Advertisement

Circulating leptin is associated with serum uric acid level and its tubular reabsorption in a sample of adult middle-aged men

  • L. D’EliaEmail author
  • A. Giaquinto
  • F. P. Cappuccio
  • R. Iacone
  • O. Russo
  • P. Strazzullo
  • F. GallettiEmail author
Original Article
  • 16 Downloads

Abstract

Purpose

Leptin is associated with cardiovascular risk factors (e.g. hypertension, insulin resistance, kidney disease and excess body weight). Experimental studies showed that leptin might affect serum uric acid, by modulation of the uric acid excretion. However, there are few observational data on the relationship between leptin and uric acid in the general population. Therefore, the aim of the present study was to evaluate the relationship between leptin and uric acid and its excretion in a large middle-aged male general population.

Methods

A sample of 930 adult male individuals (mean age: 52 years) without therapy for high uric acid was included in the analysis (the Olivetti Heart Study).

Results

Uric acid was significantly and positively associated with blood pressure, BMI, waist circumference, insulin resistance, C-reactive protein and leptin (p < 0.01), while inversely with renal function (p = 0.01). The multivariate analysis confirmed the association between leptin and uric acid after adjustment for potential confounders (p < 0.01). After division for adiposity, this trend was confirmed separately for normal weight and excess body weight participants. Moreover, leptin was inversely associated with excretion of uric acid (p < 0.01), also in multivariate analysis (p = 0.03).

Conclusion

The results of this study indicate a positive association between circulating leptin levels and uric acid, independently of potential confounders, both in normal and excess body weight men. Furthermore, an inverse association between leptin and uric acid excretion was detected.

Keywords

Cardiovascular risk Uric acid Uric acid excretion Adipocytokines Adipokines Leptin 

Notes

Funding

None.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of “Federico II” University in Naples.

Informed consent

All participants provided their informed written consent to participate.

