Abstract
Low-grade inflammation is important in the development of obesity related pathologies
such as insulin resistance and type 2 diabetes, and also cardiovascular disease. Visfatin/PBEF/Nampt
and resistin are proinflammatory adipokines secreted from adipocytes, monocytes, and
macrophages, and have been linked to atherosclerotic plaque formation, recently. The
aim of the present study was to investigate if the expression of these molecules in
circulating blood monocytes is altered in obese and/or type 2 diabetic human subjects.
Monocytes were isolated by CD14-antibody based magnetic cell sorting from blood samples
of 17 lean controls, 20 obese nondiabetic subjects, and 19 obese patients with type
2 diabetes. FACS analysis was performed to test purity of the cell preparations. Expression
of the different adipokines was measured by multiplex real-time PCR on RNA-level.
Visfatin/PBEF/Nampt was found to be very strongly expressed in monocytes, whereas
resistin levels were significantly lower. Furthermore, visfatin/PBEF/Nampt expression
was significantly upregulated in obese type 2 diabetic patients, whereas obese nondiabetics
exhibited similar levels compared to lean controls, indicating that visfatin/PBEF/Nampt
levels are related to type 2 diabetes rather than to obesity. In contrast, resistin
expression displayed a different pattern being significantly increased in obese subjects
compared to controls but not related to type 2 diabetes. These data suggest a differential
role for these two proinflammatory adipokines in linking metabolic diseases to atherosclerosis
with visfatin/PBEF/Nampt being more important in patients with type 2 diabetes and
resistin in obese but nondiabetic human subjects.
Key words
inflammation - insulin resistance - atherosclerosis
References
1
Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW.
Clinical review: Prevalence and incidence of endocrine and metabolic disorders in
the United States: a comprehensive review.
J Clin Endocrinol Metab.
2009;
94
1853-1878
2
Katagiri H, Yamada T, Oka Y.
Adiposity and cardiovascular disorders: disturbance of the regulatory system consisting
of humoral and neuronal signals.
Circ Res.
2007;
101
27-39
3
Yamagishi S, Nakamura K, Matsui T, Takenaka K, Jinnouchi Y, Imaizumi T.
Cardiovascular disease in diabetes.
Mini Rev Med Chem.
2006;
6
313-318
4
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
5
Tilg H, Moschen AR.
Inflammatory mechanism in the regulation of insulin resistance.
Mol Med.
2008;
14
222-231
6
Gerrity RG, Naito HK, Richardson M, Schwartz CJ.
Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages.
Am J Pathol.
1979;
95
775-792
7
Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC,
Connelly PW, Milstone DS.
A major role for VCAM-1, but not ICAM-1, in early atherosclerosis.
J Clin Invest.
2001;
107
1255-1262
8
Byrne GI, Kalayoglu MV.
Chlamydia pneumoniae and atherosclerosis: links to the disease process.
Am Heart J.
1999;
138
488-490
9
Laudes M, Oberhauser F, Bilkovski R, Schubert M, Udelhoven M, Wassmer G, Roth B, Krone W.
Human fetal adiponectin and retinol-binding protein (RBP)-4 levels in relation to
birth weight and maternal obesity.
Exp Clin Endocrinol Diabetes.
2009;
117
146-149
10
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM.
Positional cloning of the mouse obese gene and its human homologue.
Nature.
1994;
372
425-432
11
La Cava A, Alviggi C, Matarese G.
Unraveling the multiple roles of leptin in inflammation and autoimmunity.
J Mol Med.
2004;
82
4-11
12
Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I.
Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing
factor.
Mol Cell Biol.
1994;
14
1431-1437
13
Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T.
Association between plasma visfatin/PBEF/Nampt and vascular endothelial function in
patients with type 2 diabetes mellitus.
Metabolism.
2007;
56
451-458
14
Böttcher Y, Teupser D, Enigk B, Berndt J, Klöting N, Schön MR, Thiery J, Blüher M,
Stumvoll M, Kovacs P.
Genetic variation in the visfatin/PBEF/Nampt gene (PBEF1) and its relation to glucose
metabolism and fat-depot-specific messenger ribonucleic acid expression in humans.
J Clin Endocrinol Metab.
2006;
91
2725-2731
15
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS,
Lazar MA.
The hormone resistin links obesity to diabetes.
Nature.
2001;
409
307-312
16
Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K,
Nagai R.
Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells:
a new insight into adipocytokine-endothelial cell interactions.
Biochem Biophys Res Commun.
2004;
314
415-419
17
Ayoub SS, Botting RM, Joshi AN, Seed MP, Colville-Nash PR.
Activation of macrophage peroxisome proliferator-activated receptor-gamma by diclofenac
results in the induction of cyclooxygenase-2 protein and the synthesis of anti-inflammatory
cytokines.
Mol Cell Biochem.
2009;
327
101-110
18
Laudes M, Bilkovski R, Oberhauser F, Droste A, Gomolka M, Leeser U, Udelhoven M, Krone W.
Transcription Factor FBI-1 acts as a dual regulator in adipogenesis by coordinated
regulation of cyclin A and E2F-4.
J Mol Med.
2008;
86
597-608
19
Yamagata S, Tomita K, Sato R, Niwa A, Higashino H, Tohda Y.
Interleukin-18-deficient mice exhibit diminished chronic inflammation and airway remodelling
in ovalbumin-induced asthma model.
Clin Exp Immunol..
2008;
154
295-304
20
Lazar MA.
Resistin- and obesity-associated metabolic diseases.
Horm Metab Res.
2007;
39
710-716
21
Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C.
