Cerebrospinal Fluid Prohormone Processing and Neuropeptides

Article pubs.acs.org/jpr

Cerebrospinal Fluid Prohormone Processing and Neuropeptides Stimulating Feed Intake of Dairy Cows during Early Lactation Björn Kuhla,*,† Thomas Laeger,† Holger Husi,‡ and William Mullen‡ †

Institute of Nutritional Physiology “Oskar Kellner”, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany ‡ College of Medical, Veterinary and Life Sciences, University of Glasgow, University Avenue, Glasgow G12 8QQ, United Kingdom S Supporting Information *

ABSTRACT: After parturition, feed intake of dairy cows increases within the first weeks of lactation, but the molecular mechanisms stimulating or delaying the slope of increase are poorly understood. Some of the molecules controlling feed intake are neuropeptides that are synthesized as propeptides and subsequently processed before they bind to specific receptors in feeding centers of the brain. Cerebrospinal fluid surrounds most of the feed intake regulatory centers and contains numerous neuropeptides. In the present study, we used a proteomic approach to analyze the neuropeptide concentrations in cerebrospinal fluid taken from dairy cows between day −18 and −10, and between day +10 and +20 relative to parturition. We found 13 proteins which were only present in samples taken before parturition, 13 proteins which were only present in samples taken after parturition, and 25 proteins which were commonly present, before and after parturition. Among them, differences in pro-neuropeptide Y, proenkephalin-A, neuroendocrine convertase-2, neurosecretory protein VGF, chromogranin-A, and secretogranin-1 and -3 concentrations relative to parturition highlight propeptides and prohormone processings involved in the control of feed intake and energy homeostasis. Scaffold analysis further emphasized an increased tone of endogenous opioids associated with the postparturient increase of feed intake. KEYWORDS: cerebrospinal fluid, dairy cow, parturition, capillary electrophoresis, mass spectrometry

■

hedonism.3 Neuropeptides and peptide hormones are often synthesized as larger precursor proteins that are subjected to sequence-specific cleavages by distinct processing enzymes.4,5 These include neuroendocrine convertases also known as prohormone convertases (PCs) which generate shorter forms of many prohormones, thus participating in the conversion to the biologically active forms and consequently in the control of feed intake and energy expenditure. For example, POMC, proneuropeptide Y (pro-NPY), pro-thyrotropin-releasing hormone (pro-TRH), and pro-enkephalin are enzymatically processed by different proteases to the α-melanocyte stimulating hormone (α-MSH), NPY, TRH, and enkephalin, respectively.6 It has recently been established that a large spectrum of prohormone convertases, prohormones, and neuropeptides synthesized and secreted from the hypothalamus can be detected in human and rat cerebrospinal fluid (CSF) and that their concentrations alter in response to pregnancy, fasting, or overeating,7−11 indicating their involvement in the control of feed intake and energy homeostasis. Therefore, we hypothesized that CSF concentrations of prohormones and prohor-

INTRODUCTION The transition from parturition to early lactation of highyielding dairy cows is characterized by an enormous sudden milk secretion while feed intake increases only slowly to meet the energy requirements for maintenance and production. As a consequence, cows drop into negative energy balance, which is associated with a reduction of body weight. The control of energy balance, body weight, and feed intake is achieved within a complex process involving exogenous and endogenous signals that are integrated primarily at the level of the hypothalamus, the brain stem, and the limbic system. Neurons located in these brain areas are able to sense endogenous signals in the blood such as nutrients, metabolites, hormones, and cytokines, thereby receiving information on the nutritional and energetic status from the periphery.1 Those peripheral signals bind to their specific neuronal receptors to modulate the synthesis of neuropeptides such as orexigenic neuropeptide Y (NPY) and agouti-related peptide (Agrp) or anorexigenic cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC).2 In addition, peripheral and central opioid peptides such as enkephalins, endorphins, or dynorphins may participate in the control of feed intake by binding to δ, μ, and κ-receptor types, respectively, and thereby eliciting mechanisms involving incentive motivation upon feed consumption and © 2014 American Chemical Society

