Changes in UCP2, PPARγ2, and C/EBPα Gene Expression Induced by a Neuropeptide Y (NPY) Related Receptor Antagonist in Overweight Rats

Neuropeptide Y (NPY), a peptide released by nervous cells, appears to contribute to adiposity regulation by increasing food intake and inhibiting lipolysis. New NPY receptor related antagonists such as S.A.0204 are being developed as potential anti-obesity drugs affecting adipocyte lipid metabolism and thermogenesis. In this sense, those animals fed on a high-energy yielding (cafeteria) diet decreased body fat weight as compared to overweight controls, when they were administered with S.A.0204, and increased body temperature, which statistically correlated with high UCP2 mRNA expression levels in white adipose tissue. In addition, the in vivo NPY-antagonist administration was able to prevent white adipose tissue growth in animals fed the cafeteria (high-fat) diet by impairing PPARγ and C/EBPα mRNA expression in white fat cells. In summary, this novel NPY related-antagonist S.A.0204 may regulate body fat deposition by affecting both energy dissipation and white adipose tissue deposition, representing a potential new pharmacological strategy for obesity management.     

肺癌患者化疗前后血浆leptin和血清Hcy、NPY检测的临床意义

目的:探讨肺癌患者化疗前后血浆leptin和血清Hcy、NPY水平的变化及临床意义.方法:应用放射免疫分析和化学发光法对36例肺癌患者进行了血浆leptin和血清Hcy、NPY测定,并与35名正常健康人作比较.结果:肺癌患者在化疗前血浆leptin和血清Hcy、NPY水平均非常显著地高于正常人组(P<0.01),化疗后...     

Effects of a selective Y2R antagonist, JNJ-31020028, on nicotine abstinence-related social anxiety-like behavior, neuropeptide Y and corticotropin releasing factor mRNA levels in the novelty-seeking phenotype

An outbred rat model of novelty-seeking phenotype has predictive value for the expression of locomotor sensitization to nicotine. When experimentally naïve rats are exposed to a novel environment, some display high rates of locomotor reactivity (HRs, scores ranking at top 1/3rd of the population), whereas some display low rates (LRs, scores ranking at bottom 1/3rd of the population). Basally, HRs display lower anxiety-like behavior compared to LRs along with higher neuropeptide Y (NPY) mRNA in the amygdala and the hippocampus. Following an intermittent behavioral sensitization to nicotine regimen and 1 wk of abstinence, HRs show increased social anxiety-like behavior in the social interaction test and robust expression of locomotor sensitization to a low dose nicotine challenge. These effects are accompanied by a deficit in NPY mRNA levels in the medial nucleus of the amygdala and the CA3 field of the hippocampus, and increases in Y2R mRNA levels in the CA3 field and corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. Systemic and daily injections of a Y2R antagonist, JNJ-31020028, during abstinence fully reverse nicotine-induced social anxiety-like behavior, the expression of locomotor sensitization to nicotine challenge, the deficit in the NPY mRNA levels in the amygdala and the hippocampus, as well as result an increase in Y2R mRNA levels in the hippocampus and the CRF mRNA levels in the amygdala in HRs. These findings implicate central Y2R in neuropeptidergic regulation of social anxiety in a behavioral sensitization to nicotine regimen in the LRHR rats.     

Galanin-like peptide (GALP) is a hypothalamic regulator of energy homeostasis and reproduction

Galanin-like peptide (GALP) was discovered in 1999 in the porcine hypothalamus and was found to be a 60 amino acid neuropeptide. GALP shares sequence homology to galanin (1-13) in position 9-21 and can bind to, as well as activate, the three galanin receptor subtypes (GalR1-3). GALP-expressing cells are limited, and are mainly found in the arcuate nucleus of the hypothalamus (ARC) and the posterior pituitary. GALP-positive neurons in the ARC project to several brain regions where they appear to make contact with multiple neuromodulators. These neuromodulators are involved in the regulation of energy homeostasis and reproduction, anatomical evidence that suggests a role for GALP in these physiological functions. In support of this idea, GALP gene expression is regulated by several factors that reflect metabolic state including the metabolic hormones leptin and insulin, thyroid hormones, and blood glucose. Considerable evidence now exists to support the hypothesis that GALP has a role in the regulation of energy homeostasis and reproduction; and, that GALP’s role may be independent of the known galanin receptors. In this review, we (1) provide an overview of the distribution of GALP, and discuss the potential relationship between GALP and other neuromodulators of energy homeostasis and reproduction, (2) discuss the metabolic factors that regulate GALP expression, (3) review the evidence for the role of GALP in energy homeostasis and reproduction, (4) discuss the potential downstream mediators and mechanisms underlying GALP’s effects, and (5) discuss the possibility that GALP may mediate its effects via an as yet unidentified GALP-specific receptor.     

