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Insulin resistance and the sympathetic nervous system

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Abstract

The obesity epidemic is driving metabolic (insulin resistance) syndrome-related health problems including an approximately threefold increased coronary heart disease risk. Sympathetic hyperfunction may participate in the pathogenesis and complications of the metabolic syndrome including higher blood pressure, a more active renin-angiotensin system, insulin resistance, faster heart rates, and excess cardiovascular disease including sudden death. Possible factors augmenting sympathetic activation in the metabolic syndrome include alterations of insulin, leptin, nonesterified fatty acids (NEFAs), cytokines, tri-iodothyronine, eicosanoids, sleep apnea, nitric oxide, endorphins, and neuropeptide Y. Of note, high plasma NEFAs are a risk factor for hypertension and sudden death. In shortterm human studies, NEFAs can raise blood pressure, heart rate, and α1-adrenoceptor vasoreactivity, while reducing baroreflex sensitivity, endothelium-dependent vasodilatation, and vascular compliance. Efforts to further identify the mechanisms and consequences of sympathetic dysfunction in the metabolic syndrome may provide insights for therapeutic advances to ameliorate the excess cardiovascular risk and adverse outcomes.

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References and Recommended Reading

  1. Ferrannini E, Natali A, Bell P, et al.: Insulin resistance and hypersecretion in obesity. J Clin Invest 1997, 100:1166–1173.

    PubMed  CAS  Google Scholar 

  2. Bunker CH, Ukoli FA, Matthews KA, et al.: Weight threshold and blood pressure in a lean black population. Hypertension 1995, 26:616–623.

    PubMed  CAS  Google Scholar 

  3. Lipton RB, Liao Y, Cao G, et al.: Determinants of incident noninsulin-dependent diabetes mellitus among blacks and whites in a national sample. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1993, 138:826–839.

    PubMed  CAS  Google Scholar 

  4. Prebble WE: Obesity: observations on one thousand cases. Boston Med Surg J 1923, 88:617–621.

    Google Scholar 

  5. Mokdad AH, Ford ES, Bowman BA, et al.: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003, 289:76–79.

    Article  PubMed  Google Scholar 

  6. Kannel WB, Wilson PW, Nam BH, D’Agostino RB: Risk stratification of obesity as a coronary risk factor. Am J Cardiol 2002, 90:697–701.

    Article  PubMed  Google Scholar 

  7. Hubert HB, Feinleib M, McNamara PM, Castelli WP: Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983, 67:968–977.

    PubMed  CAS  Google Scholar 

  8. Messerli FH, Nunez BD, Ventura HO, Snyder DW: Overweight and sudden death: Increased ventricular ectopy in cardiopathy of obesity. Arch Intern Med 1987, 147:1725–1728.

    Article  PubMed  CAS  Google Scholar 

  9. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999–20. JAMA 2002, 288:1723–1727.

    Article  PubMed  Google Scholar 

  10. Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: Findings from the Third National Health and Nutrition Examination Survey. JAMA 2002, 287:356–359.

    Article  PubMed  Google Scholar 

  11. Obesity: preventing and managing the global epidemic. In Report of a WHO Consultation on Obesity. Geneva: World Health Organization, 1998.

  12. Lakka H-M, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002, 288:2709–2716.

    Article  PubMed  Google Scholar 

  13. Wolf AM, Colditz GA: Current estimates of the economic cost of obesity in the United States. Obes Res 1998, 6:97–106.

    PubMed  CAS  Google Scholar 

  14. Sturm R: The effects of obesity, smoking, and drinking on medical problems and costs. Obesity outranks both smoking and drinking in its deleterious effects on health and health costs. Health Affairs 2002, 21:245–253.

    Article  PubMed  Google Scholar 

  15. Quesenberry CP, Caan B, Jacabson A: Obesity, health services use, and health care costs among members of a health maintenance organization. Arch Intern Med 1998, 158:466–472.