Received: August 20, 2014 Published: December 30, 2014 823

DOI: 10.1021/pr500872k J. Proteome Res. 2015, 14, 823−828

Article

Journal of Proteome Research

before nanoflow liquid chromatography−mass spectroscopy (LC-MS) analysis, lyophilizates were resuspended in HPLCgrade H2O to a target final protein concentration of 2 mg/mL, as measured by the BCA test (Interchim, Montlucon, France).

mone convertases change during the periparturient period of dairy cows. To test this hypothesis, we performed a proteomic approach with CSF samples repetitively taken from dairy cows throughout the transition period.

■

LC-MS Analysis

METHODS

CSF extracts were separated on a Dionex Ultimate 3000 RSLS nano flow system (Dionex, Camberly U.K.). A 5 μL sample was loaded in 0.1% formic acid and acetonitrile (98:2) onto a Dionex 100 μm × 2 cm, 5 μm C18 nano trap column at a flow rate of 5 μL/min. Elution was performed on an Acclaim PepMap C18 nano column 75 μm × 15 cm, 2 μm, 100 Å with a linear gradient of solvent A, 0.1% formic acid and acetonitrile (98:2) against solvent B, 0.1% formic acid and acetonitrile (20:80) starting at 1% B for 5 min rising to 20% at 90 min then to 40%B at 120 min. The sample was ionized in positive ion mode using a Proxeon nano spray ESI source (Thermo Fisher Hemel U.K.) and analyzed in an Orbitrap Velos FTMS (Thermo Finnigan, Bremen, Germany). The MS was operated in a data-dependent mode (top 20) to switch between MS and MS/MS acquisition, and parent ions were fragmented by high energy collision-induced dissociation (HCD) (Supplemental File 1). Data files were searched against the Uniprot Bovine reviewed nonredundant database using SEQUEST with no enzyme specified. Oxidation of methionine and proline as variable modifications were selected. Mass error windows of 10 ppm and 0.05 Da were allowed for MS and MS/MS, respectively (Supplemental File 2). In SEQUEST, only peptides that showed mass deviation of less than 10 ppm were passed, the peptide data were extracted using high and medium peptide confidence and top one peptide rank filters.

Animals

Six German Holstein dairy cows in second (n = 5) and third (n =1) parturition were kept in tie-stalls in accordance with the guidelines for the use of animals as experimental subjects of the State Government in Mecklenburg-West Pomerania (registration no. LALLF M-V/TSD/7221.3-2.1-001/10). All cows were healthy and 44−53 months old at parturition. They were fed twice daily (0700 and 1600 h) a total mixed ration ad libitum, adjusted for transition and lactation needs, respectively, consisting of corn and grass silage, grass hay, grain feed, minerals, and vitamins, to meet the energy and nutrient recommendations of dairy cows calculated according to the German Society of Nutrition Physiology12 [6.4 MJ Net Energy Lactation/kg Dry Matter (NEL/kg DM) for the last 25 days of gestation (close-up period) and 7.2 MJ NEL/kg DM for lactation]. Cows had free access to water and were milked twice daily (0630 and 1530 h). Feed intake was measured daily and from this, daily energy intake of individual cows was calculated. CSF Sampling

