Leptin and its cardiovascular effects: Focus on angiogenesis



1 Department of Physiology and Pharmacology, Birjand University of Medical Sciences, Birjand, Iran

2 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Leptin is an endocrine hormone synthesized by adipocytes. It plays a key role in the energy homeostasis in central and peripheral tissues and has additional roles are attributed to it, such as the regulation of reproduction, immune function, bone homeostasis, and angiogenesis. The plasma concentration of leptin significantly increases in obese individuals. In the present review, we give an introduction concerning leptin, its receptors, signaling pathways, and its effect on cardiovascular system, especially on angiogenesis.


Mattu HS, Randeva HS. Role of adipokines in cardiovascular disease. J Endocrinol 2013;216:T17-36.  Back to cited text no. 1
Liu J, Butler KR, Buxbaum SG, Sung JH, Campbell BW, Taylor HA. Leptinemia and its association with stroke and coronary heart disease in the Jackson Heart Study. Clin Endocrinol (Oxf) 2010;72:32-7.  Back to cited text no. 2
Hou N, Luo JD. Leptin and cardiovascular diseases. Clin Exp Pharmacol Physiol 2011;38:905-13.  Back to cited text no. 3
Wauman J, Tavernier J. Leptin receptor signaling: Pathways to leptin resistance. Front Biosci (Landmark Ed) 2011;16:2771-93.  Back to cited text no. 4
Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632-5.  Back to cited text no. 5
Tartaglia LA. The leptin receptor. J Biol Chem 1997;272:6093-6.  Back to cited text no. 6
Yang R, Barouch LA. Leptin signaling and obesity: Cardiovascular consequences. Circ Res 2007;101:545-59.  Back to cited text no. 7
Myers MG Jr. Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 2004;59:287-304.  Back to cited text no. 8
Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, et al.; Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: A statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005;23:7-17.  Back to cited text no. 9
Tigno XT, Selaru IK, Angeloni SV, Hansen BC. Is microvascular flow rate related to ghrelin, leptin and adiponectin levels? Clin Hemorheol Microcirc 2003;29:409-16.  Back to cited text no. 10
Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult Microvasculature. Am J Physiol Heart Circ Physiol 2006;290:H560-76.  Back to cited text no. 11
Petzel M. Action of leptin on bone and its relationship to menopause. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2007;151:195-9.  Back to cited text no. 12
Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540-3.  Back to cited text no. 13
Ahrén B, Larsson H, Wilhelmsson C, Näsman B, Olsson T. Regulation of circulating leptin in humans. Endocrine 1997;7:1-8.  Back to cited text no. 14
Yildiz BO, Haznedaroglu IC. Rethinking leptin and insulin action: Therapeutic Opportunities for diabetes. Int J Biochem Cell Biol 2006;38:820-30.  Back to cited text no. 15
Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsivness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002;110:1093-103.  Back to cited text no. 16
Ahrén B, Havel PJ. Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). Am J Physiol 1999;277:R959-66.  Back to cited text no. 17
Lupi R, Marchetti P, Maffei M, Del Guerra S, Benzi L, Marselli L, et al. Effects of acute or prolonged exposure to human leptin on isolated human islet function. Biochem Biophys Res Commun 1999;256:637-41.  Back to cited text no. 18
Karlsson E, Stridsberg M, Sandler S. Leptin regulation of islet amyloid polypeptide Secretion from mouse pancreatic islets. Biochem Pharmacol 1998;56:1339-46.  Back to cited text no. 19
Seufert J, Kieffer TJ, Habener JF. Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptindeficient ob/ob mice. Proc Natl Acad Sci U S A 1999;96:674-9.  Back to cited text no. 20
Michalakis K, Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG. The complex interaction between obesity, metabolic syndrome and reproductive axis: A narrative review. Metabolism 2013;62:457-78.  Back to cited text no. 21
Donato J Jr, Cravo RM, Frazão R, Elias CF. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology 2011;93:9-18.  Back to cited text no. 22
Baldelli R, Dieguez C, Casanueva FF. The role of leptin in reproduction: Experimental and clinical aspects. Ann Med 2002;34:5-18.  Back to cited text no. 23
Dubinion JH, da Silva AA, Hall JE. Chronic blood pressure and appetite responses to central leptin infusion in rats fed a high fat diet. J Hypertens 2011;29:758-62.  Back to cited text no. 24
Vecchione C, Maffei A, Colella S, Aretini A, Poulet R, Frati G, et al. Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway. Diabetes 2002;51:168-73.  Back to cited text no. 25