Structure of Nampt/PBEF/visfatin/PBEF/Nampt, a mammalian NAD+ biosynthetic enzyme.
Nat Struct Mol Biol.
2006;
13
661-662
22
Revollo JR, Grimm AA, Imai S.
The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates
Sir2 activity in mammalian cells.
J Biol Chem.
2004;
279
50754-50763
23
Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, Tilg H.
Visfatin/PBEF/Nampt, an adipocytokine with proinflammatory and immunomodulating properties.
J Immunol.
2007;
178
1748-1758
24
Nowell MA, Richards PJ, Fielding CA, Ognjanovic S, Topley N, Williams AS, Bryant-Greenwood G,
Jones SA.
Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6
trans-signaling: implications in the pathogenesis of rheumatoid arthritis.
Arthritis Rheum.
2006;
54
2084-2095
25
Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gómez-Reino JJ, Gualillo O.
Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and
visfatin/PBEF/Nampt in patients with rheumatoid arthritis.
Ann Rheum Dis.
2006;
65
1198-1201
26
Oki K, Yamane K, Kamei N, Nojima H, Kohno N.
Circulating visfatin/PBEF/Nampt level is correlated with inflammation, but not with
insulin resistance.
Clin Endocrinol (Oxf).
2007;
67
796-800
27
Xie H, Tang SY, Luo XH, Huang J, Cui RR, Yuan LQ, Zhou HD, Wu XP, Liao EY.
Insulin-like effects of visfatin/PBEF/Nampt on human osteoblasts.
Calcif Tissue Int.
2007;
80
201-210
28
Dogru T, Sonmez A, Tasci I, Bozoglu E, Yilmaz MI, Genc H, Erdem G, Gok M, Bingol N,
Kilic S, Ozgurtas T, Bingol S.
Plasma visfatin/PBEF/Nampt levels in patients with newly diagnosed and untreated type
2 diabetes mellitus and impaired glucose tolerance.
Diabetes Res Clin Pract.
2007;
76
24-29
29
Krzyzanowska K, Krugluger W, Mittermayer F, Rahman R, Haider D, Shnawa N, Schernthaner G.
Increased visfatin/PBEF/Nampt concentrations in women with gestational diabetes mellitus.
Clin Sci (Lond).
2006;
110
605-609
30
Chan TF, Chen YL, Chen HH, Lee CH, Jong SB, Tsai EM.
Increased plasma visfatin/PBEF/Nampt concentrations in women awith polycystic ovary
syndrome.
Fertil Steril.
2007;
88
401-405
31
Sommer G, Garten A, Petzold S, Beck-Sickinger AG, Blüher M, Stumvoll M, Fasshauer M.
Visfatin/PBEF/Nampt/PBEF/Nampt: structure, regulation and potential function of a
novel adipokine.
Clin Sci (Lond).
2008;
115
13-23
32
Dahl TB, Yndestad A, Skjelland M, Øie E, Dahl A, Michelsen A, Damås JK, Tunheim SH,
Ueland T, Smith C, Bendz B, Tonstad S, Gullestad L, Frøland SS, Krohg-Sørensen K,
Russell D, Aukrust P, Halvorsen B.
Increased expression of visfatin/PBEF/Nampt in macrophages of human unstable carotid
and coronary atherosclerosis: possible role in inflammation and plaque destabilization.
Circulation..
2007;
115
972-980
33
Tsiotra PC, Tsigos C, Yfanti E, Anastasiou E, Vikentiou M, Psarra K, Papasteriades C,
Raptis SA.
Visfatin/PBEF/Nampt, TNF-alpha and IL-6 mRNA expression is increased in mononuclear
cells from type 2 diabetic women.
Horm Metab Res.
2007;
39
758-763
34
Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S.
Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated
receptor-gamma action in humans.
Diabetes.
2001;
50
2199-2202
35
Chen CC, Li TC, Li CI, Liu CS, Wang HJ, Lin CC.
Serum resistin level among healthy subjects: relationship to anthropometric and metabolic
parameters.
Metabolism.
2005;
54
471-475
36
Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS.
Circulating resistin levels are not associated with obesity or insulin resistance
in humans and are not regulated by fasting or leptin administration: cross-sectional
and interventional studies in normal, insulin-resistant, and diabetic subjects.
J Clin Endocrinol Metab.
2003;
88
4848-4856
37
Ohmori R, Momiyama Y, Kato R, Taniguchi H, Ogura M, Ayaori M, Nakamura H, Ohsuzu F.
Associations between serum resistin levels and insulin resistance, inflammation, and
coronary artery disease.
J Am Coll Cardiol..
2005;
46
379-380
38
Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ.
Resistin is an inflammatory marker of atherosclerosis in humans.
Circulation.
2005;
111
932-939
39
Díez JJ, Iglesias P, Fernández-Reyes MJ, Aguilera A, Bajo MA, Alvarez-Fidalgo P, Codoceo R,
Selgas R.
Serum concentrations of leptin, adiponectin and resistin, and their relationship with
cardiovascular disease in patients with end-stage renal disease.
Clin Endocrinol (Oxf).
2005;
62
242-249
40
Kougias P, Chai H, Lin PH, Yao Q, Lumsden AB, Chen C.
Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular
disease.
J Surg Res.
2005;
126
121-129
Correspondence
Dr. M. Laudes
Klinik II und Poliklinik für Innere Medizin
Zentrum für Molekulare Medizin
Universität zu Köln
Kerpner Straße 62
50924 Köln
Germany
Phone: +49/221/478 5481
Fax: +49/221/478 3107
Email: matthias.laudes@uk-koeln.de