Six cows were subjected to a CSF sampling protocol foreseeing the sampling twice before parturition (on day (d) −18 and again on d −10) and twice after parturition (on d +10, and again on d +20). However, a sufficient amount of CSF could not be obtained on 10 sampling days. In total, 8 CSF samples from 5 antepartum cows and 6 CSF samples from 5 postpartum cows were available for proteome analysis (Supplementary Table 1). Sampling was performed for before morning feeding as recently described.13 Briefly, after local anesthesia with 10 mL of isocain (20 mg/mL procainhydrochloride and 0.025 mg/ mL epinephrine, Selectavet, Dr. Otto Fischer GmbH, WeyarnHolzolling, Germany), CSF from spinal cord was obtained by lumbar puncture between the sixth lumbar vertebra and sacrum with a sharpened needle with fitted stylet (120 mm length, 1.2 mm diameter, Walter, Veterinär-Instrumente e.K., Baruth/ Mark, Germany). Samples of 5 mL CSF were immediately treated with 30 μL aprotinin (Carl Roth GmbH & Co. KG, Karlsruhe, Germany; 0.19% (wt/vol) in 0.9% (wt/vol) NaCl). An aliquot of 50 μL of CSF was taken for cell count analysis using a cell counter (Multisizer II, Beckman-Coulter GmbH, Krefeld, Germany). The remaining CSF was centrifuged at 4566g for 5 min at 4 °C, frozen in liquid nitrogen, and stored at −80 °C for no longer than 18 month until analyses. Sample Preparation. Individual CSF samples (n = 14) were prepared as previously described for urine.14 Briefly, 700 μL of CSF were thawed immediately before use and diluted with 700 μL of 2 M urea, 10 mM NH4OH containing 0.02% SDS (sodium dodecyl sulfate). Mixtures were filtered using a Centrisart ultracentrifugation filter device (20 kDa MW cutoff; Sartorius, Göttingen, Germany) at 3000 rcf until 1.1 mL filtrate was obtained. This step ensured the removal of proteins of with higher molecular mass (above 20 kDa). The filtrate was then loaded onto a PD-10 desalting column (GE Healthcare, Sweden) and equilibrated in 0.01% NH4OH in HPLC-grade H2O (Roth, Germany) to decrease matrix effects by removing urea, electrolytes, and salts, and also to enrich polypeptides. Finally, samples were lyophilized and stored at 4 °C. Shortly

Data Processing and Statistics

Proteome discovered data files were loaded into Scaffold (version Scaffold_4.0.3, Proteome Software Inc., Portland, OR), which was used to validate MS/MS based peptide and protein identifications. Peptide identifications were accepted if they could be established at greater than 90.0% probability by the Peptide Prophet algorithm15 with Scaffold delta-mass correction. Protein identifications were accepted if they could be established at greater than 90.0% probability and contained at least two identified peptides. Protein probabilities were assigned by the Protein Prophet algorithm.16 Proteins that contained similar peptides and could not be differentiated based on MS/MS analysis alone were grouped to satisfy the principles of parsimony. In the case of ambiguous protein identifications, BLAST searches were carried out to confirm or assign protein identities. The data was loaded into two categories for analysis, antepartum and postpartum. Scaffold total ion counts were used to quantify, compare and calculate fold changes between the two sets of data using a two-sided hypergeometric Mann−Whitney test including Benjamini− Hochberg correction. Time-dependent changes of energy intake were tested by an Analysis of Variance (ANOVA). Data Processing and Gene Onthology (GO) Analysis

Due to the low number of CSF samples obtained on d −10 and d +10 (see Supplementary Table 1), data obtained from individual samples taken in the antepartum and the postpartum period, respectively, were merged. GO analysis was performed using CytoScape (version 2.9) and the ClueGO plug-in where pre- versus postperiparturient up-regulated molecules were compared to down-regulated ones. GO-term enrichment was 824


Article


sampling period (d −18 to d −10) amounted to 84 MJ NEL, whereas it increased to 110 MJ NEL in the postpartum (d +10 to d +20) sampling period (Figure 1). This increase was due to a greater feed intake (data not shown) and a greater energy content of the lactation diet. The lactation diet differed from the close-up diet only by a greater portion of concentrate while feed components were the same between diets. Thereby, dietary changes during the transition period were minimized, despite it cannot entirely be excluded that changes in CSF composition reported herein are exclusively caused by the transition from late pregnancy to early lactation. Also, the moment of sampling should only have a minor impact on the results because energy intake did not change between d −18 and d −10 as well as between d +10 and d +20. However, in order to elucidate how neuropeptides and the associated processing of prohormones relate to the periparturient changes in energy intake, we subjected CSF samples to a HPLC-based proteomic analysis. We found 25 proteins that were present in all CSF samples, commonly before and after parturition (Table 1), whereas an additional 13 proteins were only present in samples taken before and further 13 proteins only after parturition (Supplementary Table 2). Those peptides that were detectable before as well as after parturition (Table 1) were subjected to a bioinformatic Scaffold analysis. As shown in Figure 2, identified proteins are involved in biological processes such as transmembrane ion transport, neuropeptide hormone

done by a two-sided hypergeometric Mann−Whitney test including Benjamini−Hochberg correction.

