Quantitative secretome and glycome of primary human adipocytes during insulin resistance

Clinical Proteomics

Lance Wells²  Dorothy Hausman³  Chin Fen Teo²  Edith E Wollaston-Hayden²  Jae-Min Lim¹ 

[1] Department of Chemistry, Changwon National University, Changwon, Gyeongnam 641-773, South Korea;Department of Biochemistry and Molecular Biology, The University of Georgia, 30602 Athens, Georgia;Department of Foods and Nutrition, The University of Georgia, 30602 Athens, Georgia

关键词: O-linked;    N-linked;    Glycomics;    Shotgun proteomics;    Tandem mass spectrometry;    Adipocytokine;    Type 2 diabetes;    Insulin resistance;    O-GlcNAc;   

Others  :  802483
DOI  :  10.1186/1559-0275-11-20

 received in 2013-10-28, accepted in 2014-02-04,  发布年份 2014

【 摘 要 】

Adipose tissue is both an energy storage depot and an endocrine organ. The impaired regulation of the secreted proteins of adipose tissue, known as adipocytokines, observed during obesity contributes to the onset of whole-body insulin resistance and the pathobiology of type 2 diabetes mellitus (T2DM). In addition, the global elevation of the intracellular glycosylation of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) via either genetic or pharmacological methods is sufficient to induce insulin resistance in both cultured cells and animal models. The elevation of global O-GlcNAc levels is associated with the altered expression of many adipocytokines. We have previously characterized the rodent adipocyte secretome during insulin sensitive and insulin resistant conditions. Here, we characterize and quantify the secretome and glycome of primary human adipocytes during insulin responsive and insulin resistant conditions generated by the classical method of hyperglycemia and hyperinsulinemia or by the pharmacological manipulation of O-GlcNAc levels. Using a proteomic approach, we identify 190 secreted proteins and report a total of 20 up-regulated and 6 down-regulated proteins that are detected in both insulin resistant conditions. Moreover, we apply glycomic techniques to examine (1) the sites of N-glycosylation on secreted proteins, (2) the structures of complex N- and O-glycans, and (3) the relative abundance of complex N- and O-glycans structures in insulin responsive and insulin resistant conditions. We identify 91 N-glycosylation sites derived from 51 secreted proteins, as well as 155 and 29 released N- and O-glycans respectively. We go on to quantify many of the N- and O-glycan structures between insulin responsive and insulin resistance conditions demonstrating no significant changes in complex glycosylation in the time frame for the induction of insulin resistance. Thus, our data support that the O-GlcNAc modification is involved in the regulation of adipocytokine secretion upon the induction of insulin resistance in human adipocytes.

【 授权许可】

   
2014 Lim et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Prevention., C. f. D. C. a: National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. Atlanta, GA: US: Department of Health and Human Services, Centers for Disease Control and Prevention; 2011.
• [2]Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54:1615-1625.
• [3]O'Rahilly S: Human genetics illuminates the paths to metabolic disease. Nature 2009, 462:307-314.
• [4]Guilherme A, Virbasius JV, Puri V, Czech MP: Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 2008, 9:367-377.
• [5]Harwood HJ Jr: The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology 2011.
• [6]Ouchi N, Parker JL, Lugus JJ, Walsh K: Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011, 11:85-97.
• [7]Chen X, Hess S: Adipose proteome analysis: focus on mediators of insulin resistance. Expert Rev Proteomics 2008, 5:827-839.
• [8]Arner P: Resistin: yet another adipokine tells us that men are not mice. Diabetologia 2005, 48:2203-2205.
• [9]Cianflone K, Xia Z, Chen LY: Critical review of acylation-stimulating protein physiology in humans and rodents. Biochim Biophys Acta 2003, 1609:127-143.
• [10]Poulos SP, Dodson MV, Hausman GJ: Cell line models for differentiation: preadipocytes and adipocytes. Exp Biol Med (Maywood) 2010, 235:1185-1193.