Momin AU, Melikian N, Shah AM, Grieve DJ, Wheatcroft SB, John L, et al. Leptin is an endothelial-independent vasodilator in humans with coronary artery disease: Evidence for tissue specificity of leptin resistance. Eur Heart J 2006;27:2294-9.  Back to cited text no. 26
Wolk R, Somers VK. Leptin and vascular function: Friend or foe? Eur Heart J 2006;27:2263-5.  Back to cited text no. 27
Palanivel R, Eguchi M, Shuralyova I, Coe I, Sweeney G. Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytes. Metabolism 2006;55:1067-75.  Back to cited text no. 28
McGaffin KR, Zou B, McTiernan CF, O'Donnell CP. Leptin attenuates cardiac apoptosis after chronic ischaemic injury. Cardiovasc Res 2009;83:313-24.  Back to cited text no. 29
Lieb W, Sullivan LM, Aragam J, Harris TB, Roubenoff R, Benjamin EJ, et al. Relation of serum leptin with cardiac mass and left atrial dimension in individuals >70 years of age. Am J Cardiol 2009;104:602-5.  Back to cited text no. 30
Smith CC, Mocanu MM, Davidson SM, Wynne AM, Simpkin JC, Yellon DM. Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. Br J Pharmacol 2006;149:5-13.  Back to cited text no. 31
Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. Cardiovasc Res 2004;61:372-85.  Back to cited text no. 32
Wannamethee SG, Tchernova J, Whincup P, Lowe GD, Kelly A, Rumley A, et al. Plasma leptin: Associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis 2007;191:418-26.  Back to cited text no. 33
Tahergorabi Z, Khazaei M. Obesity and angiogenesis. J Isfahan Med School 2012;29:1-16.  Back to cited text no. 34
Tahergorabi Z, Khazaei M. The relationship between inflammatory markers, angiogenesis, and obesity. ARYA Atheroscler 2013;9:247-53.  Back to cited text no. 35
McMahon M, Skaggs BJ, Sahakian L, Grossman J, FitzGerald J, Ragavendra N, et al. High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis 2011;70:1619-24.  Back to cited text no. 36
Rodríguez A, Fortuño A, Gómez-Ambrosi J, Zalba G, Díez J, Frühbeck G. The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism. Endocrinology 2007;148:324-31.  Back to cited text no. 37
Beltowski J, Wójcicka 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;170:21-9.  Back to cited text no. 38
Beltowski J. Role of leptin in blood pressure regulation and arterial hypertension. J Hypertens 2006;24:789-801.  Back to cited text no. 39
Hare JM, Stamler JS. NO/redox disequilibrium in the failing heart and cardiovascular system. J Clin Invest 2005;115:509-17.  Back to cited text no. 40
Tahergorabi Z, Khazaei M. Changes of serum angiogenic biomarkers and their correlations with serum leptin concentration. Bratisl Lek Listy 2014;115:330-3.  Back to cited text no. 41
Reilly MP, Iqbal N, Schutta M, Wolfe ML, Scally M, Localio AR, et al. Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. J Clin Endocrinol Metab 2004;89:3872-8.  Back to cited text no. 42
Bodary PF, Westrick RJ, Wickenheiser KJ, Shen Y, Eitzman DT. Effect of leptin on arterial thrombosis following vascular injury in mice. JAMA 2002;287:1706-9.  Back to cited text no. 43
Rajapurohitam V, Javadov S, Purdham DM, Kirshenbaum LA, Karmazyn M. An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. J Mol Cell Cardiol 2006;41:265-74.  Back to cited text no. 44
Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, et al. Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 2004;110:1269-75.  Back to cited text no. 45
Zeidan A, Hunter JC, Javadov S, Karmazyn M. mTOR mediates RhoA-dependent leptin-induced cardiomyocyte hypertrophy. Mol Cell Biochem 2011;352:99-108.  Back to cited text no. 46
Salehi E, Amjadi F, Khazaei M. Angiogenesis in Health and Disease: Role of Vascular Endothelial Growth Factor (VEGF). J Isfahan Med School 2011;29:1-15.  Back to cited text no. 47
Salehi E, Khazaei M, Rashidi B, Javanmard SH. Effect of rosiglitazone on coronary angiogenesis in diabetic and control rats. J Isfahan Med School 2011;29:1-8.  Back to cited text no. 48
Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000;6:389-95.  Back to cited text no. 49
Artwohl M, Roden M, Hölzenbein T, Freudenthaler A, Waldhäusl W, Baumgartner-Parzer SM. Modulation by leptin of proliferation and apoptosis in vascular endothelial cells. Int J Obes Relat Metab Disord 2002;26:577-80.  Back to cited text no. 50
Sierra-Honigmann MR, Nath AK, Murakami C, García-Cardeña G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science 1998;281:1683-6.  Back to cited text no. 51
Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A 2001;98:6390-5.  Back to cited text no. 52
Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, 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.  Back to cited text no. 53
Ribatti D, Nico B, Belloni AS, Vacca A, Roncali L, Nussdorfer GG. Angiogenic activity of leptin in the chick embryo chorioallantoic membrane is in part mediated by endogenous fibroblast growth factor-2. Int J Mol Med 2001;8:265-8.  Back to cited text no. 54