■

RESULTS AND DISCUSSION As expected, energy intake of dairy cows decreased within the last days of pregnancy and increased during early lactation (Figure 1). The mean daily energy intake in the prepartum CSF

Figure 1. Energy intake of dairy cows before and after parturition. Data are presented as the mean + SE (n = 6). Gray arrows indicate times of CSF samplings. For further details, see Supplementary Table 1. Energy intake significantly differed over time at P < 0.05 (ANOVA).

Table 1. List of Identified Proteins Which Were Present in CSF Samples before and after Parturition (n = 25)a protein name

Swissprot ID

gene name primary

frequency % antepartum

frequency % postpartum

fold change postpartum/antepartum

BH-corrected p value

collagen alpha-1(I) chain pro-neuropeptide Y phospholemman ferric-chelate reductase 1 fibrinogen alpha chain platelet-activating factor acetylhydrolase IB subunit alpha beta-1,3-N-acetylglucosaminyltransferase lunatic fringe GA-binding protein subunit beta-1 integral membrane protein 2B homeobox protein Hox-A3 specifically androgen-regulated gene protein GTPase-activating protein and VPS9 domaincontaining protein 1 glycine receptor subunit beta FXYD domain-containing ion transport regulator 6 chromogranin-A proenkephalin-A prosaposin receptor GPR37L1 mitogen-activated protein kinase 7 neurosecretory protein VGF neuroendocrine convertase 2 secretogranin-3 collagen alpha-1(II) chain secretogranin-1 Wiskott−Aldrich syndrome protein family member 1 zinc finger protein 750

CO1A1_BOVIN NPY_BOVIN PLM_BOVIN FRRS1_BOVIN FIBA_BOVIN LIS1_BOVIN

COL1A1 NPY FXYD1 FRRS1 FGA PAFAH1B1

78 67 33 56 100 22

17 33 17 33 100 17

−9.09 −2.78 −2.63 −2.17 −1.96 −1.64

2 2 1 4 4 4

LFNG_BOVIN

LFNG

67

67

−1.56

4 × 10−06

GABP1_BOVIN ITM2B_BOVIN HXA3_BOVIN SARG_BOVIN GAPD1_BOVIN

GABPB1 ITM2B HOXA3 SARG GAPVD1

89 67 67 11 22

67 67 50 17 17

−1.56 −1.47 −1.47 −1.45 −1.35

4 3 3 3 3

GLRB_BOVIN FXYD6_BOVIN

GLRB FXYD6

33 100

33 83

−1.19 −1.16

2 × 10−06 2 × 10−06

CMGA_BOVIN PENK_BOVIN ETBR2_BOVIN MK07_BOVIN VGF_BOVIN NEC2_BOVIN SCG3_BOVIN CO2A1_BOVIN SCG1_BOVIN WASF1_BOVIN

CHGA PENK GPR37L1 MAPK7 VGF PCSK2 SCG3 COL2A1 CHGB WASF1

100 67 67 22 89 33 11 56 22 89

100 67 50 33 83 50 17 33 33 100

−1.06 1.05 1.14 1.26 1.29 1.41 1.59 2.55 2.70 2.77

3 8 1 3 4 4 4 4 1 8

ZN750_BOVIN

ZNF750

11

33

3.37

× × × × × ×

× × × × ×

× × × × × × × × × ×

10−06 10−06 10−06 10−06 10−06 10−06

10−06 10−06 10−06 10−06 10−06

10−06 10−05 10−05 10−06 10−06 10−06 10−06 10−06 10−05 10−05

2 × 10−05

a Frequency (%) indicates the percentage of CSF samples, in which the identified protein was detected in the ante- and postpartum period. Fold change after parturition was calculated as the averaged total ion counts after and before parturition. p values were determined by the Mann−Whitney test including Benjamini−Hochberg (BH) correction.

