The Lipocalins Retinol-Binding Protein-4, Lipocalin-2 and Lipocalin-Type Prostaglandin D2-Synthase Correlate with Markers of Inflammatory Activity, Alcohol Intake and Blood Lipids, But not with Insulin Sensitivity in Metabolically Healthy 58-year-Old Swedish Men

Abstract

The lipocalins retinol-binding protein (RBP)-4, lipocalin-2 and lipocalin-type prostaglandin D-synthase (L-PGDS) have been suggested to mediate obesity-associated insulin resistance and other metabolic co-morbidities. The role of lipocalins is however controversial and it is unclear whether they have a physiological role in regulation of insulin sensitivity and metabolic function in clinically healthy humans. Therefore, we examined the correlations between serum levels of RBP-4, L-PGDS and lipocalin-2 and insulin sensitivity and other metabolic parameters in non-diabetic subjects selected to display variations in insulin sensitivity. 100 clinically healthy 58-year-old Swedish men were selected by stratified sampling among 818 screened subjects to represent quintiles of varying degrees of insulin sensitivity. Insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp method. Serum levels of lipocalins and cytokines were determined using antibody-based techniques. Serum lipids were measured by standardized laboratory methods. None of the measured lipocalins showed any correlations with insulin sensitivity. However, we found that lipocalin-2 and L-PGDS were correlated with each other, but not with RBP-4. Lipocalin-2 and L-PGDS were positively correlated with soluble TNF- receptors 1 and 2 and negatively with alcohol consumption and serum HDL. Further, lipocalin-2 was correlated with interleukin-6 whereas RBP-4 was negatively correlated with TNF-α. □These results suggest that RBP-4, lipocalin-2 and L-PGDS do not regulate insulin sensitivity in healthy men. Rather the expression levels of lipocalin-2 and L-PGDS, but not RBP-4, seemed to reflect inflammatory activity and were inversely correlated with alcohol intake and serum HDL levels.

Key words

lipocalins - retinol-binding protein-4 - lipocalin-2 - lipocalin-type prostaglandin D2-synthase - insulin sensitivity - inflammation - TNF