• [11]Marshall S, Bacote V, Traxinger RR: Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem 1991, 266:4706-4712.
• [12]Teo CF, Wollaston-Hayden EE, Wells L: Hexosamine flux, the O-GlcNAc modification, and the development of insulin resistance in adipocytes. Mol Cell Endocrinol 2010, 318:44-53.
• [13]Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L: A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998, 393:684-688.
• [14]Hazel M, Cooksey RC, Jones D, Parker G, Neidigh JL, Witherbee B, Gulve EA, McClain DA: Activation of the hexosamine signaling pathway in adipose tissue results in decreased serum adiponectin and skeletal muscle insulin resistance. Endocrinology 2004, 145:2118-2128.
• [15]McClain DA, Alexander T, Cooksey RC, Considine RV: Hexosamines stimulate leptin production in transgenic mice. Endocrinology 2000, 141:1999-2002.
• [16]Considine RV, Cooksey RC, Williams LB, Fawcett RL, Zhang P, Ambrosius WT, Whitfield RM, Jones R, Inman M, Huse J, McClain DA: Hexosamines regulate leptin production in human subcutaneous adipocytes. J Clin Endocrinol Metab 2000, 85:3551-3556.
• [17]McClain DA: Hexosamines as mediators of nutrient sensing and regulation in diabetes. J Diabetes Complications 2002, 16:72-80.
• [18]Wells L, Vosseller K, Hart GW: A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance. Cell Mol Life Sci 2003, 60:222-228.
• [19]Vosseller K, Wells L, Lane MD, Hart GW: Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. Proc Natl Acad Sci U S A 2002, 99:5313-5318.
• [20]Parker GJ, Lund KC, Taylor RP, McClain DA: Insulin resistance of glycogen synthase mediated by o-linked N-acetylglucosamine. J Biol Chem 2003, 278:10022-10027.
• [21]McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA: Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci U S A 2002, 99:10695-10699.
• [22]Arias EB, Kim J, Cartee GD: Prolonged incubation in PUGNAc results in increased protein O-Linked glycosylation and insulin resistance in rat skeletal muscle. Diabetes 2004, 53:921-930.
• [23]Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM: Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 2008, 451:964-969.
• [24]Dentin R, Hedrick S, Xie J, Yates J 3rd, Montminy M: Hepatic glucose sensing via the CREB coactivator CRTC2. Science 2008, 319:1402-1405.
• [25]Lim JM, Sherling D, Teo CF, Hausman DB, Lin D, Wells L: Defining the regulated secreted proteome of rodent adipocytes upon the induction of insulin resistance. J Proteome Res 2008, 7:1251-1263.
• [26]Chui D, Sellakumar G, Green R, Sutton-Smith M, McQuistan T, Marek K, Morris H, Dell A, Marth J: Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc Natl Acad Sci U S A 2001, 98:1142-1147.
• [27]Delves PJ: The role of glycosylation in autoimmune disease. Autoimmunity 1998, 27:239-253.
• [28]Dennis JW, Granovsky M, Warren CE: Glycoprotein glycosylation and cancer progression. Biochim Biophys Acta 1999, 1473:21-34.
• [29]Gleeson PA: Glycoconjugates in autoimmunity. Biochim Biophys Acta 1994, 1197:237-255.
• [30]Isaji T, Gu J, Nishiuchi R, Zhao Y, Takahashi M, Miyoshi E, Honke K, Sekiguchi K, Taniguchi N: Introduction of bisecting GlcNAc into integrin alpha5beta1 reduces ligand binding and down-regulates cell adhesion and cell migration. J Biol Chem 2004, 279:19747-19754.
• [31]Krueger KE, Srivastava S: Posttranslational protein modifications: current implications for cancer detection, prevention, and therapeutics. Mol Cell Proteomics 2006, 5:1799-1810.
• [32]Schachter H: Congenital disorders involving defective N-glycosylation of proteins. Cell Mol Life Sci 2001, 58:1085-1104.