825


Article


Figure 2. Bioinformatic analysis of CSF samples taken before (on d −20 and d −10) and after (on d +10 and d +20) parturition. Data was analyzed by Gene Ontology using ClueGO including a statistical term-enrichment for the classes “Biological Processes”, “Molecular Functions”, “Reactome”, and “KEGG” pathways, and comparison of pre- and postparturition. The color coding relates to the up-regulation before (green) or after parturition (red). Molecules are indicated by small circles, whereas big circles are GO terms. Color intensity is based on statistical testing by enrichment (darker as more enriched) using a two-sided hypergeometric Mann−Whitney test including Benjamini−Hochberg correction.

activity, protein digestion and absorption, regulation of protein binding, formation of secretory granules, and thyroid gland development. Among all proteins detected before and after parturition, concentrations of three peptides possessing neuropeptide hormone functionality were altered relative to calving (Figure 2). Although the concentration of proneuropeptide Y was diminished, concentrations of the neurosecretory protein VGF and proenkephalin-A were higher after calving (Table 1). Considering the well-known orexigenic effect of NPY, reduced proneuropeptide Y concentration after calving may be interpreted as shortage for a sufficient increase of feed intake. However, a reduction of proneuropeptide Y (Table 1) could also be the consequence of an increased cleavage of proneuropeptide Y, yielding to increased formation of the biologically active form NPY, but unfortunately, the presence of any mature NPY could not be determined in the present study.

On the other hand, we identified the neurosecretory protein VGF, which is the prohormone of the neuroendocrine regulatory peptide-2 (NERP2), to be more highly concentrated in CSF after calving (Table 1). Intracerebroventricular administration of NERP-2 increased food intake, body temperature, oxygen consumption, and locomotor activity in rats by activation of the orexin system in the lateral hypothalamus.17 On the contrary, NERP-2 did not induce food intake or locomotor activity in orexin-deficient mice.17 Assuming that the physiological effects of NERP-2 determined in rodents are also true for ruminants, our findings indicate that increased postparturient neurosecretory protein VGF concentrations likely accounts for the increased feed intake of dairy cows in early lactation. Furthermore, the CSF concentration of proenkephalin-A, a member of the opioid peptide family, increased from late pregnancy to early lactation (Table 1). Injection of synthetic 826


Article


and proenkephalin-A postpartum. Interestingly, besides the storage of hormones in the vesicle core, some granins may function as helper proteins in sorting and proteolytic processing of prohormones.29 In summary, on the basis of our findings, we conclude that in early lactation, prohormone processing involving the prohormone convertase PC2 is an important process for the activation of various propeptides controlling feed intake and energy homeostasis. Our data particularly emphasize the importance of an increased amount of neurosecretory protein VGF, proenkephalin-A, and secretogranins in the postparturient increase of feed intake. There may be additional processes occurring during this period; however, the sample number available limited the power of this study. A larger study would be required to investigate this and also to confirm the result of our investigation.

