Skip to main content

Advertisement

Log in

Interaction between leptin and sympathetic nervous system in hypertension

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Leptin is a protein produced by adipose tissue that acts in the central nervous system (CNS) to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback loop that maintains stable adipose tissue mass. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Leptin also increases sympathetic nerve activity to tissues not usually considered thermogenic, including the kidney, hindlimb, and adrenal gland. Chronic systemic CNS administration of leptin increases arterial pressure and heart rate in conscious animals. However, leptin has additional cardiovascular actions that may act to oppose sympathetically mediated vasoconstriction. These actions include natriuresis, insulin sensitization, endothelium-dependent dilatation, and angiogenesis. Thus, the overall effect of leptin on arterial pressure has been unclear. Recent studies have demonstrated that leptin-deficient ob/ob obese mice have lower arterial pressure than lean controls with normal leptin levels. These studies suggest that leptin contributes physiologically to maintenance of arterial pressure. Leptin expression and plasma leptin concentrations are elevated in obese humans. Abnormalities in the generation or actions of leptin may, therefore, have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Kuczmarski RJ, Flegal KM, Campbell SM, et al.: Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960–1991. JAMA 1994, 272:205–211.

    Article  PubMed  CAS  Google Scholar 

  2. Wood JE, Cash JR: Obesity and hypertension: clinical and experimental observations. Ann Intern Med 1939, 13:81–91.

    Google Scholar 

  3. Kushner RF: Body weight and mortality. Nutr Rev 1993, 51:127–136.

    Article  PubMed  CAS  Google Scholar 

  4. Manson JE, Willett WC, Stampfer MJ, et al.: Body weight and mortality among women. N Engl J Med 1995, 333:677–685.

    Article  PubMed  CAS  Google Scholar 

  5. Stamler RA, Stamler J, Riedlinger WF, et al.: Weight and blood pressure findings in hypertension screening of 1 million Americans. JAMA 1978, 240:1607–1610.

    Article  PubMed  CAS  Google Scholar 

  6. Reisen E, Abel R, Modan M, et al.: Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 1978, 298:1–6.

    Article  Google Scholar 

  7. Hsueh WA, Buchanan TA: Obesity and hypertension. Endocr Hypertens 1994, 23:405–427.

    CAS  Google Scholar 

  8. Anderson EA, Mark AL: The vasodilator action of insulin: implications for the insulin hypothesis of hypertension. Hypertension 1993, 21:136–141.

    PubMed  CAS  Google Scholar 

  9. Kassab S, Kato T, Wilkins FC, et al.: Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension. 1995, 25:893–895.

    PubMed  CAS  Google Scholar 

  10. Zhang Y, Proenca R, Maffei M, et al.: Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372:425–432.

    Article  PubMed  CAS  Google Scholar 

  11. Stephens TW, Basinski M, Bristow PK, et al.: The role of neuropeptide Y in the anti-obesity action of the obese gene product. Nature 1995, 377:530–532.

    Article  PubMed  CAS  Google Scholar 

  12. Schwartz M, Seeley RJ, Campfield LA, et al.: Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996, 98:1101–1106.

    PubMed  CAS  Google Scholar 

  13. Huszar D, Lynch CA, Fairchild-Huntress V, et al.: Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997, 88:131–141. This study offers proof that the melanocortin system acts to control body weight.

    Article  PubMed  CAS  Google Scholar 

  14. Fan W, Boston BA, Kesterson RA, et al.: Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997, 385:165–168.

    Article  PubMed  CAS  Google Scholar 

  15. Arner P. The b3-adrenergic receptor: a cause and cure of obesity. N Engl J Med 1995, 333:382–383.

    Article  PubMed  CAS  Google Scholar 

  16. Fleury C, Neverova M, Collins S, et al.: Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet 1997, 15:269–272. An important study that demonstrated the existence of an uncoupling protein expressed outside of brown adipose tissue. Changes in expression or activity of this gene product may contribute to obesity.

    Article  PubMed  CAS  Google Scholar 

  17. Coleman DL: Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 1973, 9:294–298.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    PubMed  CAS  Google Scholar 

  19. Maffei M, Halaas J, Ravussin E, et al.: Leptin levels in human and rodent: measurement of plasma leptin and Ob RNA in obese and weight-reduced subjects. Nat Med 1995, 1:1155–1161.