Liapaki I, Anagnostoulis S, Karayiannakis A, Korkolis D, Labropoulou M, Matarasso A, et al. Burn wound angiogenesis is increased by exogenously administered recombinant leptin in rats. Acta Cir Bras 2008;23:118-24.  Back to cited text no. 55
Garonna E, Botham KM, Birdsey GM, Randi AM, Gonzalez-Perez RR, Wheeler-Jones CP. Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PLoS One 2011;6:e18823.  Back to cited text no. 56
Sharma D, Saxena NK, Vertino PM, Anania FA. Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. Endocr Relat Cancer 2006;13:629-40.  Back to cited text no. 57
Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, et al. Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem 2006;281:26320-8.  Back to cited text no. 58
Wang CN, Chang SD, Peng HH, Lee YS, Chang YL, Cheng PJ, et al. Change in amniotic fluid levels of multiple anti-angiogenic proteins before development of preeclampsia and intrauterine growth restriction. J Clin Endocrinol Metab 2010;95:1431-41.  Back to cited text no. 59
Ribeiro AM, Andrade S, Pinho F, Monteiro JD, Costa M, Lopes C, et al. Prostate cancer cell proliferation and angiogenesis in different obese mice models. Int J Exp Pathol 2010;91:374-86.  Back to cited text no. 60
Aronis KN, Diakopoulos KN, Fiorenza CG, Chamberland JP, Mantzoros CS. Leptin administered in physiological or pharmacological doses does not regulate circulating angiogenesis factors in humans. Diabetologia 2011;54:2358-67.  Back to cited text no. 61
Cao Y. Angiogenesis modulate adipogenesis and obesity. J Clin Invest 2007;117:2362-8.  Back to cited text no. 62
Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii M, et al. Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol 2008;74:1610-9.  Back to cited text no. 63
Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84:491-5.  Back to cited text no. 64
Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, et al. Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J Clin Invest 1995;95:2986-8.  Back to cited text no. 65
Zhang Y, Scarpace PJ. The role of leptin in leptin resistance and obesity. Physiol Behav 2006;88:249-56.  Back to cited text no. 66
Wilsey J, Scarpace PJ. Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: Role of leptin in the regulation of hypothalamic long-form leptin receptor expression. J Endocrinol 2004;181:297-306.  Back to cited text no. 67
Martin SS, Qasim A, Reilly MP. Leptin resistance: A possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 2008;52:1201-10.  Back to cited text no. 68
Bjørbaek C, El-Haschimi K, Frantz JD, Flier JS. The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 1999;274:30059-65.  Back to cited text no. 69
Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2002;2:497-503.  Back to cited text no. 70
Emilsson V, Arch JR, de Groot RP, Lister CA, Cawthorne MA. Leptin treatment increases suppressors of cytokine signaling in central and peripheral tissues. FEBS Lett 1999;455:170-4.  Back to cited text no. 71
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001;107:881-91.  Back to cited text no. 72
Narin F, Atabek ME, Karakukcu M, Narin N, Kurtoglu S, Gumus H, et al. The association of plasma homocysteine levels with serum leptin and apolipoprotein B levels in childhood obesity. Ann Saudi Med 2005;25:209-14.  Back to cited text no. 73
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Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab 2007;5:181-94.  Back to cited text no. 74
Münzberg H, Björnholm M, Bates SH, Myers MG Jr. Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci 2005;62:642-52.  Back to cited text no. 75
Tups A, Ellis C, Moar KM, Logie TJ, Adam CL, Mercer JG, et al. Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression. Endocrinology 2004;145:1185-93.  Back to cited text no. 76
Krol E, Tups A, Archer ZA, Ross AW, Moar KM, Bell LM, et al. Altered expression of SOCS3 in the hypothalamic arcuate nucleus during seasonal body mass changes in the field vole, Microtus agrestis. J Neuroendocrinol 2007;19:83-94.  Back to cited text no. 77
Figlewicz DP. Adiposity signals and food reward: Expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 2003;284:R882-92.  Back to cited text no. 78
Kelley AE, Berridge KC. The neuroscience of natural rewards: Relevance to addictive drugs. J Neurosci 2002;22:3306-11.  Back to cited text no. 79
Chen K, Li F, Li J, Cai H, Strom S, Bisello A, et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 2006;12:425-32.  Back to cited text no. 80
Gertler A, Niv-Spector L, Reicher S. Is leptin an important physiological regulator of CRP? Nat Med 2007;13:18-21.  Back to cited text no. 81