Abstract BACKGROUND： The gut hormone fragment peptide YY3-36 (PYY) reduces appetite and food intake when infused into subjects of normal weight. In common with the adipocyte hormone leptin， PYY reduces food intake by modulating appetite circuits in the hypothalamus. However， in obesity there is a marked resistance to the action of leptin， which greatly limits its therapeutic effectiveness. We investigated whether obese subjects were also resistant to the anorectic effects of PYY. METHODS： We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12 lean subjects in a double-blind， placebo-controlled， crossover study. The plasma levels of PYY， ghrelin， leptin， and insulin were also determined. RESULTS： Caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects (P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hour caloric intake in both obese and lean subjects. PYY infusion reduced plasma levels of the appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levels of PYY were significantly lower in obese subjects (the mean [+/-SE] fasting PYY levels were 10.2+/-0.7 pmol per liter in the obese group and 16.9+/-0.8 pmol per liter in the lean group， P<0.001). Furthermore， the fasting PYY levels correlated negatively with the body-mass index (r = -0.84， P<0.001). CONCLUSIONS： We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects， suggesting that PYY deficiency may contribute to the pathogenesis of obesity. Copyright 2003 Massachusetts Medical Society
Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis， dietary failure， and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice， we determined the effects of diet-induced obesity (DIO)， subsequent dieting， and GIBP surgery on ghrelin， peptide YY (PYY)， and glucagon-like peptide-1 (GLP-1). To evaluate PYY's role in mediating weight loss post-GIBP， we undertook GIBP surgery in PyyKO mice.Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days postoperatively. Fasting acyl-ghrelin， total PYY， active GLP-1 concentrations， stomach ghrelin expression， and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP-1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups.DIO progressively reduced circulating fasting acyl-ghrelin， PYY， and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP， WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast， the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice.PYY plays a key role in mediating the early weight loss observed post-GIBP， whereas relative PYY deficiency during dieting may compromise weight-loss attempts.
Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36).
Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis， we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model， Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus， but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly， we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However， 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus， POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding， but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.
Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY.
Consumption of deoxynivalenol (DON)， a trichothecene mycotoxin known to commonly contaminate grain-based foods， suppresses growth of experimental animals， thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia， the initiating mechanisms for appetite suppression remain unknown. Here， we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1， leptin， amylin， pancreatic polypeptide， gastric inhibitory peptide， or ghrelin; however， the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically， ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY)， corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide， individually， suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together， these findings suggest that PYY might be one critical mediator of DON-induced anorexia and， ultimately， growth suppression.
Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor HIF-1α in a p53-independent manner.
In response to hypoxic stress， hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes， and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However， the role of YY1 under tumor hypoxic condition is poorly understood. Herein， we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition， and consequently downregulated the expression of HIF-1α target genes. Interestingly， our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally， the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively， our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore， YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status.
Cardiogenesis is regulated by a complex interplay between transcription factors. However， little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective： To identify novel regulators of mesodermal cardiac lineage commitment.We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell-derived CPCs. From 32 candidate transcription factors screened， we found that Yin Yang 1 (YY1)， a repressor of sarcomeric gene expression， is present in CPCs in vivo. Interestingly， we uncovered the ability of YY1 to transcriptionally activate Nkx2.5， a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays， in vivo chromatin immunoprecipitation， and genome-wide sequencing analysis. Furthermore， the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell-based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs.These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes.