    Article  PubMed  Google Scholar 

  16. Field AE, Coakley EH, Must A, et al.: Impact of overweight on the risk of developing common chronic disease during a 10-year period. Arch Intern Med 2001, 161:1581–1586.

    Article  PubMed  CAS  Google Scholar 

  17. National Task Force on the Prevention and Treatment of Obesity: Weight cycling. JAMA 1994, 272:1196–1202.

  18. Snitker S, Macdonald I, Ravussin E, Astrup A: The sympathetic nervous system and obesity: role in aetiology and treatment. Obes Rev 2000, 1:5–15.

    Article  PubMed  CAS  Google Scholar 

  19. Esler M, Magdalena R, Wiesner G, et al.: Sympathetic nervous system and insulin resistance: From obesity to diabetes. Am J Hypertens 2001, 14:304S-309S. This review article summarizes a substantial body of work on regional norepinephrine kinetics in healthy volunteers, obese subjects, and hypertensive patients by a very productive group of scientific investigators.

    Article  PubMed  CAS  Google Scholar 

  20. Grassi G, Seravalle G, Dell-Oro R, et al.: Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension 2000, 36:538–542. This is an original article comparing MSNA in lean and obese normotensive and hypertensive patients. The results indicate separate and essentially additive effects of obesity and hypertension on MSNA.

    PubMed  CAS  Google Scholar 

  21. Egan B, Panis R, Hinderliter A, et al.: Mechanism of increased a-adrenergic vasoconstriction in human essential hypertension. J Clin Invest 1987, 80:812–817.

    PubMed  CAS  Google Scholar 

  22. Quillot D, Fluckiger L, Zannad F, et al.: Impaired autonomic control of heart rate and blood pressure in obesity: role of age and of insulin-resistance. Clin Autonom Res 2001, 11:79–86.

    Article  Google Scholar 

  23. Gao YY, Lovejoy, Spart An, et al.: Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women. Obes Res 1996, 4:55–63.

    PubMed  CAS  Google Scholar 

  24. Pollare T, Lithell H, Selinus I, Berne C: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 1988, 31:415–420.

    Article  PubMed  CAS  Google Scholar 

  25. Jamerson KA, Julius S, Gudbrandsson T, et al.: Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 1993, 21:618–623.

    PubMed  CAS  Google Scholar 

  26. Rocchini AP, Mao HZ, Babu K, et al.: Clonidine prevents insulin resistance and hypertension in obese dogs. Hypertension 1999, 33(part 2):548–553. This paper represents an important extension of a large body of work on obesity-induced hypertension by this investigative team. The results demonstrate a critical role for the sympathetic nervous system in the blood pressure elevation and hyperinsulinemia that occur with overfeeding in dogs.

    PubMed  CAS  Google Scholar 

  27. Hall JE, Brands MW, Hildebrandt DA, et al.: Role of sympathetic nervous system and neuropeptides in obesity hypertenson. Brazil J Med Biol Res 2000, 33:605–618.

    CAS  Google Scholar 

  28. Wofford MR, Anderson DC, Brown CA, et al.: Antihypertensive -effect of a- and b-adrenergic blockade in obese and lean hypertensive subjects. Am J Hypertens 2001, 14:694–698.

    Article  PubMed  CAS  Google Scholar 

  29. Sower JR, Nyby M, Stern N, et al.: Blood pressure and hormone changes associated with weight reduction in the obese. Hypertension 1982, 4:686–691.

    Google Scholar 

  30. Esler M, Zweifler A, Randall O, et al.: The determinants of plasma-renin activity in essential hypertension. Ann Intern Med 1978, 88:746–752.

    PubMed  CAS  Google Scholar 

  31. Egan BM, Stepniakowski K, Goodfriend TL: Renin and aldosterone are higher and the hyperinsulinemic effects of salt restriction greater in subjects with risk factor clustering. Am J Hypertens 1994, 7:886–893.