opioid peptides increased plasma growth hormone (GH) and prolactin concentration in calves,18 suggesting that increased proenkephalin concentrations after parturition may account for the GH peak generally observed during early lactation. The assumption that a postparturient increase of enkephalins would be due to parturition as an event that involves stress and pain for the mother can be excluded because Met-enkephalin concentrations returned to basal levels within few hours after the phases of labor of goats and heifers.19 Apart from parturition, enkephalins seem to play prominent role in the regulation of feed intake of ruminants. Intracerebroventricular injection of enkephalinase inhibitors depressed early and daily feed intake of sheep,20 and blocking of opioid receptors by intravenous injection of naloxone reduced feed intake and altered oro-sensorial preferences of calves within the first 2 h after application.21 Thus, endogenous opioids are so far the solely peptides with significant orexigenic relevance for ruminants, whereas ghrelin has recently been demonstrated to exert only minor orexigenic effects in dairy cows.22 Although it is known that enkephalin-A and enkephalin-B preferentially bind to the delta and kappa receptors, respectively, and that this receptor is locatedamong othersin various nuclei of the hypothalamus, the mechanism by which enkephalins exert their orexigenic action at the brain is not entirely clear. A recent study suggests that inhibition of anorexigenic POMC neurons may be one mechanism underlying the orexigenic actions of enkephalin-B (dynorphin).23 In summary, data on CSF neuropeptide activity provide first molecular hints of why feed intake may be reduced in the transition period but also emphasize the involvement of the opioid system in increasing feed intake during early lactation. Pro-neuropeptides such as proenkephalin-A, pro-NPY, proTRH and POMC are subjected to sequence-specific cleavages by distinct processing enzymes. The endoproteolytical neuroendocrine convertase 2 (prohormone convertase 2; PC2) may cleave, for example, pro-TRH, resulting in the formation of TRH which subsequently releases the thyroid hormones T3 and T4 from the thyroid gland. The observed increased PC2 concentrations after parturition (Table 1) may thus contribute to the increase of plasma T3 and T4 concentrations, and in line with this, plasma T3 and T4 concentrations slowly increase within the first 20 days of lactation, thereby increasing the metabolic rate.24 Furthermore, PC2 cleaves POMC and to a minor extent proenkephalin at least in vitro.6 Accordingly, processing of POMC, proenkephalin, and some other pro-neuropeptides was impaired in PC2 knockout mice.25 A natural regulator with inhibitory effects on PC2 is the neuroendocrine protein 7B2. In 7B2 and PC2, null mice, radioactive-labeling experiments demonstrated a buildup of POMC, high molecular weight intermediates, and intact adrenocorticotropic hormone ACTH, as well as the disappearance of alpha-MSH.26 On the contrary, overexpression of PC2 and proenkephalin in AtT-20 cells revealed that the initial kinetic of proenkephalin cleavage was unaffected, whereas late processing events (formation of bioactive octa- or penta peptides) and the amount of opioidactive peptides stored in granules were increased.27 Various secretogranins, particularly secretogranin-1, -2, and -3, are major proteins forming secretory granules for the storage and secretion of neuropeptides (e.g., NPY, POMC, orexin and melanin-concentrating hormone (MCH)).28 Concentrations of secretogranin-1 and -3 in CSF increased after parturition and thus parallel the concentrations of neurosecretory protein VGF

■

ASSOCIATED CONTENT

S Supporting Information *

Supplementary Table 1: List of CSF samples obtained from six individual cows before and after parturition; Supplementary Table 2: List of proteins only found in samples before parturition (n = 13) and proteins only found in samples after parturition (n = 13); Supplemental File 1: Method used for high energy collision-induced dissociation; Supplemental File 2: Node for the Sequest search. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected]. Phone: +49-3820868695. Fax: +49-38208-68652. Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Sartin, J. L.; Whitlock, B. K.; Daniel, J. A. Triennial Growth Symposium: neural regulation of feed intake: modification by hormones, fasting, and disease. J. Anim. Sci. 2011, 89 (7), 1991−2003. (2) Morton, G. J.; Cummings, D. E.; Baskin, D. G.; Barsh, G. S.; Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 2006, 443 (7109), 285−295. (3) Berridge, K. C.; Ho, C. Y.; Richard, J. M.; DiFeliceantonio, A. G. The tempted brain eats: pleasure and desire circuits in obesity and eating disorders. Brain Res. 2010, 1350, 43−64. (4) Sanchez, V. C.; Goldstein, J.; Stuart, R. C.; Hovanesian, V.; Huo, L.; Munzberg, H.; Friedman, T. C.; Bjorbaek, C.; Nillni, E. A. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J. Clin. Invest. 2004, 114 (3), 357−369. (5) Fortenberry, Y.; Hwang, J. R.; Apletalina, E. V.; Lindberg, I. Functional characterization of ProSAAS: similarities and differences with 7B2. J. Biol. Chem. 2002, 277 (7), 5175−5186. (6) Hook, V. Y.; Schiller, M. R.; Azaryan, A. V. The processing proteases prohormone thiol protease, PC1/3 and PC2, and 70-kDa aspartic proteinase show preferences among proenkephalin, proneuropeptide Y, and proopiomelanocortin substrates. Arch. Biochem. Biophys. 1996, 328 (1), 107−114. (7) Brunani, A.; Invitti, C.; Dubini, A.; Piccoletti, R.; Bendinelli, P.; Maroni, P.; Pezzoli, G.; Ramella, G.; Calogero, A.; Cavagnini, F. Cerebrospinal fluid and plasma concentrations of SRIH, betaendorphin, CRH, NPY and GHRH in obese and normal weight subjects. Int. J. Obes. Relat. Metab. Disord. 1995, 19 (1), 17−21. 827


