Current Diabetes Reports

, Volume 5, Issue 4, pp 260–266 | Cite as

Endothelial effects of leptin: Implications in health and diseases

  • Kamal Rahmouni
  • William G. Haynes
Article

Abstract

Leptin is an adipocyte-derived hormone that plays a major role in the regulation of energy homeostasis through its action in the central nervous system. Leptin also acts on several peripheral tissues, including the vascular endothelium. The leptin receptor has been identified in endothelial cells. Leptin action on the endothelium modulates several physiologic processes, with potential implications in pathophysiologic diseases associated with obesity. Leptin stimulation of angiogenesis has attracted attention because of its potential involvement in retinopathy and atherosclerosis. Leptin activation of endothelial oxidative stress also has implications in atherosclerosis and inflammation. However, data on the impact of the endothelial effect of leptin on arterial pressure are contrasting. Although some investigators have shown that leptin action on the endothelial nitric oxide system tends to decrease arterial pressure, others have shown no contribution from the endothelial effect of leptin to the control of arterial pressure. Further characterization of the endothelial effects of leptin will, it is hoped, help in the understanding of the different pathophysiologic diseases associated with obesity.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 1998, 395:763–770.PubMedCrossRefGoogle Scholar
  2. 2.
    Banks WA, Kastin AJ, Huang W, et al.: Leptin enters the brain by a saturable system independent of insulin. Peptides 1996, 17:305–311.PubMedCrossRefGoogle Scholar
  3. 3.
    Farooqi IS, O’Rahilly S: Monogenic obesity in humans. Annu Rev Med 2005, 56:443–458.PubMedCrossRefGoogle Scholar
  4. 4.
    Haynes WG, Morgan DA, Walsh SA, et al.: Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997, 100:270–278.PubMedGoogle Scholar
  5. 5.
    Dunbar JC, Hu Y, Lu H: Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 1997, 46:2040–2043.PubMedCrossRefGoogle Scholar
  6. 6.
    Sinha MK, Opentanova I, Ohannesian JP, et al.: Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest 1996, 98:1277–1282.PubMedGoogle Scholar
  7. 7.
    Considine RV, Sinha MK, Heiman ML, et al.: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996, 334:292–295.PubMedCrossRefGoogle Scholar
  8. 8.
    Rahmouni K, Correia ML, Haynes WG, Mark AL: Obesityassociated hypertension: new insights into mechanisms. Hypertension 2005, 45:9–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Tartaglia LA: The leptin receptor. J Biol Chem 1997, 272:6093–6096.PubMedGoogle Scholar
  10. 10.
    Chua SCJr, Chung WK, Wu-Peng XS, et al.: Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996, 271:994–996.PubMedCrossRefGoogle Scholar
  11. 11.
    Phillips MS, Liu Q, Hammond HA, et al.: Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996, 13:18–19.PubMedCrossRefGoogle Scholar
  12. 12.
    Sierra-Honigmann MR, Nath AK, Murakami C, et al. Biological action of leptin as an angiogenic factor. Science 1998, 28:683–1686.Google Scholar
  13. 13.
    Bouloumie A, Drexler HC, Lafontan M, Busse R: Leptin, the product of Ob gene, promotes angiogenesis. Circ Res 1998, 83:1059–1066.PubMedGoogle Scholar
  14. 14.
    KnudsonJD, Dincer UD, Zhang C, et al.: Leptin receptors are expressed in coronary arteries and hyperleptinemia causes significant coronary endothelial dysfunction. Am J Physiol Heart Circ Physiol 2005, 289:H48-H56. Shows that doses of leptin that caused coronary vascular dilation ex vivo have little, if any, effect on coronary blood flow in open-chest, anesthetized dogs.PubMedCrossRefGoogle Scholar
