Regulation of Dipeptidyl Peptidase-4, its Substrate Chemokines, and Their Receptors in Adipose Tissue of ob/ob Mice

Abstract

The physiological function of DPP-4 in proteolytic inactivation of incretins has been well established, however, there is limited information on the expression and the significance of DPP-4 in white adipose tissue with regard to obesity. The objective of the work was to reveal the expression and regulation of DPP-4 in adipocytes and compare the expression and activity of DPP-4 in white adipose tissue and several other organs such as the liver, muscle and kidney. We also investigated the gene expression levels of DPP-4 substrate chemokines, and their receptors in white adipose tissue. DPP-4 was mainly expressed in stromal vascular fraction (SVF), and downregulated in adipose tissue of ob/ob compared with C57BL6/J mice. Mimetic conditions of obese fat in vitro showed that differentiation of mouse primary preadipocytes into adipocytes was associated with marked downregulation of DPP-4 expression. Treatment with TNF-α or ROS even decreased DPP-4 expression in mouse primary adipocytes. Various DPP-4 substrate chemokines were expressed in white adipose tissue and regulated by obesity. The expression of receptors for DPP-4 substrate chemokines was markedly high and tightly regulated by obesity in white adipose tissue. Expression of DPP-4 was reduced in adipose tissues of ob/ob mice. Actions of several substrate chemokines might be potentiated by downregulation of DPP-4, synergistically with upregulation of chemokines and their receptors in adipose tissues of obese mice.