Article

Journal of Proteome Research (8) Stark, M.; Danielsson, O.; Griffiths, W. J.; Jörnvall, H.; Johansson, J. Peptide repertoire of human cerebrospinal fluid: novel proteolytic fragments of neuroendocrine proteins. J. Chromatogr. B: Biomed. Sci. Appl. 2001, 754 (2), 357−367. (9) Strömbom, U.; Krotkiewski, M.; Blennow, K.; Månsson, J. E.; Ekman, R.; Bjö rntorp, P. The concentrations of monoamine metabolites and neuropeptides in the cerebrospinal fluid of obese women with different body fat distribution. Int. J. Obes. Relat. Metab. Disord. 1996, 20 (4), 361−368. (10) Pritchard, L. E.; Oliver, R. L.; McLoughlin, J. D.; Birtles, S.; Lawrence, C. B.; Turnbull, A. V.; White, A. Proopiomelanocortinderived peptides in rat cerebrospinal fluid and hypothalamic extracts: evidence that secretion is regulated with respect to energy balance. Endocrinology 2003, 144 (3), 760−766. (11) Page-Wilson, G.; Reitman-Ivashkov, E.; Meece, K.; White, A.; Rosenbaum, M.; Smiley, R. M.; Wardlaw, S. L. Cerebrospinal fluid levels of leptin, proopiomelanocortin, and agouti-related protein in human pregnancy: evidence for leptin resistance. J. Clin. Endocrinol. Metab. 2013, 98 (1), 264−271. (12) German Society of Nutrition Physiology. Ausschuss für Bedarfsnormen der Gesellschaft für Ernährungsphysiologie, No. 8. Empfehlungen zur Energie- und Nährstoffversorgung der Milchkühe und Aufzuchtrinder (Recommended energy and nutrient supply for dairy cows and growing cattle); DLG-Verlag : Frankfurt am Main, Germany, 2001. (13) Laeger, T.; Sauerwein, H.; Tuchscherer, A.; Bellmann, O.; Metges, C. C.; Kuhla, B. Concentrations of hormones and metabolites in cerebrospinal fluid and plasma of dairy cows during the periparturient period. J. Dairy Sci. 2013, 96 (5), 2883−2893. (14) Good, D. M.; Zürbig, P.; Argilés, A.; Bauer, H. W.; Behrens, G.; Coon, J. J.; Dakna, M.; Decramer, S.; Delles, C.; Dominiczak, A. F.; Ehrich, J. H.; Eitner, F.; Fliser, D.; Frommberger, M.; Ganser, A.; Girolami, M. A.; Golovko, I.; Gwinner, W.; Haubitz, M.; HergetRosenthal, S.; Jankowski, J.; Jahn, H.; Jerums, G.; Julian, B. A.; Kellmann, M.; Kliem, V.; Kolch, W.; Krolewski, A. S.; Luppi, M.; Massy, Z.; Melter, M.; Neusüss, C.; Novak, J.; Peter, K.; Rossing, K.; Rupprecht, H.; Schanstra, J. P.; Schiffer, E.; Stolzenburg, J. U.; Tarnow, L.; Theodorescu, D.; Thongboonkerd, V.; Vanholder, R.; Weissinger, E. M.; Mischak, H.; Schmitt-Kopplin, P. Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease. Mol. Cell. Proteomics 2010, 9 (11), 2424−2437. (15) Keller, A.; Nesvizhskii, A. I.; Kolker, E.; Aebersold, R. Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal. Chem. 2002, 74 (20), 5383−5392. (16) Nesvizhskii, A. I.; Keller, A.; Kolker, E.; Aebersold, R. A statistical model for identifying proteins by tandem mass spectrometry. Anal. Chem. 2003, 75 (17), 4646−4658. (17) Toshinai, K.; Yamaguchi, H.; Kageyama, H.; Matsuo, T.; Koshinaka, K.; Sasaki, K.; Shioda, S.; Minamino, N. M.; Nakazato, M. Neuroendocrine regulatory peptide-2 regulates feeding behavior via the orexin system in the hypothalamus. Am. J. Physiol.: Endocrinol. Metab. 2010, 299 (3), E394−E401. (18) Johnson, D. W.; Barnes, M. A.; Akers, R. M.; Pearson, R. E. A synthetic opioid peptide increases plasma growth hormone and prolactin in Holstein calves. J. Anim. Sci. 1993, 71 (4), 1004−1009. (19) Hydbring, E.; Madej, A.; MacDonald, E.; Drugge-Boholm, G.; Berglund, B.; Olsson, K. Hormonal changes during parturition in heifers and goats are related to the phases and severity of labour. J. Endocrinol. 1999, 160 (1), 75−85. (20) Rivière, P. J.; Buéno, L. Origin of the stimulation of food intake by oral administration of enkephalinase inhibitors in sheep. Life Sci. 1987, 41 (3), 333−339. (21) Montoro, C.; Ipharraguerre, I. R.; Bach, A. Blocking opioid receptors alters short-term feed intake and oro-sensorial preferences in weaned calves. J. Dairy Sci. 2012, 95 (5), 2531−2539. (22) Börner, S.; Derno, M.; Hacke, S.; Kautzsch, U.; Schäff, C.; Thanthan, S.; Kuwayama, H.; Hammon, H. M.; Röntgen, M.; Weikard, R.; Kühn, C.; Tuchscherer, A.; Kuhla, B. Plasma ghrelin is positively