    Article  PubMed  CAS  Google Scholar 

  20. Saladin R, De Vos P, Guerre-Millo M, et al.: Transient increase in expression in obese gene expression after food intake or insulin expression. Nature 1995, 377:527–529.

    Article  PubMed  CAS  Google Scholar 

  21. Cusin I, Sainsbury A, Doyle P, et al.: The ob gene and insulin: a relationship leading to clues to the understanding of obesity. Diabetes 1995, 44:1467–1470.

    Article  PubMed  CAS  Google Scholar 

  22. De Vos P, Saladin R, Auwerx J, et al.: Induction of ob gene expression by corticosteroids is accompanied by weight loss and reduced food intake. J Biol Chem 1995, 270:15958–15961.

    Article  PubMed  Google Scholar 

  23. Trayhurn P, Duncan JS, Rayner DV: Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system. Biochemical J 1995, 311:729–733.

    CAS  Google Scholar 

  24. Sivitz WI, Fink BD, Morgan DA, et al.: Sympathetic inhibition, leptin and uncoupling protein subtype expression in normal fasting rats. Am J Physiol 1999, 277:E668-E677.

    PubMed  CAS  Google Scholar 

  25. Caro JF, Kolaczynski JW, Nyce MR, et al.: Decreased cerebrospinal fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996, 348:159–161.

    Article  PubMed  CAS  Google Scholar 

  26. Golden P, 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.

    PubMed  CAS  Google Scholar 

  27. Lee G-H, Proenca R, Montez JM, et al.: Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996, 379:632–635.

    Article  PubMed  CAS  Google Scholar 

  28. Vaisse C, Halaas JL, Horvath CM, et al.: Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice, but not db/db mice. Nature Genet 1996, 14:95–97.

    Article  PubMed  CAS  Google Scholar 

  29. Emilsson V, Liu YL, Cawthorne MA, et al.: Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997, 46:313–316. This was one of the first studies to demonstrate that functional leptin receptors are expressed outside of the CNS and that leptin can have direct peripheral effects to reduce insulin secretion.

    Article  PubMed  CAS  Google Scholar 

  30. Sierra-Honigmann MR, Nath AK, Murakami C, et al.: Biological action of leptin as an angiogenic factor. Science 1998, 281:1683–1686. This elegant study demonstrates that leptin causes growth of new blood vessels in vivo by stimulation of full-length leptin receptors expressed in vascular endothelial cells.

    Article  PubMed  CAS  Google Scholar 

  31. Pelleymounter MA, Cullen MJ, Baker MB, et al.: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995, 269:540–543.

    Article  PubMed  CAS  Google Scholar 

  32. Halaas JL, Gajiwalla KS, Maffei M, et al.: Weight reducing effects of the plasma protein encoded by the obese gene. Science 1995, 269:543–546.

    Article  PubMed  CAS  Google Scholar 

  33. Collins S, Kuhn CM, Petro AE, et al.: Role of leptin in fat regulation. Nature 1996, 380:677.

    Article  PubMed  CAS  Google Scholar 

  34. Haynes WG, Morgan DA, Walsh SA, et al.: Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997, 100:270–278. This study provided the first evidence that leptin increased sympathetic nerve traffic to multiple tissues, including the kidney, hindlimb, and adrenal gland.

    PubMed  CAS  Google Scholar 

  35. Haynes WG, Morgan DA, Walsh SA, et al.: Sympathetic activation to leptin is mediated by the hypothalamus [abstract]. J Hypertens 1998, 16:S11.

    Article  Google Scholar 

  36. Dunbar JC, Lu H: Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products. Brain Res Bull 1999, 50:215–221. Leptin causes sympathoactivation through stimulation of the melanocortin system.

    Article  PubMed  CAS  Google Scholar 

  37. Phillips MS, Liu Q, Hammond HA, et al.: Leptin receptor missense mutation in the fatty Zucker rat. Nature Genet 1996, 13:18–19.

    Article  PubMed  CAS  Google Scholar 

  38. Kotz CM, Briggs JE, Pomonis JD, et al.: Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein. Am J Physiol 1998, 275:R478-R484.

    PubMed  CAS  Google Scholar 

  39. Korner J, Chua SC, Williams JA, et al.: Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. Neuroendocrinology 1999, 70:377–383.

    Article  PubMed  CAS  Google Scholar 

  40. Haynes WG, Morgan DA, Djalali A, et al.: Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 1999, 33:537–541. Melanocortin-4 receptor stimulation increases sympathetic nerve traffic in rats. Leptin-induced renal sympathoactivation is mediated by the melanocortin system.