References

  1. 1.
    Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295PubMedCrossRefGoogle Scholar
  2. 2.
    Haynes WG (2005) Role of leptin in obesity-related hypertension. Exp Physiol 90:683–688PubMedCrossRefGoogle Scholar
  3. 3.
    Galletti F, D’Elia L, De Palma D et al (2012) Hyperleptinemia is associated with hypertension, systemic inflammation and insulin resistance in overweight but not in normal weight men. Nutr Metab Cardiovasc Dis 22(3):300–306PubMedCrossRefGoogle Scholar
  4. 4.
    Galletti F, D’Elia L, Barba G et al (2008) High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an 8-year follow-up study. J Clin Endocrinol Metab 93(10):3922–3926PubMedCrossRefGoogle Scholar
  5. 5.
    Galletti F, Barbato A, Versiero M et al (2007) Circulating leptin levels predict the development of metabolic syndrome in middle aged men: an 8-year follow-up study. J Hypertens 25(8):1671–1677PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    D’Elia L, Strazzullo P, Iacone R, Russo O, Galletti F (2019) Leptin levels predict the development of insulin resistance in a sample of adult men—the Olivetti Heart Study. Nutr Metab Cardiovasc Dis 29(1):39–44PubMedCrossRefGoogle Scholar
  7. 7.
    D’Elia L, Manfredi M, Perna L, Iacone R, Russo O, Strazzullo P, Galletti F (2018) Circulating leptin levels predict the decline in renal function with age in a sample of adult men (The Olivetti Heart Study). Intern Emerg Med.  https://doi.org/10.1007/s11739-018-1924-9 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cortese F, Giordano P, Scicchitano P, Faienza MF, De Pergola G, Calculli G, Meliota G, Ciccone MM (2019) Uric acid: from a biological advantage to a potential danger. A focus on cardiovascular effects. Vascul Pharmacol 29:106565.  https://doi.org/10.1016/j.vph.2019.106565 CrossRefGoogle Scholar
  9. 9.
    De Pergola G, Giagulli VA, Bartolomeo N, Gaeta F, Petruzzella A, Guastamacchia E, Triggiani V, Silvestris F (2017) Independent relationship between serum osteocalcin and uric acid in a cohort of apparently healthy obese subjects. Endocr Metab Immune Disord Drug Targets 17(3):207–212.  https://doi.org/10.2174/1871530317666170825164415 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    De Pergola G, Cortese F, Termine G, Meliota G, Carbonara R, Masiello M, Cortese AM, Silvestris F, Caccavo D, Ciccone MM (2018) Uric acid, metabolic syndrome and atherosclerosis: the chicken or the egg, which comes first? Endocr Metab Immune Disord Drug Targets 18(3):251–259.  https://doi.org/10.2174/1871530318666180212101548 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Feig DI, Kang DH, Johnson RJ (2008) Uric acid and cardiovascular risk. N Engl J Med 359:1811–1821PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT, Manolis AJ, Perez-Ruiz F, Mancia G (2015) Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens 33(9):1729–1741PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Benn CL, Dua P, Gurrell R, Loudon P, Pike A, Storer RI, Vangjeli C (2018) Physiology of hyperuricemia and urate-lowering treatments. Front Med [Lausanne] 5:160CrossRefGoogle Scholar
  14. 14.
    Caulfield MJ, Munroe PB, O’Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P, Shaw-Hawkins S, Dobson RJ, Wallace C, Newhouse SJ, Brown M, Connell JM, Dominiczak A, Farrall M, Lathrop GM, Samani NJ, Kumari M, Marmot M, Brunner E, Chambers J, Elliott P, Kooner J, Laan M, Org E, Veldre G, Viigimaa M, Cappuccio FP, Ji C, Iacone R, Strazzullo P, Moley KH, Cheeseman C (2008) SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 5(10):e197.  https://doi.org/10.1371/journal.pmed.0050197 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Testa A, Prudente S, Leonardis D, Spoto B, Sanguedolce MC, Parlongo RM et al (2015) A genetic marker of hyperuricemia predicts cardiovascular events in a meta-analysis of three cohort studies in high risk patients. Nutr Metab Cardiovasc Dis 25(12):1087–1094.  https://doi.org/10.1016/j.numecd.2015.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G (2001) Sympathetic nervous system and insulin resistance: from obesity to diabetes. Am J Hypertens 14(11 Pt 2):304S–309SPubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Mahnensmith RL, Aronson PS (1985) The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res 57:773–788CrossRefGoogle Scholar
  18. 18.
    Modan M, Halkin H, Karasik A, Lusky A (1987) Elevated serum uric acid: a facet of hyperinsulinemia. Diabetologia 30:713–718PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Doria A, Fioretto P, Avogaro A et al (1991) Insulin resistance is associated with high sodium-lithium countertransport in essential hypertension. Am J Physiol 261:E684–E691PubMedPubMedCentralGoogle Scholar
  20. 20.
    Ding N, Liu B, Song J et al (2016) Leptin promotes endothelial dysfunction in chronic kidney disease through AKT/GSK3β and β-catenin signals. Biochem Biophys Res Commun 480(4):544–551PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ambarkar M, Pemmaraju SV, Gouroju S et al (2016) Adipokines and their relation to endothelial dysfunction in patients with chronic kidney disease. J Clin Diagn Res 10(1):BC04PubMedPubMedCentralGoogle Scholar
  22. 22.
    Gomart S, Gaudreau-MeÂnard C, Jespers P et al (2017) Leptin induced endothelium-independent vasoconstriction in thoracic aorta and pulmonary artery of spontaneously hypertensive rats: role of calcium channels and stores. PLoS One 12(1):e0169205PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Matsubara M, Chiba H, Maruoka S, Katayose S (2002) Elevated serum leptin concentrations in women with hyperuricemia. J Atheroscler Thromb 9:28–34PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Fruehwald-Schultes B, Peters A, Kern W, Beyer J, Pfutzner A (1999) Serum leptin is associated with serum uric acid concentrations in humans. Metabolism 48:677–680PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Bedir A, Topbas M, Tanyeri F, Alvur M, Arik N (2003) Leptin might be a regulator of serum uric acid concentrations in humans. Jpn Heart J 44:527–536PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Samara A, Herbeth B, Aubert R, Berrahmoune H, Fumeron F, Siest G, Visvikis-Siest S (2010) Sex-dependent associations of leptin with metabolic syndrome-related variables: the Stanislas study. Obesity (Silver Spring) 18(1):196–201CrossRefGoogle Scholar