Persistent DNA Damage Measured by Comet Assay of Sprague Dawley Rat Lung Cells after Five Days of Inhalation Exposure and 1 Month Post-Exposure to Dispersed Multi-Wall Carbon Nanotubes (MWCNTs) Generated by New MWCNT Aerosol Generation System
ABSTRACT Carbon nanotubes (CNTs) have specific physico-chemical properties that are useful for the electronics， automotive， and construction industries. Yet， despite their many advantages， there is a current lack of available information on the human health and environmental hazards of CNTs. For this reason， the current study investigated the inhalation toxicity potential of multiwall CNTs (MWCNTs). Eight-week-old rats were divided into four groups (10 rats in each group)， the fresh-air control (0mg/m(3))， low-concentration group (0.16mg/m(3))， middle-concentration group (0.34mg/m(3))， and high-concentration group (0.94mg/m(3))， and the whole body was exposed to MWCNTs for 5 days (6h/day). Lung cells were then isolated from five rats in each group on day 0 and 1 month after the 5-day exposure， respectively. The MWCNTs were generated by a newly designed generation system， and the MWCNT concentrations in the exposure chambers monitored in accordance with National Institute for Occupational Safety and Health (NIOSH) 0500 using a membrane filter. The MWCNTs were also sampled for an elemental carbon concentration analysis using a glass filter. The animals exhibited no significant body weight changes， abnormal clinical signs， or mortality during the experiment. A single-cell gel electrophoresis assay (Comet assay) was conducted to determine the DNA damage in lung cells obtained from the right lung. As a result， the Olive tail moments were 23.00±1.76， 30.39±1.96， 22.96±1.26， and 33.98±2.21 for the control， low-， middle-， and high-concentration groups， respectively， on day 0 postexposure. Meanwhile， 1 month postexposure， the Olive tail moments were 25.00±2.71， 28.39±3.55， 22.56±1.36， and 31.97±3.16 for the control， low-， middle-， and high-concentration groups， respectively. Thus， the MWCNTs caused a statistically significant increase in lung DNA damage at high concentration (0.94mg/m(3)) when compared with the negative control group on day 0 and 1 month postexposure.
Cranial visceral afferents enter the brain at the solitary tract nucleus (NTS). GABAergic neurons are scattered throughout the NTS， but their relation to solitary tract (ST) afferent pathways is imprecisely known. We hypothesized that most GABAergic NTS neurons would be connected only indirectly to the ST. We identified GABAergic neurons in brain stem horizontal slices using transgenic mice in which enhanced green fluorescent protein (EGFP) expression was linked to glutamic acid decarboxylase expression (GAD(+)). Finely graded electrical shocks to ST recruit ST-synchronized synaptic events with all-or-none thresholds and individual waveforms did not change with greater suprathreshold intensities--evidence consistent with initiation by single afferent axons. Most (approximately 70%) GAD(+) neurons received ST-evoked excitatory postsynaptic currents (EPSCs) that had minimally variant latencies (jitter， SD of latency <200 micros) and waveforms consistent with single， direct ST connections (i.e.， monosynaptic). Increasing stimulus intensity evoked additional ST-synchronized synaptic responses with jitters >200 micros including inhibitory postsynaptic currents (IPSCs)， indicating indirect connections (polysynaptic). Shocks of suprathreshold intensity delivered adjacent (50-300 microm) to the ST failed to excite non-ST inputs to second-order neurons， suggesting a paucity of axons passing near to ST that connected to these neurons. Despite expectations， we found similar ST synaptic patterns in GAD(+) and unlabeled neurons. Generally， ST information that arrived indirectly had small amplitudes (EPSCs and IPSCs) and frequency-dependent failures that reached >50% for IPSCs to bursts of stimuli. This ST afferent pathway organization is strongly use-dependent--a property that may tune signal propagation within and beyond NTS.
Identification, expression analysis, and functional characterization of peptide YY in chickens (Gallus gallus domesticus).
Abstract Peptide YY (PYY) functions as a postprandial satiety signal in mammals. However， the genomic information and physiological roles of chicken PYY have not yet been clarified， although PYY peptide was isolated from chicken intestines in 1992. In this study， we identified a full-length complementary DNA (cDNA) sequence encoding the chicken PYY precursor. The deduced amino acid sequence of chicken PYY was completely consistent with the previously identified peptide sequence. PYY mRNA was abundantly expressed in the small intestine compared with the large intestine. PYY mRNA levels in the jejunum were significantly higher during ad libitum feeding compared with fasting， suggesting that intestinal PYY expression is altered in response to nutritional status in chicks. Intravenous administration of PYY significantly suppressed food intake in chicks. Furthermore， neuropeptide Y receptor Y2， a possible target of PYY， was expressed in various brain regions including the appetite-regulating centers in chicks. This is the first evidence that the intestinal hormone PYY may function as an anorexigenic hormone in chicks. Copyright © 2016. Published by Elsevier Inc.
The increased production and use of multi-walled carbon nanotubes (MWCNTs) in a diverse array of consumer， medical， and industrial applications have raised concerns about potential human exposure to t