  15. 15.
    Golden PL, Maccagnan TJ, Pardridge WM: Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest 1997, 99:14–18.PubMedGoogle Scholar
  16. 16.
    Niswender KD, Gallis B, Blevins JE, et al.: Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin. J Histochem Cytochem 2003, 51:275–283.PubMedGoogle Scholar
  17. 17.
    Goetze S, Bungenstock A, Czupalla C, et al.: Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. Hypertension 2002, 40:748–754.PubMedCrossRefGoogle Scholar
  18. 18.
    Vecchione C, Maffei A, Colella S, et al.: Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway. Diabetes 2002, 51:168–173.PubMedCrossRefGoogle Scholar
  19. 19.
    Bouloumie A, Marumo T, Lafontan M, Busse R: Leptin induces oxidative stress in human endothelial cells. FASEB J 1999, 13:1231–1238.PubMedGoogle Scholar
  20. 20.
    Yamagishi SI, Edelstein D, Du XL, et al.: Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 2001, 276:25096–25100.PubMedCrossRefGoogle Scholar
  21. 21.
    Jin X, Fukuda N, Su J, et al.: Effects of leptin on endothelial function with OB-Rb gene transfer in Zucker fatty rats. Atherosclerosis 2003, 169:225–233.PubMedCrossRefGoogle Scholar
  22. 22.
    Rupnick MA, Panigrahy D, Zhang CY, et al.: Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A 2002, 99:10730–10735.PubMedCrossRefGoogle Scholar
  23. 23.
    Cao R, Brakenhielm E, Wahlestedt C, et al.: Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A 2001, 98:6390–6395.PubMedCrossRefGoogle Scholar
  24. 24.
    Suganami E, Takagi H, Ohashi H, et al.: Leptin stimulates ischemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes 2004, 53:2443–2448.PubMedCrossRefGoogle Scholar
  25. 25.
    Uckaya G, Ozata M, Sonmez A, et al.: Is leptin associated with hypertensive retinopathy? J Clin Endocrinol Metab 2000, 85:683–687.PubMedCrossRefGoogle Scholar
  26. 26.
    Park HY, Kwon HM, Lim HJ, et al.: Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med 2001, 33:95–102.PubMedGoogle Scholar
  27. 27.
    Newby AC: Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005, 85:1–31.PubMedCrossRefGoogle Scholar
  28. 28.
    SchaferK, Halle M, Goeschen C, et al.: Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 2004, 24:112–117. Demonstrates the involvement of leptin in atherosclerotic lesion formation, because leptin appears to enhance neointimal and medial thickening of the vascular wall after induction of carotid artery injury in mice.PubMedCrossRefGoogle Scholar
  29. 29.
    Frank S, Stallmeyer B, Kampfer H, et al.: Leptin enhances wound re-epithelialization and constitutes a direct function of leptin in skin repair. J Clin Invest 2000, 106:501–509.PubMedGoogle Scholar
  30. 30.
    Ring BD, Scully S, Davis CR, et al.: Systemically and topically administered leptin both accelerate wound healing in diabetic ob/ob mice. Endocrinology 2000, 141:446–449.PubMedCrossRefGoogle Scholar
  31. 31.
    Wolf G, Hamann A, Han DC, et al.: Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis. Kidney Int 1999, 56:860–872.PubMedCrossRefGoogle Scholar
  32. 32.
    Beltowski J, Wojcicka G, Jamroz A: Leptin decreases plasma paraoxonase 1 (PON1) activity and induces oxidative stress: the possible novel mechanism for proatherogenic effect of chronic hyperleptinemia. Atherosclerosis 2003, 170:21–29.PubMedCrossRefGoogle Scholar
  33. 33.
    Nakazono K, Watanabe N, Matsuno K, et al.: Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci U S A 1991, 88:10045–10048.PubMedCrossRefGoogle Scholar
  34. 34.