associated with body fat, liver fat and milk fat content but not with feed intake of dairy cows after parturition. J. Endocrinol. 2013, 216 (2), 217−229. (23) Zhang, X.; van den Pol, A. N. Direct inhibition of arcuate proopiomelanocortin neurons: a potential mechanism for the orexigenic actions of dynorphin. J. Physiol. 2013, 591 (Pt 7), 1731− 1747. (24) Meikle, A.; Kulcsar, M.; Chilliard, Y.; Febel, H.; Delavaud, C.; Cavestany, D.; Chilibroste, P. Effects of parity and body condition at parturition on endocrine and reproductive parameters of the cow. Reproduction 2004, 127 (6), 727−737. (25) Pan, H.; Che, F. Y.; Peng, B.; Steiner, D. F.; Pintar, J. E.; Fricker, L. D. The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. J. Neurochem. 2006, 98 (6), 1763−1777. (26) Laurent, V.; Jaubert-Miazza, L.; Desjardins, R.; Day, R.; Lindberg, I. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 2004, 145 (2), 519−528. (27) Johanning, K.; Mathis, J. P.; Lindberg, I. Role of PC2 in proenkephalin processing: antisense and overexpression studies. J. Neurochem. 1996, 66 (3), 898−907. (28) Hotta, K.; Hosaka, M.; Tanabe, A.; Takeuchi, T. Secretogranin II binds to secretogranin III and forms secretory granules with orexin, neuropeptide Y, and POMC. J. Endocrinol. 2009, 202 (1), 111−121. (29) Hosaka, M.; Watanabe, T.; Sakai, Y.; Kato, T.; Takeuchi, T. Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules. J. Cell Sci. 2005, 118 (Pt 20), 4785−4795.

828


Cerebrospinal Fluid Prohormone Processing and Neuropeptides

Recommend Documents