In response to stress, some people lose while others gain weight. This is believed to be due to either increased β-adrenergic activation, the body's main fat-burning mechanism, or increased intake of sugar-and fat-rich "comfort foods." A high-fat, high-sugar (HFS) diet alone, however, cannot account for the epidemic of obesity, and chronic stress alone tends to lower adiposity in mice. Here we discuss how chronic stress, when combined with an HFS diet, leads to abdominal obesity by releasing a sympathetic neurotransmitter, neuropeptide Y (NPY), directly into the adipose tissue. In vitro, when "stressed" with dexamethasone, sympathetic neurons shift toward expressing more NPY, which stimulates endothelial cell (angiogenesis) and preadipocyte proliferation, differentiation, and lipid-filling (adipogenesis) by activating the same NPY-Y2 receptors (Y2Rs). In vivo, chronic stress, consisting of cold water or aggression in HFS-fed mice, stimulates the release of NPY and the expression of Y2Rs in visceral fat, increasing its growth by 50% in 2 weeks. After 3 months, this results in metabolic syndrome-like symptoms with abdominal obesity, inflammation, hyperlipidemia, hyperinsulinemia, glucose intolerance, hepatic steatosis, and hypertension. Remarkably, local intra-fat Y2R inhibition pharmacologically or via adenoviral Y2R knock-down reverses or prevents fat accumulation and metabolic complications. These studies demonstrated for the first time that chronic stress, via the NPY-Y2R pathway, amplifies and accelerates diet-induced obesity and the metabolic syndrome. Our findings also suggest the use of local administration of Y2R antagonists for treatment of obesity and NPY-Y2 agonists for fat augmentation in other clinical applications.

Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which cleave NPY to its shorter form, NPY 3-36 , not active at Y1Rs. We have shown that NPYinduced cell death can be abolished by overexpression of DPPs and enhanced by their down-regulation. Both NPY treatment and DPP blockade activated the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and apoptosisinducing factor (AIF). Moreover, the decrease in cell survival induced by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9. Thus, this is the first evidence of these intracellular DPPs cleaving releasable peptides, such as NPY, in live cells. In contrast, another membrane DPP, fibroblast activation protein (FAP), did not affect NPY actions. In conclusion, DPPs act as survival factors for ESFT cells and protect them from cell death induced by endogenous NPY. This is the first demonstration that intracellular DPPs are involved in regulation of ESFT growth and may become potential therapeutic targets for these tumors.

Atopic dermatitis (AD) is a chronic inflammatory disease persisting predominantly in the pediatric population. Its development is most presumably multifactorial and a derivative of interplay between genetic, immunologic, and environmental causes. To the authors’ knowledge, no multinational and systematic database of AD prevalence is established and maintained for Europe. Thus, epidemiologic data originating from the multinational studies was compiled to draw a picture of AD in both pediatric and adult populations in Europe. The outcomes of this exercise support the general observation that AD prevalence follows the latitudinal pattern with higher prevalence values in northern Europe and decreases progressively towards southern Europe. Noteworthy, the data shows significant differences on the country-level, with higher prevalence in municipal areas than rural. Finally, and unsurprisingly, the collected data reinforces the observation of AD prevalence being highest in pediatric populations in contrast to adults. Herein, data presented was additionally supplemented with the information on current standing on AD etiology.

Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES.

Neuroblastoma (NB) is a pediatric tumor of neural crest origin with heterogeneous phenotypes. While low stage tumors carry a favorable prognosis, over 50% of high risk NB relapses after treatment with a fatal outcome. Thus, developing therapies targeting refractory NB remains an unsolved clinical problem. Brain-derived neurotrophic factor (BDNF) and its TrkB receptor are known to protect NB cells from chemotherapy-induced cell death, while neuropeptide Y (NPY), acting via its Y2 receptor (Y2R), is an autocrine proliferative and angiogenic factor crucial for maintaining NB tumor growth. Here, we show that in NB cells, BDNF stimulates the synthesis of NPY and induces expression of another one of its receptors, Y5R. In human NB tissues, the expression of NPY and Y5R positively correlated with the expression of BDNF and TrkB. Functionally, BDNF triggered Y5R internalization in NB cells, while Y5R antagonist inhibited BDNF-induced p44/42-MAPK activation and its pro-survival activity. These observations suggested TrkB-Y5R transactivation that resulted in cross-talk between their signaling pathways. Additionally, NPY and Y5R were up-regulated in a BDNF-independent manner in NB cells under pro-apoptotic conditions, such as serum deprivation and chemotherapy, as well as in cell lines and tissues derived from post-treatment NB tumors. Blocking Y5R in chemoresistant NB cells rich in this receptor sensitized them to chemotherapy-induced apoptosis and inhibited their growth in vivo by augmenting cell death. In summary, the NPY/Y5R axis is an inducible survival pathway activated in NB by BDNF or cellular stress. Upon such activation, Y5R augments the pro-survival effect of BDNF via its interactions with TrkB receptor and exerts an additional BDNF-independent anti-apoptotic effect, both of which contribute to NB chemoresistance. Therefore, the NPY/Y5R pathway may become a novel therapeutic target for patients with refractory NB, thus far an incurable form of this disease.

