. Lower levels of NPY are associated with major depression and bipolar disorder. These findings are consistent with NPY modulating emotional behavior and may help to explain interindividual variation in resiliency to stress. In the g) autonomic nervous system effects are mediated predominantly via Y₁, Y₂, and Y₅ receptors. These receptors are expressed in neurons supplying the vascular smooth muscle cells, the cardiomyocytes and are involved in physiological processes including vasoconstriction and -dilatation, heart rate variability, cardiac remodeling, and angiogenesis. However, additional peripheral mediated Y receptor-ligand effects have received far less attention than central. Besides its several physiological roles, NPY has been implicated in several common diseases, such as chronic pain, depression, hypertension, and atherosclerosis. Therefore, the NPY-multi-signaling-system could be a therapeutic target but as well an interesting neurotransmitter which plays obviously an important role in human adaptation to extreme environments, including space.