References

• 1 Bokemark L, Froden A, Attvall S. et al . The euglycemic hyperinsulinemic clamp examination: Variability and reproducibility.  Scand J Clin Lab Invest. 2000;  60 27-36
• 2 Bokemark L, Wikstrand J, Wedel H. et al . Insulin, insulin propeptides and intima-media thickness in the carotid artery in 58-year-old clinically healthy men. The atherosclerosis and insulin resistance study (air).  Diabet Med. 2002;  19 144-151
• 3 Di Castelnuovo A, Costanzo S, Bagnardi V. et al . Alcohol dosing and total mortality in men and women: An updated meta-analysis of 34 prospective studies.  Arch Intern Med. 2006;  166 2437-2445
• 4 Englund Ogge L, Brohall G, Behre CJ. et al . Alcohol consumption in relation to metabolic regulation, inflammation, and adiponectin in 64-year-old caucasian women: A population-based study with a focus on impaired glucose regulation.  Diabetes Care. 2006;  29 908-913
• 5 Erikstrup C, Mortensen O H, Nielsen AR. et al . Rbp-to-retinol ratio, but not total rbp, is elevated in patients with type 2 diabetes.  Diabetes Obes Metab. 2009;  11 204-212
• 6 Erikstrup C, Mortensen OH, Pedersen BK. Retinol-binding protein 4 and insulin resistance.  N Engl J Med. 2006;  355 1393-1394 ; author reply 1394–1395
• 7 Fagerberg B, Lindstedt G, Berglund G. Effects of alcohol intake and obesity on serum liver enzyme activity in obese men with mild hypertension.  J Intern Med. 1993;  233 477-484
• 8 Flo TH, Smith KD, Sato S. et al . Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron.  Nature. 2004;  432 917-921
• 9 Gao W, Schmidtko A, Wobst I. et al . Prostaglandin d2 produced by hematopoietic prostaglandin d synthase contributes to lps-induced fever.  J Physiol Pharmacol. 2009;  60 145-150
• 10 Gavi S, Stuart LM, Kelly P. et al . Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes.  J Clin Endocrinol Metab. 2007;  92 1886-1890
• 11 Graham TE, Wason CJ, Bluher M. et al . Shortcomings in methodology complicate measurements of serum retinol binding protein (rbp4) in insulin-resistant human subjects.  Diabetologia. 2007;  50 814-823
• 12 Graham TE, Yang Q, Bluher M. et al . Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.  N Engl J Med. 2006;  354 2552-2563
• 13 Imhof A, Woodward M, Doering A. et al . Overall alcohol intake, beer, wine, and systemic markers of inflammation in western europe: Results from three monica samples (augsburg, glasgow, lille).  Eur Heart J. 2004;  25 2092-2100
• 14 Law IK, Xu A, Lam KS. et al . Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity.  Diabetes. 2010;  59 872-882
• 15 Moreno-Navarrete JM, Manco M, Ibanez J. et al . Metabolic endotoxemia and saturated fat contribute to circulating ngal concentrations in subjects with insulin resistance.  Int J Obes (Lond). 2009; 
• 16 Ohinata K, Takagi K, Biyajima K. et al . Central prostaglandin d(2) stimulates food intake via the neuropeptide y system in mice.  FEBS Lett. 2008;  582 679-684
• 17 Oliveira A, Rodriguez-Artalejo F, Lopes C. Alcohol intake and systemic markers of inflammation – shape of the association according to sex and body mass index.  Alcohol Alcohol. 45 119-125
• 18 Pettersson C, Fogelstrand L, Rosengren B. et al . Increased lipolysis by secretory phospholipase a(2) group v of lipoproteins in diabetic dyslipidaemia.  J Intern Med. 2008;  264 155-165
• 19 Qi Q, Yu Z, Ye X. et al . Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in chinese people.  J Clin Endocrinol Metab. 2007;  92 4827-4834
• 20 Ragolia L, Palaia T, Hall CE. et al . Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin d2 synthase knock-out mice.  J Biol Chem. 2005;  280 29946-29955
• 21 Ribel-Madsen R, Friedrichsen M, Vaag A. et al . Retinol-binding protein 4 in twins: Regulatory mechanisms and impact of circulating and tissue expression levels on insulin secretion and action.  Diabetes. 2009;  58 54-60
• 22 Rosengren B, Peilot H, Umaerus M. et al . Secretory phospholipase a2 group v: Lesion distribution, activation by arterial proteoglycans, and induction in aorta by a western diet.  Arterioscler Thromb Vasc Biol. 2006;  26 1579-1585
• 23 Schlehuber S, Skerra A. Lipocalins in drug discovery: From natural ligand-binding proteins to “Anticalins”.  Drug Discov Today. 2005;  10 23-33
• 24 Tanaka R, Miwa Y, Mou K. et al . Knockout of the l-pgds gene aggravates obesity and atherosclerosis in mice.  Biochem Biophys Res Commun. 2009;  378 851-856
• 25 Tanaka T, Urade Y, Kimura H. et al . Lipocalin-type prostaglandin d synthase (beta-trace) is a newly recognized type of retinoid transporter.  J Biol Chem. 1997;  272 15789-15795
• 26 Urade Y, Kitahama K, Ohishi H. et al . Dominant expression of mrna for prostaglandin d synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain.  Proc Natl Acad Sci USA. 1993;  90 9070-9074
• 27 Wang Y, Lam KS, Kraegen EW. et al . Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans.  Clin Chem. 2007;  53 34-41
• 28 Yan QW, Yang Q, Mody N. et al . The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance.  Diabetes. 2007;  56 2533-2540
• 29 Yang Q, Graham TE, Mody N. et al . Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.  Nature. 2005;  436 356-362
• 30 Yao-Borengasser A, Varma V, Bodles AM. Retinol binding protein 4 expression in humans: Relationship to insulin resistance, inflammation, and response to pioglitazone.  J Clin Endocrinol Metab. 2007;  92 2590-2597
• 31 Yusuf S, Hawken S, Ounpuu S. et al . Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): Case-control study.  Lancet. 2004;  364 937-952

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