Neuropeptide Y stimulates autophagy in hypothalamic neurons

Abstract

Aging is characterized by autophagy impairment that contributes to age-related disease aggravation. Moreover, it was described that the hypothalamus is a critical brain area for whole-body aging development and has impact on lifespan. Neuropeptide Y (NPY) is one of the major neuropeptides present in the hypothalamus, and it has been shown that, in aged animals, the hypothalamic NPY levels decrease. Because caloric restriction (CR) delays aging, at least in part, by stimulating autophagy, and also increases hypothalamic NPY levels, we hypothesized that NPY could have a relevant role on autophagy modulation in the hypothalamus. Therefore, the aim of this study was to investigate the role of NPY on autophagy in the hypothalamus. Using both hypothalamic neuronal in vitro models and mice overexpressing NPY in the hypothalamus, we observed that NPY stimulates autophagy in the hypothalamus. Mechanistically, in rodent hypothalamic neurons, NPY increases autophagy through the activation of NPY Y 1 and Y 5 receptors, and this effect is tightly associated with the concerted activation of PI3K, MEK/ERK, and PKA signaling pathways. Modulation of hypothalamic NPY levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging.ging is associated with accumulation of specific cellular proteins within neurons, a pathologic hallmark of many neurodegenerative diseases. Because average human life expectancy has increased, but also the prevalence of cognitive decline and dementia, aging research is now focused in finding strategies that increase both lifespan and healthspan.Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis (1, 2). It is well described that basal autophagic activity decreases with age, contributing to the accumulation of altered macromolecules (3). In addition, autophagy impairment contributes to different aspects of aging phenotype and to aggravation of age-related diseases (4).Caloric restriction (CR), the reduced intake of calories without malnutrition, extends lifespan of many organisms, from yeast to mammals, and delays the progression of age-related diseases, at least in part, by stimulating autophagy (5-8). One major neuroendocrine effect of CR is the increase of neuropeptide Y (NPY) in the hypothalamus (9-12). The hypothalamus has a key role in the control of body homeostasis, neuroendocrine outputs, and feeding behavior. Recently, it was described that this brain area is critical for the development of whole-body aging and has impact on lifespan (13,14). In the hypothalamus, NPY is involved in the regulation of different physiological functions, such as regulation of food intake, body temperature, circadian rhythms, memory processing, and cognition (15-19). These diverse actions of NPY are mediated by G protein-coupled receptor subtypes named NPY Y 1 , Y 2 , Y 4 , and/or Y 5 (20, 21), all of which have been reported to be...

Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway

“…It was found that IL-17/IL-17R increased the phosphorylation of JAK2 and STAT3, which was consistent with the fact that STAT3 controls Th17 cell differentiation (54). Previous studies have shown that the PI3K signaling pathway has a crucial role in autophagy (55)(56)(57). Therefore, to confirm the roles of the PI3K and/or the JAK2/STAT3 signaling pathway in autophagy activation in oxaliplatin-treated HCC cells, SMMC-7721 cells were pre-treated with both LY294002 and AG490 to block PI3K and JAK2/STAT3.…”

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

“…NPY (neuropeptide Y): An endogenous neuropeptide produced mainly by the hypothalamus that mediates caloric restriction-induced macroautophagy. 1906 NR1D1/Rev-erba (nuclear receptor subfamily 1, group D, member 1): A nuclear receptor that represses macroautophagy in mouse skeletal muscle. nr1d1 -/mice display increased autophagy gene expression along with consistent changes in autophagy protein levels and macroautophagic flux.…”

Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

“…Numerous studies suggested that the NPY system might play a critical role in aging and lifespan as well as in further cancer-related hallmarks (17,(19)(20)(21)(22)(23)(24)51). Hypothalamic NPY levels decrease in aged animals (18), and a reduced cerebral NPY production could contribute to altered reproductive function and food intake in aged subjects (81). In contrast, activation of the NPY system was shown in several human disorders, including chronic liver disease (25,26,82) as well as hepatic glucose (29) and lipid (30) metabolism, but its potential role in liver cancer was unknown.…”

“…Thus, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function (16). Several milestone studies also suggested key roles of the NPY system in the regulation of diverse common hallmarks of aging, metabolic disorders, and cancer (17), including autophagy (18), nutrient sensing, caloric restriction, appetite regulation (19)(20)(21), mitochondrial dysfunction (22), cell proliferation (23), and hematopoietic stem and progenitor cell properties like migration and intra-/ extravasation (24).…”