• [33]Stanley P: Biological consequences of overexpressing or eliminating N-acetylglucosaminyltransferase-TIII in the mouse. Biochim Biophys Acta 2002, 1573:363-368.
• [34]Varki A: Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 1993, 3:97-130.
• [35]Aoki K, Perlman M, Lim JM, Cantu R, Wells L, Tiemeyer M: Dynamic developmental elaboration of N-linked glycan complexity in the Drosophila melanogaster embryo. J Biol Chem 2007, 282:9127-9142.
• [36]Kudo T, Nakagawa H, Takahashi M, Hamaguchi J, Kamiyama N, Yokoo H, Nakanishi K, Nakagawa T, Kamiyama T, Deguchi K, Nishimura S, Todo S: N-glycan alterations are associated with drug resistance in human hepatocellular carcinoma. Mol Cancer 2007, 6:32. BioMed Central Full Text
• [37]Dennis JW, Nabi IR, Demetriou M: Metabolism, cell surface organization, and disease. Cell 2009, 139:1229-1241.
• [38]Boehmelt G, Wakeham A, Elia A, Sasaki T, Plyte S, Potter J, Yang Y, Tsang E, Ruland J, Iscove NN, Dennis JW, Mak TW: Decreased UDP-GlcNAc levels abrogate proliferation control in EMeg32-deficient cells. EMBO J 2000, 19:5092-5104.
• [39]Koles K, Lim JM, Aoki K, Porterfield M, Tiemeyer M, Wells L, Panin V: Identification of N-glycosylated proteins from the central nervous system of Drosophila melanogaster. Glycobiology 2007, 17:1388-1403.
• [40]Lim JM, Aoki K, Angel P, Garrison D, King D, Tiemeyer M, Bergmann C, Wells L: Mapping glycans onto specific N-linked glycosylation sites of Pyrus communis PGIP redefines the interface for EPG-PGIP interactions. J Proteome Res 2009, 8:673-680.
• [41]Dell A, Reason AJ, Khoo KH, Panico M, McDowell RA, Morris HR: Mass spectrometry of carbohydrate-containing biopolymers. Methods Enzymol 1994, 230:108-132.
• [42]Morelle W, Faid V, Michalski JC: Structural analysis of permethylated oligosaccharides using electrospray ionization quadrupole time-of-flight tandem mass spectrometry and deutero-reduction. Rapid Commun Mass Spectrom 2004, 18:2451-2464.
• [43]Prien JM, Huysentruyt LC, Ashline DJ, Lapadula AJ, Seyfried TN, Reinhold VN: Differentiating N-linked glycan structural isomers in metastatic and nonmetastatic tumor cells using sequential mass spectrometry. Glycobiology 2008, 18:353-366.
• [44]Reinhold VN, Sheeley DM: Detailed characterization of carbohydrate linkage and sequence in an ion trap mass spectrometer: glycosphingolipids. Anal Biochem 1998, 259:28-33.
• [45]Sheeley DM, Reinhold VN: Structural characterization of carbohydrate sequence, linkage, and branching in a quadrupole Ion trap mass spectrometer: neutral oligosaccharides and N-linked glycans. Anal Chem 1998, 70:3053-3059.
• [46]Viseux N, de Hoffmann E, Domon B: Structural analysis of permethylated oligosaccharides by electrospray tandem mass spectrometry. Anal Chem 1997, 69:3193-3198.
• [47]Wuhrer M, Deelder AM, Hokke CH: Protein glycosylation analysis by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2005, 825:124-133.
• [48]Abbott KL, Aoki K, Lim JM, Porterfield M, Johnson R, O'Regan RM, Wells L, Tiemeyer M, Pierce M: Targeted glycoproteomic identification of biomarkers for human breast carcinoma. J Proteome Res 2008, 7:1470-1480.
• [49]Aoki K, Porterfield M, Lee SS, Dong B, Nguyen K, McGlamry KH, Tiemeyer M: The diversity of O-linked glycans expressed during Drosophila melanogaster development reflects stage- and tissue-specific requirements for cell signaling. J Biol Chem 2008, 283:30385-30400.
