Current Obesity Reports

, Volume 5, Issue 4, pp 397–404 | Cite as

Leptin as a Mediator of Obesity-Induced Hypertension

  • Balyssa B. Bell
  • Kamal RahmouniEmail author
Metabolism (J Proietto, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Metabolism


Hypertension and associated cardiovascular diseases represent the most common health complication of obesity and the leading cause of morbidity and mortality in overweight and obese patients. Emerging evidence suggests a critical role for the central nervous system particularly the brain action of the adipocyte-derived hormone leptin in linking obesity and hypertension. The preserved ability of leptin to cause cardiovascular sympathetic nerve activation despite the resistance to the metabolic actions of the hormone appears essential in this pathological process. This review describes the evidence supporting the neurogenic bases for obesity-associated hypertension with a particular focus on the neuronal and molecular signaling pathways underlying leptin’s effects on sympathetic nerve activity and blood pressure.


Blood pressure Adiposity Sympathetic nervous system Leptin 


Compliance with Ethical Standards

Conflict of Interest

Balyssa B. Bell and Kamal Rahmouni declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Sources of Funding

The authors’ research is supported by the US National Institutes of Health (HL084207), the American Heart Association (Award #14EIA18860041), the University of Iowa Fraternal Order of Eagles Diabetes Research Center, and the University of Iowa Center for Hypertension Research.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Garrison RJ et al. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med. 1987;16(2):235–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Holecki M, Dulawa J, Chudek J. Resistant hypertension in visceral obesity. Eur J Intern Med. 2012;23(7):643–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Fidan-Yaylali G et al. The association between central adiposity and autonomic dysfunction in obesity. Med Princ Pract. 2016;25:442.CrossRefPubMedGoogle Scholar
  4. 4.
    Hall JE et al. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res. 2015;116(6):991–1006.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Esler M et al. Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension. 2006;48(5):787–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Neter JE et al. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42(5):878–84.CrossRefPubMedGoogle Scholar
  7. 7.
    Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol. 2009;53(21):1925–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Straznicky NE et al. Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome. J Clin Endocrinol Metab. 2005;90(11):5998–6005.CrossRefPubMedGoogle Scholar
  9. 9.
    Fortmann SP, Haskell WL, Wood PD. Effects of weight loss on clinic and ambulatory blood pressure in normotensive men. Am J Cardiol. 1988;62(1):89–93.CrossRefPubMedGoogle Scholar
  10. 10.
    Williams IL et al. Endothelial function and weight loss in obese humans. Obes Surg. 2005;15(7):1055–60.CrossRefPubMedGoogle Scholar
  11. 11.••
    Skinner AC et al. Cardiometabolic risks and severity of obesity in children and young adults. N Engl J Med. 2015;373(14):1307–17. The work reported in this paper demonstrate the close link between obesity, hypertension and other cardiovascular risks in children.CrossRefPubMedGoogle Scholar
  12. 12.
    Twig G et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N Engl J Med. 2016;374(25):2430–40.CrossRefPubMedGoogle Scholar
  13. 13.
    Hubert HB et al. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983;67(5):968–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Kurajoh M et al. Plasma leptin level is associated with cardiac autonomic dysfunction in patients with type 2 diabetes: HSCAA study. Cardiovasc Diabetol. 2015;14:117.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Selvaraj S et al. Association of central adiposity with adverse cardiac mechanics: findings from the hypertension genetic epidemiology network study. Circ Cardiovasc Imaging. 2016;9(6):e004396.CrossRefPubMedGoogle Scholar
  16. 16.
    Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116(6):976–90.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Alvarez GE et al. Sympathetic neural activation in visceral obesity. Circulation. 2002;106(20):2533–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Lambert E et al. Differing pattern of sympathoexcitation in normal-weight and obesity-related hypertension. Hypertension. 2007;50(5):862–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Grassi G et al. Sympathetic activation in obese normotensive subjects. Hypertension. 1995;25(4 Pt 1):560–3.CrossRefPubMedGoogle Scholar
  20. 20.
    Cooper JN et al. Associations between arterial stiffness and platelet activation in normotensive overweight and obese young adults. Clin Exp Hypertens. 2014;36(3):115–22.CrossRefPubMedGoogle Scholar
  21. 21.
    Robinson MR et al. Uncomplicated obesity is associated with abnormal aortic function assessed by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2008;10:10.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Masuo K et al. Differences in mechanisms between weight loss-sensitive and -resistant blood pressure reduction in obese subjects. Hypertens Res. 2001;24(4):371–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Muntzel MS et al. Cafeteria diet increases fat mass and chronically elevates lumbar sympathetic nerve activity in rats. Hypertension. 2012;60(6):1498–502.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Armitage JA et al. Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet. Hypertension. 2012;60(1):163–71.CrossRefPubMedGoogle Scholar
  25. 25.
    Henegar JR et al. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am J Hypertens. 2014;27(10):1285–92.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.•
    Bhatt DL et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–401. This study reported the finding from SIMPLICITY-3 trials showing that in patients with resistant hypertension, the effect of renal denervation is similar to sham intervention.CrossRefPubMedGoogle Scholar
  27. 27.
    Shibao C et al. Autonomic contribution to blood pressure and metabolism in obesity. Hypertension. 2007;49(1):27–33.CrossRefPubMedGoogle Scholar
  28. 28.•
    Simonds SE et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159(6):1404–16. This paper confirmed the critical role for leptin in mediating obesity-associated hypertension both in humans and animal models.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Aizawa-Abe M et al. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest. 2000;105(9):1243–52.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mark AL. Selective leptin resistance revisited. Am J Physiol Regul Integr Comp Physiol. 2013;305(6):R566–81.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lim K, Burke SL, Head GA. Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits. Hypertension. 2013;61(3):628–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Mark AL et al. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens. 1999;17(12 Pt 2):1949–53.CrossRefPubMedGoogle Scholar