  27. 27.
    Bo S, Gambino R, Durazzo M et al (2008) Associations between serum uric acid and adipokines, markers of inflammation, and endothelial dysfunction. J Endocrinol Invest 31(6):499–504PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    D’Elia L, De Palma D, Rossi G, Strazzullo V, Russo O, Iacone R, Fazio V, Strazzullo P, Galletti F (2014) Not smoking is associated with lower risk of hypertension: results of the Olivetti Heart Study. Eur J Public Health 24(2):226–230PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    D’Elia L, Manfredi M, Sabino P, Strazzullo P, Galletti F (2016) The Olivetti Heart Study: predictive value of a new adiposity index on risk of hypertension, blood pressure, and subclinical organ damage. Nutr Metab Cardiovasc Dis 26(7):630–636PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I (2018) 2018 ESC/ESH guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens 36(10):1953–2041PubMedCrossRefGoogle Scholar
  31. 31.
    Iacone R, Russo O, Russo P, Venezia A, Varriale V, Gerardi MC, Strazzullo P (2002) Plasma leptin measurements in epidemiological investigation: comparison of two commonly used assays and estimate of regression dilution bias. Nutr Metab Cardiovasc Dis 12(2):71–79PubMedGoogle Scholar
  32. 32.
    Strazzullo P, Barba G, Cappuccio FP, Siani A, Trevisan M, Farinaro E, Pagano E, Barbato A, Iacone R, Galletti F (2001) Altered renal sodium handling in men with abdominal adiposity: a link to hypertension. J Hypertens 19(12):2157–2164PubMedCrossRefGoogle Scholar
  33. 33.
    Johnson RJ, Bakris GL, Borghi C, Chonchol MB, Feldman D, Lanaspa MA, Merriman TR, Moe OW, Mount DB, Sanchez Lozada LG, Stahl E, Weiner DE, Chertow GM (2018) Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the National Kidney Foundation. Am J Kidney Dis 71(6):851–865PubMedCrossRefGoogle Scholar
  34. 34.
    Desideri G, Virdis A, Casiglia E, Borghi C, Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension (2018) Exploration into uric and cardiovascular disease: Uric Acid Right for heArt Health [URRAH] Project, a study protocol for a retrospective observational study. High Blood Press Cardiovasc Prev 25(2):197–202PubMedCrossRefGoogle Scholar
  35. 35.
    Cicero AFG, Fogacci F, Giovannini M, Grandi E, Rosticci M, D’Addato S, Borghi C (2018) Serum uric acid predicts incident metabolic syndrome in the elderly in an analysis of the Brisighella Heart Study. Sci Rep 8(1):11529PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yadav D, Lee ES, Kim HM, Choi E, Lee EY, Lim JS, Ahn SV, Koh SB, Chung CH (2015) Prospective study of serum uric acid levels and incident metabolic syndrome in a Korean rural cohort. Atherosclerosis 241(1):271–277PubMedCrossRefGoogle Scholar
  37. 37.
    Jackson EK, Li P (1997) Human leptin has natriuretic activity in the rat. Am J Physio 1272:F333–F338Google Scholar
  38. 38.
    Quinones Galvan A, Natali A, Baldi S et al (1995) Effect of insulin on uric acid excretion in humans. Am J Physiol 268:E1–E5PubMedGoogle Scholar
  39. 39.
    D’Elia L, Cappuccio FP, Iacone R, Russo O, Galletti F, Strazzullo P (2017) Altered renal sodium handling and risk of incident hypertension: results of the Olivetti Heart Study. PLoS One 12(2):e0171973PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M (1993) Uric acid metabolism and tubular sodium handling. Results from a population-based study. JAMA 270(3):354–359PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Martin SS, Qasim A, Reilly MP (2008) Leptin resistance a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 52:1201–1210PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Singh P, Hoffmann M, Wolk R, Shamsuzzaman AS, Somers VK (2007) Leptin induces C-reactive protein expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol 27:e302–e307PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Santos-Alvarez J, Goberna R, Sanchez-Margalet V (1999) Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol 194:6–11PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Grunfeld C, Zhao C, Fuller J et al (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 97:2152–2157PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Katsiki N, Mikhailidis DP, Banach M (2018) Leptin, cardiovascular diseases and type 2 diabetes mellitus. Acta Pharmacol Sin 39(7):1176e88CrossRefGoogle Scholar
  46. 46.
    Li S, Li H, Wang R, Zhang JP (2017) The effect of sitagliptin on obese patients with insulin treatment-induced diabetes mellitus. Eur Rev Med Pharmacol Sci 21:3490–3495PubMedPubMedCentralGoogle Scholar
  47. 47.
    Negrotto L, Farez MF, Correale J (2016) Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis. JAMA Neurol 73:520e8CrossRefGoogle Scholar
  48. 48.
    Vickers SP, Cheetham SC, Headland KR et al (2014) Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet. Diabetes Metab Syndr Obes 7:265–275PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Li N, Zhao Y, Yue Y, Chen L, Yao Z, Niu W (2016) Liraglutide ameliorates palmitate-induced endothelial dysfunction through activating AMPK and reversing leptin resistance. Biochem Biophys Res Commun 478:46–52PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Singh P, Zhang Y, Sharma P et al (2018) Statins decrease leptin expression in human white adipocytes. Physiol Rep.  https://doi.org/10.14814/phy2.13566 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ueno S, Hamada T, Taniguchi S et al (2016) Effect of antihypertensive drugs on uric acid metabolism in patients with hypertension: cross-sectional cohort study. Drug Res [Stuttg] 66(12):628–632CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.Department of Clinical Medicine and Surgery, ESH Excellence Center of Hypertension“Federico II” University of Naples Medical SchoolNaplesItaly
  2. 2.World Health Organization Collaborating Centre for NutritionUniversity of WarwickCoventryUK
  3. 3.Division of Health Sciences, Warwick Medical SchoolUniversity of WarwickCoventryUK

Personalised recommendations