• [50]Macauley MS, Bubb AK, Martinez-Fleites C, Davies GJ, Vocadlo DJ: Elevation of global O-GlcNAc levels in 3T3-L1 adipocytes by selective inhibition of O-GlcNAcase does not induce insulin resistance. J Biol Chem 2008, 283:34687-34695.
• [51]Ciucanu I, Kerek F: A simple and rapid method for the permethylation of carbohydrates. Carbohydr Res 1984, 131:209-217.
• [52]Yates JR 3rd, McCormack AL, Eng J: Mining genomes with MS. Anal Chem 1996, 68:534A-540A.
• [53]Peng J, Elias JE, Thoreen CC, Licklider LJ, Gygi SP: Evaluation of multidimensional chromatography coupled with tandem mass spectrometry (LC/LC-MS/MS) for large-scale protein analysis: the yeast proteome. J Proteome Res 2003, 2:43-50.
• [54]Kristiansen TZ, Bunkenborg J, Gronborg M, Molina H, Thuluvath PJ, Argani P, Goggins MG, Maitra A, Pandey A: A proteomic analysis of human bile. Mol Cell Proteomics 2004, 3:715-728.
• [55]Weatherly DB, Atwood JA 3rd, Minning TA, Cavola C, Tarleton RL, Orlando R: A Heuristic method for assigning a false-discovery rate for protein identifications from Mascot database search results. Mol Cell Proteomics 2005, 4:762-772.
• [56]Shah P, Gutierrez-Sanchez G, Orlando R, Bergmann C: A proteomic study of pectin-degrading enzymes secreted by Botrytis cinerea grown in liquid culture. Proteomics 2009, 9:3126-3135.
• [57]Park SY, Ryu J, Lee W: O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes. Exp Mol Med 2005, 37:220-229.
• [58]Dorfmueller HC, Borodkin VS, Schimpl M, Shepherd SM, Shpiro NA, van Aalten DM: GlcNAcstatin: a picomolar, selective O-GlcNAcase inhibitor that modulates intracellular O-glcNAcylation levels. J Am Chem Soc 2006, 128:16484-16485.
• [59]Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R: Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 1999, 17:994-999.
• [60]Haqqani AS, Hutchison JS, Ward R, Stanimirovic DB: Biomarkers and diagnosis; protein biomarkers in serum of pediatric patients with severe traumatic brain injury identified by ICAT-LC-MS/MS. J Neurotrauma 2007, 24:54-74.
• [61]Haqqani AS, Nesic M, Preston E, Baumann E, Kelly J, Stanimirovic D: Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and ICAT-nanoLC-MS/MS. FASEB J 2005, 19:1809-1821.
• [62]Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M: Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 2002, 1:376-386.
• [63]Ong SE, Kratchmarova I, Mann M: Properties of 13C-substituted arginine in stable isotope labeling by amino acids in cell culture (SILAC). J Proteome Res 2003, 2:173-181.
• [64]Ong SE, Mann M: Mass spectrometry-based proteomics turns quantitative. Nat Chem Biol 2005, 1:252-262.
• [65]Schnolzer M, Jedrzejewski P, Lehmann WD: Protease-catalyzed incorporation of 18O into peptide fragments and its application for protein sequencing by electrospray and matrix-assisted laser desorption/ionization mass spectrometry. Electrophoresis 1996, 17:945-953.
• [66]Shevchenko A, Wilm M, Mann M: Peptide sequencing by mass spectrometry for homology searches and cloning of genes. J Protein Chem 1997, 16:481-490.
• [67]Uttenweiler-Joseph S, Neubauer G, Christoforidis S, Zerial M, Wilm M: Automated de novo sequencing of proteins using the differential scanning technique. Proteomics 2001, 1:668-682.
• [68]Andreev VP, Li L, Cao L, Gu Y, Rejtar T, Wu SL, Karger BL: A new algorithm using cross-assignment for label-free quantitation with LC-LTQ-FT MS. J Proteome Res 2007, 6:2186-2194.