Key words

DPP-4 - obesity - differentiation - preadipocytes - chemokine

• References

• 1 Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. J Atheroscler Thromb 2011; 18: 629-639
• 2 Coppack SW. Adipose tissue changes in obesity. Biochem Soc Trans 2005; 33: 1049-1052
• 3 Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314: 1-16
• 4 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548-2556
• 5 Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, Eckardt K, Kaufman JM, Ryden M, Muller S, Hanisch FG, Ruige J, Arner P, Sell H, Eckel J. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60: 1917-1925
• 6 Chung KM, Cheng JH, Suen CS, Huang CH, Tsai CH, Huang LH, Chen YR, Wang AH, Jiaang WT, Hwang MJ, Chen X. The dimeric transmembrane domain of prolyl dipeptidase DPP-IV contributes to its quaternary structure and enzymatic activities. Protein Sci 2010; 19: 1627-1638
• 7 Cordero OJ, Salgado FJ, Nogueira M. On the origin of serum CD26 and its altered concentration in cancer patients. Cancer Immunol Immunother 2009; 58: 1723-1747
• 8 Ishibashi Y, Matsui T, Maeda S, Higashimoto Y, Yamagishi S. Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovasc Diabetol 2013; 12: 125
• 9 Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705
• 10 Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter KC, Kipnes MS, Snyder K, Hilliard D, Tanen M, Cilissen C, De Smet M, de Lepeleire I, Van Dyck K, Wang AQ, Zeng W, Davies MJ, Tanaka W, Holst JJ, Deacon CF, Gottesdiener KM, Wagner JA. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91: 4612-4619
• 11 Ahren B. Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications. Diabetes Care 2007; 30: 1344-1350
• 12 Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?. Trends Pharmacol Sci 2009; 30: 600-607
• 13 Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol 2015; 16: 850-858
• 14 Zillessen P, Celner J, Kretschmann A, Pfeifer A, Racke K, Mayer P. Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes. Sci Rep 2016; 6: 23074
• 15 Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, Glass CK, Hume DA, Kellie S, Sweet MJ. Expression analysis of G Protein-Coupled Receptors in mouse macrophages. Immunome Res 2008; 4: 5
• 16 Gorrell MD, Gysbers V, McCaughan GW. CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol 2001; 54: 249-264
• 17 Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996; 221: 286-289
• 18 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79-83
• 19 Qiang L, Wang H, Farmer SR. Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha. Mol Cell Biol 2007; 27: 4698-4707
• 20 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91
• 21 Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761
• 22 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56: 901-911
• 23 Jeong JA, Ko KM, Park HS, Lee J, Jang C, Jeon CJ, Koh GY, Kim H. Membrane proteomic analysis of human mesenchymal stromal cells during adipogenesis. Proteomics 2007; 7: 4181-4191
• 24 Chowdhury HH, Velebit J, Radic N, Francic V, Kreft M, Zorec R. Hypoxia Alters the expression of dipeptidyl peptidase 4 and induces developmental remodeling of human preadipocytes. J Diabetes Res 2016; 7481470
• 25 Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 2013; 19: 1338-1344
• 26 Stefanovic V, Ardaillou N, Vlahovic P, Placier S, Ronco P, Ardaillou R. Interferon-gamma induces dipeptidylpeptidase IV expression in human glomerular epithelial cells. Immunology 1993; 80: 465-470
• 27 Yamabe T, Takakura K, Sugie K, Kitaoka Y, Takeda S, Okubo Y, Teshigawara K, Yodoi J, Hori T. Induction of the 2B9 antigen/dipeptidyl peptidase IV/CD26 on human natural killer cells by IL-2, IL-12 or IL-15. Immunology 1997; 91: 151-158
• 28 Eltzschig HK, Faigle M, Knapp S, Karhausen J, Ibla J, Rosenberger P, Odegard KC, Laussen PC, Thompson LF, Colgan SP. Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood 2006; 108: 1602-1610
• 29 Salgado FJ, Vela E, Martin M, Franco R, Nogueira M, Cordero OJ. Mechanisms of CD26/dipeptidyl peptidase IV cytokine-dependent regulation on human activated lymphocytes. Cytokine 2000; 12: 1136-1141
• 30 Bohm SK, Gum Jr. JR, Erickson RH, Hicks JW, Kim YS. Human dipeptidyl peptidase IV gene promoter: tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter. Biochem J 1995; 311 Pt 3 835-843
• 31 Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y, Makris C, Rothwarf D, Baud V, Natoli G, Guido F, Li N. Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. Biofactors 2001; 15: 87-89
• 32 Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 2008; 453: 807-811
• 33 Kirino Y, Kamimoto T, Sato Y, Kawazoe K, Minakuchi K, Nakahori Y. Increased plasma dipeptidyl peptidase IV (DPP IV) activity and decreased DPP IV activity of visceral but not subcutaneous adipose tissue in impaired glucose tolerance rats induced by high-fat or high-sucrose diet. Biol Pharm Bull 2009; 32: 463-467
• 34 Lenhard JM, Croom DK, Minnick DT. Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments. Biochem Biophys Res Commun 2004; 324: 92-97
• 35 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr. AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
• 36 Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494-1505
• 37 Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL, Sweeney JF, Peterson LE, Chan L, Smith CW, Ballantyne CM. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 2007; 115: 1029-1038
• 38 Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun D, Skurk T, Hauner H, Bluher M, Unger T, Wolf AM, Knippschild U, Hombach V, Marx N. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol 2008; 28: 1304-1310
• 39 Van Damme J, Struyf S, Wuyts A, Van Coillie E, Menten P, Schols D, Sozzani S, De Meester I, Proost P. The role of CD26/DPP IV in chemokine processing. Chem Immunol 1999; 72: 42-56
• 40 Ludwig A, Schiemann F, Mentlein R, Lindner B, Brandt E. Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine. J Leukoc Biol 2002; 72: 183-191
• 41 Proost P, Menten P, Struyf S, Schutyser E, De Meester I, Van Damme J. Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist. Blood 2000; 96: 1674-1680
• 42 Proost P, Schutyser E, Menten P, Struyf S, Wuyts A, Opdenakker G, Detheux M, Parmentier M, Durinx C, Lambeir AM, Neyts J, Liekens S, Maudgal PC, Billiau A, Van Damme J. Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties. Blood 2001; 98: 3554-3561
• 43 Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 2014; 32: 659-702
• 44 Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante Jr. AW. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116: 115-124
• 45 Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, Takamura T, Yamamoto H, Miyamoto K, Ginsberg HN, Mukaida N, Kaneko S, Ota T. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 2012; 61: 1680-1690
• 46 Deiuliis JA, Oghumu S, Duggineni D, Zhong J, Rutsky J, Banerjee A, Needleman B, Mikami D, Narula V, Hazey J, Satoskar AR, Rajagopalan S. CXCR3 modulates obesity-induced visceral adipose inflammation and systemic insulin resistance. Obesity (Silver Spring) 2014; 22: 1264-1274
• 47 Busso N, Wagtmann N, Herling C, Chobaz-Peclat V, Bischof-Delaloye A, So A, Grouzmann E. Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am J Pathol 2005; 166: 433-442
• 48 Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 2011; 332: 243-247
• 49 Godiska R, Chantry D, Raport CJ, Sozzani S, Allavena P, Leviten D, Mantovani A, Gray PW. Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells. J Exp Med 1997; 185: 1595-1604
• 50 Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175-184
• 51 Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 2008; 49: 1562-1568
• 52 Altintas MM, Azad A, Nayer B, Contreras G, Zaias J, Faul C, Reiser J, Nayer A. Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res 2011; 52: 480-488
• 53 Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 2010; 33: 1607-1609