Coarse woody debris (CWD) represents a relatively stable habitat in many lakes with forested shorelines providing a living place for a wide range of species. The spatial complexity of CWD is recognized as an important factor promoting the abundance, diversity and productivity of littoral biota, mainly by providing shelters and moderating predator-prey interactions. However, little is as yet known on the response of different species to various levels of CWD complexity and the effects of the spatial arrangement of CWD on the connectivity between littoral populations. It is also unclear how CWD decay, which modifies the surface complexity of wood and the quality of food, affects the diversity of wood-associated species and trophic interactions. Further research is also needed to recognize the contribution of littoral wood to carbon sequestration and nutrient fluxes, considering factors affecting the CWD decay rate, such as wood species and environmental conditions. CWD resources are systematically depleted by shoreline development which leads to disruptions in the functioning of lake ecosystems. Attempts at restoring CWD habitat provided ambiguous effects on littoral species and therefore better understanding of the role of CWD in lake ecosystems is crucial to the development of successful restoration projects and effective management programmes.

Because of the increasing anthropogenic pressure, the amount of solid waste discarded in water is growing considerably. It can affect aquatic organisms, modifying their distribution and abundance. This study was designed to investigate the effect of several types of solid waste (bottles, textiles, bundles of string, pieces of polythene and rubber) upon the taxonomic composition and biodiversity of macroinvertebrates inhabiting the near-shore zone (up to 1-m depth) of the Włocławek Reservoir (the River Vistula, central Poland). The epifauna developing on these materials was compared with organisms living on natural substrata: bare sandy bottom (from which the waste was collected), macrophytes and sandy bottom overgrown by plants. The communities inhabiting the artificial substrata (except strings) were much more diverse (in terms of taxon richness, Shannon-Wiener index and evenness) than the surrounding bare sandy bottom. The biodiversity on the waste was similar to that found on the macrophytes and bottom among them, located nearby. The most suitable materials appeared to be bottles, providing shelters in their interiors. The artificial substrata differed considerably from all natural habitats with respect to taxonomic composition, though they were more similar to the macrophytes than to the bottom sediments. Furthermore, the variability among the assemblages developing on the particular waste objects, even of the same type, was much larger than that observed on the macrophytes, indicating the patchy nature of the former habitat. Thus, discarded waste can constitute alternative habitats for invertebrates, especially when natural substrata are unsuitable (e.g. sandy bottom), but they cannot fully replace natural substrata, such as plants, in their habitat-forming role in ecosystems.

1. Coarse woody debris (CWD) in the littoral zone of lakes constitutes a preferred habitat for macroinvertebrates and fish. CWD differs in the surface complexity depending on its decay status. Therefore, CWD may provide distinct types of shelters and thus modify the structure of the macroinvertebrate community as well as its susceptibility to fish predation. 2. We ran an enclosure experiment in a lake littoral zone to test the effect of surface complexity of CWD on the interactions between the predator, Eurasian perch (Perca fluviatilis) and its potential macroinvertebrate prey. We deployed 10 enclosures containing fresh wood with a smooth surface and 10 enclosures containing decayed wood with a more complex, rough surface and allowed colonisation by macroinvertebrates. Five enclosures of each type were then stocked by perch and exposed to fish predation. 3. The abundance and biomass of macroinvertebrates were significantly higher on decayed wood with greater surface complexity than on fresh wood; however, the type of CWD did not strongly influence the taxonomic composition and diversity of invertebrates. 4. The direct effect of perch predation on the macroinvertebrate community was weak. Perch reduced only the abundance of adult Dikerogammarus villosus, while other potential prey, such as chironomids, was more abundant in the presence of the fish. The impact of perch consumption of these larvae was probably obscured by interspecific interactions among chironomids and D. villosus, which were impaired in the fish enclosures. 5. We found no clear evidence that the influence of perch on macroinvertebrates was mediated by the complexity of the wood surface. However, fish diet analysis showed that on decayed wood, perch preferentially consumed chironomids, and consumption of D. villosus was much lower, while on fresh wood, the preferential consumption of chironomids decreased with increasing consumption of gammarids. This suggests that such differences in fish diet could be an effect of complex interactions between wood microstructure, prey density and its ability to find refuge in CWD. 6. The effect of CWD microstructure on predator-prey interactions was visible with respect to interspecific relationships between chironomids and gammarids, which on more complex decayed wood were moderated in the absence of perch.