• [69]Bondarenko PV, Chelius D, Shaler TA: Identification and relative quantitation of protein mixtures by enzymatic digestion followed by capillary reversed-phase liquid chromatography-tandem mass spectrometry. Anal Chem 2002, 74:4741-4749.
• [70]Chelius D, Bondarenko PV: Quantitative profiling of proteins in complex mixtures using liquid chromatography and mass spectrometry. J Proteome Res 2002, 1:317-323.
• [71]Higgs RE, Knierman MD, Gelfanova V, Butler JP, Hale JE: Comprehensive label-free method for the relative quantification of proteins from biological samples. J Proteome Res 2005, 4:1442-1450.
• [72]Liu H, Sadygov RG, Yates JR 3rd: A model for random sampling and estimation of relative protein abundance in shotgun proteomics. Anal Chem 2004, 76:4193-4201.
• [73]Mallick P, Schirle M, Chen SS, Flory MR, Lee H, Martin D, Ranish J, Raught B, Schmitt R, Werner T, Kuster B, Aebersold R: Computational prediction of proteotypic peptides for quantitative proteomics. Nat Biotechnol 2007, 25:125-131.
• [74]Nesvizhskii AI, Keller A, Kolker E, Aebersold R: A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem 2003, 75:4646-4658.
• [75]Old WM, Meyer-Arendt K, Aveline-Wolf L, Pierce KG, Mendoza A, Sevinsky JR, Resing KA, Ahn NG: Comparison of label-free methods for quantifying human proteins by shotgun proteomics. Mol Cell Proteomics 2005, 4:1487-1502.
• [76]Wiener MC, Sachs JR, Deyanova EG, Yates NA: Differential mass spectrometry: a label-free LC-MS method for finding significant differences in complex peptide and protein mixtures. Anal Chem 2004, 76:6085-6096.
• [77]Dorfmueller HC, Borodkin VS, Schimpl M, van Aalten DM: GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation. Biochem J 2009, 420:221-227.
• [78]Alvarez-Manilla G, Warren NL, Abney T, Atwood J 3rd, Azadi P, York WS, Pierce M, Orlando R: Tools for glycomics: relative quantitation of glycans by isotopic permethylation using 13CH3I. Glycobiology 2007, 17:677-687.
• [79]Atwood JA 3rd, Cheng L, Alvarez-Manilla G, Warren NL, York WS, Orlando R: Quantitation by isobaric labeling: applications to glycomics. J Proteome Res 2008, 7:367-374.
• [80]Chen X, Cushman SW, Pannell LK, Hess S: Quantitative proteomic analysis of the secretory proteins from rat adipose cells using a 2D liquid chromatography-MS/MS approach. J Proteome Res 2005, 4:570-577.
• [81]Chen X, Hunt D, Cushman SW, Hess S: Proteomic characterization of thiazolidinedione regulation of obese adipose secretome in Zucker obese rats. Proteomics Clin Appl 2009, 3:1099-1111.
• [82]Zhou H, Xiao Y, Li R, Hong S, Li S, Wang L, Zeng R, Liao K: Quantitative analysis of secretome from adipocytes regulated by insulin. Acta Biochim Biophys Sin 2009, 41:910-921.
• [83]Hocking SL, Wu LE, Guilhaus M, Chisholm DJ, James DE: Intrinsic depot-specific differences in the secretome of adipose tissue, preadipocytes, and adipose tissue-derived microvascular endothelial cells. Diabetes 2010, 59:3008-3016.
• [84]Kim J, Choi YS, Lim S, Yea K, Yoon JH, Jun DJ, Ha SH, Kim JW, Kim JH, Suh PG, Ryu SH, Lee TG: Comparative analysis of the secretory proteome of human adipose stromal vascular fraction cells during adipogenesis. Proteomics 2010, 10:394-405.