神经肽Y在子痫前期患者胎盘中的表达及意义

目的探讨子痫前期患者胎盘中神经肽Y基因和蛋白表达变化与组织的病理情况。方法采用RT-PCR、Western-Blot检测轻度子痫前期组25例、重度子痫前期组共25例和正常妊娠组25例的胎盘组织中神经肽Y mRNA及其蛋白在各组患者病理标本组织中的表达量。同时常规HE染色观察各组胎盘的病理变化。结果神经肽Y mRNA及其蛋白在患者病理组织中表达:重度子痫前期组最高,轻度子痫前期组次之,正常妊娠组最低,各组间的差异有统计学意义(P<0.05)。HE染色可见子痫前期组胎盘组织中,合体细胞结节纤维素样坏死显著增多等病理变化,与对照组相比差异有显著性。结论神经肽Y(NPY)基因和蛋白高表达的升高可能是子痫前期发病的重要机制。     

NPY Intraperitoneal Injections Produce Antidepressant‐Like Effects and Downregulate BDNF in the Rat Hypothalamus

Aims: Several studies have documented an involvement of Neuropeptide Y (NPY) in stress‐related disorders. Stress‐related disorders are also characterized by changes in brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF), neurotrophins implicated in the survival and function of neurons. Thus the aim of this study was to investigate whether an NPY intraperitoneal treatment has antidepressant‐like effects in rats subjected to a classical stress paradigm, the Forced Swim Test (FST), in association with changes in local brain neurotrophin production. Methods: Rats were intraperitoneally injected with either NPY (60 μg/kg) or a vehicle for three consecutive days between two FST sessions and then tested for time spent (or delay onset) in immobile posture. Moreover, we measured by enzyme‐linked immunosorbent assay (ELISA) neurotrophin levels in the hypothalamus and corticosterone levels in plasma. Results: The data showed that NPY induced a significant delay in the onset and a significant reduction in the duration of the immobility posture in FST. We also found that NPY decreased BDNF levels in the hypothalamus and corticosterone levels in plasma. Discussion: Immobility posture in FST can be reduced by antidepressant drugs. Thus, our data show an antidepressant‐like effect of NPY associated with changes in BDNF levels in the hypothalamus and reduced activity of hypothalamic–pituitary–adrenal (HPA) axis. Conclusion: These findings, while confirming the involvement of the NPY system in stress‐related disorders, suggest that a less invasive route of administration, such as an intraperitoneal injection, may be instrumental in coping with stressful events in animal models and perhaps in humans.     

Neuropeptide Y Protects Rat Cortical Neurons against β-Amyloid Toxicity and Re-establishes Synthesis and Release of Nerve Growth Factor

Neuropeptide Y (NPY) is a 36 amino acid peptide, widely distributed within central nervous system neurons. More recently, it has been shown that NPY is involved in Alzheimer's disease (AD), a disorder characterized by accumulation of amyloid β-peptide (Aβ) in neurons. In a previous study, we investigated the effect of NPY on neuronal damage by exposing SH-SY5Y cells (an established human derived neuroblastoma cell line) to Aβ's pathogenic fragment 25-35 (Aβ(25-35)). We found a NPY-neuroprotective action associated with changes in intracellular production of nerve growth factor (NGF), a member of the neurotrophin family. Since our results were encouraging, we decided to replicate our data using primary cortical neurons cultured in presence of Aβ(25-35), and investigated whether NPY had similar neuroprotective action. Moreover, since cortical neurons are able to produce and release NGF, we investigated whether the synthesis and release of NGF were modified in such experimental conditions. Our results showed that a preincubation with NPY counteracted the toxic effect of Aβ, as measured by increased cell viability. Moreover, NPY pretreatment had an effect on NGF since its intracellular synthesis was increased, release was normalized, and mRNA expression was downregulated. Notably, these effects on NGF were in the opposite direction of those produced by incubating the cells with Aβ alone. This study in primary cortical neurons supports the hypothesis that NPY may be a neuroprotective agent against β-amyloid neurotoxicity. These data also suggest that NPY may influence the synthesis and the release of NGF by cortical neurons.     

Meta-analysis of genome-wide association studies for panic disorder in the Japanese population

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10⁻⁵, odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10⁻⁴). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.     

Neuropeptide Y and extracellular signal-regulated kinase mediate injury-induced neuroregeneration in mouse olfactory epithelium

In the olfactory epithelium (OE), injury induces ATP release, and subsequent activation of P2 purinergic receptors by ATP promotes neuroregeneration by increasing basal progenitor cell proliferation. The molecular mechanisms underlying ATP-induced increases in OE neuroregeneration have not been established. In the present study, the roles of neuroproliferative factors neuropeptide Y (NPY) and fibroblast growth factor 2 (FGF2), and p44/42 extracellular signal-regulated kinase (ERK) on ATP-mediated increases of neuroregeneration in the OE were investigated. ATP increased basal progenitor cell proliferation in the OE via activation of P2 purinergic receptors in vitro and in vivo as monitored by incorporation of 5′-ethynyl-2′-deoxyuridine, a thymidine analog, into DNA, and proliferating cell nuclear antigen (PCNA) protein levels. ATP induced p44/42 ERK activation in globose basal cells (GBCs) but not horizontal basal cells (HBCs). ATP differentially regulated p44/42 ERK over time in the OE both in vitro and in vivo with transient inhibition (5-15 min) followed by activation (30 min-1 h) of p44/42 ERK. In addition, ATP indirectly activated p44/42 ERK in the OE via ATP-induced NPY release and subsequent activation of NPY Y1 receptors in the basal cells. There were no synergistic effects of ATP and NPY or FGF2 on OE neuroregeneration. These data clearly have implications for the pharmacological modulation of neuroregeneration in the olfactory epithelium.