    BeltowskiJ, Wojcicka G, Marciniak A, Jamroz A: Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension. Life Sci 2004, 74:2987–3000. Shows that leptin increases systemic and intrarenal oxidative stress associated with a decrease in the amount of bioactive NO, possibly due to its degradation by reactive oxygen species.PubMedCrossRefGoogle Scholar
  35. 35.
    Contreras F, Rivera M, Vasquez J, et al.: Endothelial dysfunction in arterial hypertension. J Hum Hypertens 2000, 14:S20-S25.PubMedCrossRefGoogle Scholar
  36. 36.
    Lembo G, Vecchione C, Fratta L, et al.: Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes 2000, 49:293–297.PubMedCrossRefGoogle Scholar
  37. 37.
    Kimura K, Tsuda K, Baba A, et al.: Involvement of nitric oxide in endothelium-dependent arterial relaxation by leptin. Biochem Biophys Res Commun 2000, 273:745–749.PubMedCrossRefGoogle Scholar
  38. 38.
    Winters B, Mo Z, Brooks-Asplund E: Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice. J Appl Physiol 2000, 89:2382–2390.PubMedGoogle Scholar
  39. 39.
    Pannirselvam M, Verma S, Anderson TJ, Triggle CR: Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db -/-) mice: role of decreased tetrahydrobiopterin bioavailability. Br J Pharmacol 2002, 136:255–263.PubMedCrossRefGoogle Scholar
  40. 40.
    Nakagawa K, Higashi Y, Sasaki S, et al.: Leptin causes vasodilation in humans. Hypertens Res 2002, 25:161–165. The first study to assess the vascular effect of leptin in humans. The results show that leptin causes vasodilation through an NO-independent pathway.PubMedCrossRefGoogle Scholar
  41. 41.
    Matsuda K, Teragawa H, Fukuda Y, et al.: Leptin causes nitric-oxide independent coronary artery vasodilation in humans. Hypertens Res 2003, 26:147–152.PubMedCrossRefGoogle Scholar
  42. 42.
    Fruhbeck G: Pivotal role of nitric oxide in the control of blood pressure after leptin administration. Diabetes 1999, 48:903–908.PubMedCrossRefGoogle Scholar
  43. 43.
    Gardiner SM, Kemp PA, March JE, Bennett T: Regional haemodynamic effects of recombinant murine or human leptin in conscious rats. Br J Pharmacol 1999, 130:805–810.CrossRefGoogle Scholar
  44. 44.
    MitchellJL, Morgan DA, Correia ML, et al.: Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation? Hypertension 2001, 38:1081–1086. Demonstrates the lack of vasorelaxation effect of leptin in vivo because leptin infusion did not change arterial pressure or blood flow measured from the mesenteric, lower aortic, and renal arteries.PubMedGoogle Scholar
  45. 45.
    Jalali A, Morgan DA, Sivitz WI, et al.: Does leptin cause functional peripheral sympatholysis? Am J Hypertens 2001, 14:615–618.PubMedCrossRefGoogle Scholar
  46. 46.
    Kuo JJ, Jones OB, Hall JE: Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 2001, 37:670–676.PubMedGoogle Scholar
  47. 47.
    Zanetti M, Barazzoni R, Vadori M, et al.: Lack of direct effect of moderate hyperleptinemia to improve endothelial function in lean rat aorta: role of calorie restriction. Atherosclerosis 2004, 175:253–259.PubMedCrossRefGoogle Scholar
  48. 48.
    Aizawa-Abe M, Ogawa Y, Masuzaki H, et al.: Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 2000, 105:1243–1252.PubMedCrossRefGoogle Scholar
  49. 49.
    Mark AL, Shaffer RA, Correia ML, et al.: Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens 1999, 17:1949–1953.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2005

Authors and Affiliations

  • Kamal Rahmouni
  • William G. Haynes
    • 1
  1. 1.Department of Internal Medicine and General Clinical Research CenterUniversity of Iowa College of MedicineIowa CityUSA

Personalised recommendations