• [85]Zhong J, Krawczyk SA, Chaerkady R, Huang H, Goel R, Bader JS, Wong GW, Corkey BE, Pandey A: Temporal profiling of the secretome during adipogenesis in humans. J Proteome Res 2010, 9:5228-5238.
• [86]Zvonic S, Lefevre M, Kilroy G, Floyd ZE, DeLany JP, Kheterpal I, Gravois A, Dow R, White A, Wu X, Gimble JM: Secretome of primary cultures of human adipose-derived stem cells: modulation of serpins by adipogenesis. Mol Cell Proteomics 2007, 6:18-28.
• [87]Alvarez-Llamas G, Szalowska E, de Vries MP, Weening D, Landman K, Hoek A, Wolffenbuttel BH, Roelofsen H, Vonk RJ: Characterization of the human visceral adipose tissue secretome. Mol Cell Proteomics 2007, 6:589-600.
• [88]Rosenow A, Arrey TN, Bouwman FG, Noben JP, Wabitsch M, Mariman EC, Karas M, Renes J: Identification of novel human adipocyte secreted proteins by using SGBS cells. J Proteome Res 2010, 9:5389-5401.
• [89]Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW: Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004, 145:2273-2282.
• [90]Sell H, Dietze-Schroeder D, Eckardt K, Eckel J: Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AICAR, and troglitazone. Biochem Biophys Res Commun 2006, 343:700-706.
• [91]Roelofsen H, Dijkstra M, Weening D, de Vries MP, Hoek A, Vonk RJ: Comparison of isotope-labeled amino acid incorporation rates (CILAIR) provides a quantitative method to study tissue secretomes. Mol Cell Proteomics 2009, 8:316-324.
• [92]Hwang CS, Loftus TM, Mandrup S, Lane MD: Adipocyte differentiation and leptin expression. Annu Rev Cell Dev Biol 1997, 13:231-259.
• [93]MacDougald OA, Lane MD: Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem 1995, 64:345-373.
• [94]Trujillo ME, Scherer PE: Adipose tissue-derived factors: impact on health and disease. Endocr Rev 2006, 27:762-778.
• [95]Sun K, Kusminski CM, Scherer PE: Adipose tissue remodeling and obesity. J Clin Invest 2011, 121:2094-2101.
• [96]Olefsky JM, Glass CK: Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010, 72:219-246.
• [97]Nagaraju GP, Sharma D: Anti-cancer role of SPARC, an inhibitor of adipogenesis. Cancer Treat Rev 2011, 37:559-566.
• [98]Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, He CH, Takyar S, Elias JA: Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol 2011, 73:479-501.
• [99]Dupont A, Tokarski C, Dekeyzer O, Guihot AL, Amouyel P, Rolando C, Pinet F: Two-dimensional maps and databases of the human macrophage proteome and secretome. Proteomics 2004, 4:1761-1778.
• [100]Coombs KM: Quantitative proteomics of complex mixtures. Expert Rev Proteomics 2011, 8:659-677.
• [101]Brimble S, Wollaston-Hayden EE, Teo CF, Morris AC, Wells L: The Role of the O-GlcNAc Modification in Regulating Eukaryotic Gene Expression. Curr Signal Transduct Ther 2010, 5:12-24.
• [102]Einstein FH, Fishman S, Bauman J, Thompson RF, Huffman DM, Atzmon G, Barzilai N, Muzumdar RH: Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance. FASEB J 2008, 22:3450-3457.
• [103]Zhang P, Klenk ES, Lazzaro MA, Williams LB, Considine RV: Hexosamines regulate leptin production in 3T3-L1 adipocytes through transcriptional mechanisms. Endocrinology 2002, 143:99-106.
• [104]Taniguchi N, Korekane H: Branched N-glycans and their implications for cell adhesion, signaling and clinical applications for cancer biomarkers and in therapeutics. BMB Rep 2011, 44:772-781.
• [105]Hart GW, Copeland RJ: Glycomics hits the big time. Cell 2010, 143:672-676.
• [106]Zaia J: Mass spectrometry and glycomics. OMICS 2010, 14:401-418.