  33. 33.
    Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999;84(10):3686–95.CrossRefPubMedGoogle Scholar
  34. 34.
    Minocci A et al. Leptin plasma concentrations are dependent on body fat distribution in obese patients. Int J Obes Relat Metab Disord. 2000;24(9):1139–44.CrossRefPubMedGoogle Scholar
  35. 35.
    Van Harmelen V et al. Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes. 1998;47(6):913–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Cnop M et al. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments. Diabetes. 2002;51(4):1005–15.CrossRefPubMedGoogle Scholar
  37. 37.
    Cohen P et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest. 2001;108(8):1113–21.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    van de Wall E et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology. 2008;149(4):1773–85.CrossRefPubMedGoogle Scholar
  39. 39.
    Rahmouni K. Cardiovascular regulation by the arcuate nucleus of the hypothalamus: neurocircuitry and signaling systems. Hypertension. 2016;67(6):1064–71.CrossRefPubMedGoogle Scholar
  40. 40.
    Harlan SM et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res. 2011;108(7):808–12.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Rahmouni K, Morgan DA. Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension. 2007;49(3):647–52.CrossRefPubMedGoogle Scholar
  42. 42.
    do Carmo JM et al. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension. 2011;57(5):918–26.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.•
    Lim K et al. Origin of aberrant blood pressure and sympathetic regulation in diet-induced obesity. Hypertension. 2016;68(2):491–500. This paper investigates the role of various hypothalamic regions in mediating leptin’s contribution to obesity-associated hypertension.CrossRefPubMedGoogle Scholar
  44. 44.
    Marsh AJ et al. Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension. 2003;42(4):488–93.CrossRefPubMedGoogle Scholar
  45. 45.
    Shih CD, Au LC, Chan JY. Differential role of leptin receptors at the hypothalamic paraventricular nucleus in tonic regulation of food intake and cardiovascular functions. J Biomed Sci. 2003;10(4):367–78.CrossRefPubMedGoogle Scholar
  46. 46.
    Mark AL et al. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension. 2009;53(2):375–80.CrossRefPubMedGoogle Scholar
  47. 47.
    Smith PM, Ferguson AV. Cardiovascular actions of leptin in the subfornical organ are abolished by diet-induced obesity. J Neuroendocrinol. 2012;24(3):504–10.CrossRefPubMedGoogle Scholar
  48. 48.
    Young CN et al. The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects. Hypertension. 2013;61(3):737–44.CrossRefPubMedGoogle Scholar
  49. 49.
    Farooqi IS et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–95.CrossRefPubMedGoogle Scholar
  50. 50.
    Greenfield JR et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360(1):44–52.CrossRefPubMedGoogle Scholar
  51. 51.
    Tallam LS et al. Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension. 2005;46(2):326–32.CrossRefPubMedGoogle Scholar
  52. 52.
    Rahmouni K et al. Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin. J Neurosci. 2003;23(14):5998–6004.PubMedGoogle Scholar
  53. 53.
    Bates SH et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421(6925):856–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Gao Q et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci U S A. 2004;101(13):4661–6.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Harlan SM et al. Cardiovascular and sympathetic effects of disrupting tyrosine 985 of the leptin receptor. Hypertension. 2011;57(3):627–32.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.•
    Dubinion JH et al. Role of proopiomelanocortin neuron STAT3 in regulating arterial pressure and mediating the chronic effects of leptin. Hypertension. 2013;61(5):1066–74. This paper demonstrates a critical role for STAT3 signaling in POMC neurons in mediating both the metabolic and cardiovascular sympathetic effects of leptin.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145(11):4880–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Patterson CM et al. Leptin action via LepR-b Tyr1077 contributes to the control of energy balance and female reproduction. Mol Metab. 2012;1(1–2):61–9.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Cota D et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312(5775):927–30.CrossRefPubMedGoogle Scholar
  60. 60.
    Mori H et al. Critical role for hypothalamic mTOR activity in energy balance. Cell Metab. 2009;9(4):362–74.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.••
    Harlan SM et al. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. 2013;17(4):599–606. This is the first report to implicate hypothalamic mTORC1 in sympathetic and cardiovascular regulation.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Harlan SM, Rahmouni K. PI3K signaling: a key pathway in the control of sympathetic traffic and arterial pressure by leptin. Mol Metab. 2013;2(2):69–73.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Rahmouni K et al. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes. 2009;58(3):536–42.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Do Carmo JM et al. Shp2 signaling in POMC neurons is important for leptin’s actions on blood pressure, energy balance, and glucose regulation. Am J Physiol Regul Integr Comp Physiol. 2014;307(12):R1438–47.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    do Carmo JM et al. Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin. Int J Obes (Lond). 2014;38(6):775–83.CrossRefGoogle Scholar
  66. 66.
    Bjorbaek C et al. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell. 1998;1(4):619–25.CrossRefPubMedGoogle Scholar
  67. 67.
    Pedroso JA et al. Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity. Mol Metab. 2014;3(6):608–18.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Bence KK et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006;12(8):917–24.CrossRefPubMedGoogle Scholar
  69. 69.
    Belin de Chantemele EJ et al. Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. Circulation. 2009;120(9):753–63.CrossRefPubMedGoogle Scholar
  70. 70.
    Bruder-Nascimento T et al. Deletion of protein tyrosine phosphatase 1b in proopiomelanocortin neurons reduces neurogenic control of blood pressure and protects mice from leptin- and sympatho-mediated hypertension. Pharmacol Res. 2015;102:235–44.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Iowa Carver College of MedicineIowa CityUSA
  2. 2.Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityUSA

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