    PubMed  Google Scholar 

  41. Egawa M, Yoshimatsu H, Bray GA: Effect of corticotrophin releasing hormone and neuropeptide Y on electrophysiological activity of sympathetic nerves to interscapular brown adipose tissue. Neuroscience 1990, 34:771–775.

    Article  PubMed  CAS  Google Scholar 

  42. Correia MLG, Morgan DA, Sivitz WS, et al.: Corticotrophin releasing factor mediates thermogenic sympathoactivation to leptin. J Hypertens 2000 (In Press).

  43. Lembo G, Vecchione C, Fratta L, et al.: Leptin induces nitricoxide mediated vasorelaxation in aortic-rings of WKY rats [abstract]. Hypertension 1998, 32:599.

    Google Scholar 

  44. Fruhbeck G: Pivotal role of nitric oxide in the control of blood pressure after leptin administration. Diabetes 1999, 48:903–908.

    Article  PubMed  CAS  Google Scholar 

  45. Jackson EK, Li P: Human leptin has natriuretic activity in the rat. Am J Physiol 1997, 272:F333-F338. Human leptin has direct renal effects that cause natriuresis in rats. This action may compensate for leptin-induced sympathoactivation.

    PubMed  CAS  Google Scholar 

  46. Villarreal D, Reams G, Freeman RH, et al.: Renal effects of leptin in normotensive, hypertensive, and obese rats. Am J Physiol 1998, 275:R2056-R2060.

    PubMed  CAS  Google Scholar 

  47. Chen GX, Koyama K, Yuan X, et al.: Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci U S A 1996, 93:14795–14799.

    Article  PubMed  CAS  Google Scholar 

  48. Sivitz WI, Walsh SA, Morgan DA, et al.: Effects of leptin on insulin sensitivity in normal rats. Endocrinology 1997, 138:3395–3401. Leptin acutely increases insulin-mediated glucose disposal, even in the absence of changes in adipose tissue mass.

    Article  PubMed  CAS  Google Scholar 

  49. Shek EW, Brands MW, Hall JE: Chronic leptin infusion increases arterial pressure. Hypertension 1998, 31:409. This study demonstrated that long-term infusion of leptin increases arterial pressure, suggesting that hyperleptinemia may play a role in obesity-related hypertension.

    PubMed  CAS  Google Scholar 

  50. Correia MLG, Morgan DA, Sivitz WS, et al.: Cerebroventricular leptin prevents hypotension caused by weight loss [abstract]. Circulation 1998, 98:I336.

    Google Scholar 

  51. Ogawa Y, Masuzaki H, Aizawa M, et al.: Blood pressure elevation in transgenic mice over-expressing leptin, the obese gene product [abstract]. J Hypertens 1998, 16:S7.

    Google Scholar 

  52. Mark AL, Shaffer RA, Correia MLG, et al.: Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens 1999, 17:1949. Leptin-deficient mice have lower arterial pressure than lean littermates, despite obesity. This supports the concept that leptin may contribute to the physiologic maintenance of arterial pressure.

    Article  PubMed  CAS  Google Scholar 

  53. Haynes WG, Morgan DA, Ernsberger P, et al.: The combination of genetic obesity and hypertension is associated with exaggerated hemodynamic responses to salt and stress [abstract]. Am J Hypertens 1996, 9:41A.

    Article  Google Scholar 

  54. Koletsky RJ, Ernsberger P: Phenotypic characterization of a genetically obese and hypertensive rat. Rat Genome 1996, 2:10–22.

    Google Scholar 

  55. 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.

    Article  PubMed  CAS  Google Scholar 

  56. Ravussin E, Pratley RE, Maffei M, et al.: Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat Med 1997, 3:238–240.

    Article  PubMed  CAS  Google Scholar 

  57. Vanheek M, Compton DS, France CF, et al.: Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 1997, 99:385–390. This important paper demonstrated that diet-induced obesity is associated with leptin resistance, which can be localized to a failure of transport of leptin across the blood-brain barrier.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haynes, W.G. Interaction between leptin and sympathetic nervous system in hypertension. Current Science Inc 2, 311–318 (2000). https://doi.org/10.1007/s11906-000-0015-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-000-0015-1

Keywords

Navigation