    PubMed  CAS  Google Scholar 

  32. Rothwell NJ: Central regulation of thermogenesis. Crit Rev Neurobiol 1994, 8:1–10.

    PubMed  CAS  Google Scholar 

  33. Carroll JF, Hunag M, Hester RL, et al.: Hemodynamic alterations in hypertensive obese rabbits. Hypertension 1995, 26:465–470.

    PubMed  CAS  Google Scholar 

  34. Mark AL, Correia M, Morgan DA, et al.: State-of-the-art lecture: Obesity-induced hypertension: New concepts from the emerging biology of obesity. Hypertension 1999, 33(part 2):537–541. The review article represents an insightful perspective on the biologic variables linking obesity to blood pressure control, with a focus on central neurogenic action of selected peptides and the peripheral extension of the central effects.

    PubMed  CAS  Google Scholar 

  35. Hwang I-S, Ho H, Hoffman BB, Reaven GM: Fructose-induced insulin resistance and hypertension in rats. Hypertension 1987, 10:512–516.

    PubMed  CAS  Google Scholar 

  36. Tuck ML: Obesity, the sympathetic nervous system, and essential hypertension. Hypertension 1992, 19(Suppl 1):I67-I77.

    PubMed  CAS  Google Scholar 

  37. Rocchini AP, Key J, Bondie D, et al.: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989, 321:580–585.

    Article  PubMed  CAS  Google Scholar 

  38. Esler M, Ferrier C, Lambert G, et al.: Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension 1991, 17(Suppl III):III29-III35.

    PubMed  CAS  Google Scholar 

  39. Guyton AC: Blood pressure control—special role of the kidneys and body fluids. Science 1991, 252:1813–1816.

    Article  PubMed  CAS  Google Scholar 

  40. Grassi G, Seravalle G, Dell’Oro R, et al.: Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension 2000, 36:538–542.

    PubMed  CAS  Google Scholar 

  41. Grassi G, Seravalle G, Colombo M, et al.: Body weight reduction, sympathetic nerve activity, and arterial baroreflex in obese normotensive humans. Circulation 1998, 97:2037–2042.

    PubMed  CAS  Google Scholar 

  42. Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. J Clin Invest 1990, 85:1844–1852.

    PubMed  CAS  Google Scholar 

  43. Andersson B, Elam M, Wallin BG, et al.: Effect of energyrestricted diet on sympathetic muscle nerve activity in obese women. Hypertension 1991, 18:783–789.

    PubMed  CAS  Google Scholar 

  44. Jones PP, Snitker S, Skinner JS, Ravussin E: Gender differences in muscle sympathetic nerve activity: effect of body fat distribution. Am J Physiol 1996, 270:E363-E366.

    PubMed  CAS  Google Scholar 

  45. Kissebah AH, Krakower GR: Regional adiposity and morbidity. Physiol Rev 1994, 74:761–811.

    PubMed  CAS  Google Scholar 

  46. Stern M, Haffner S: Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis 1986, 6:123–129.

    PubMed  CAS  Google Scholar 

  47. Heitmann BL: Body fat distribution in the adult Danish population aged 35 – 65 years: an epidemiological study. Int J Obes 1991, 58:535–545.

    Google Scholar 

  48. MacMahon SW, Blacket RB, Macdonald GJ, Hall W: Obesity, alcohol consumption and blood pressure in Australian men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. J Hypertens 1984, 2:85–91.

    Article  PubMed  CAS  Google Scholar 

  49. Emdin M, Gastaldelli A, Muscelli E, et al.: Hyperinsulinemia and autonomic nervous system dysfunction in obesity: Effects of weight loss. Circulation 2001, 103:513–519.

    PubMed  CAS  Google Scholar 

  50. Hirsch J, Leibel RL, Mackintosh R, Aguirre A: Heart rate variability as a measure of autonomic function during weight change in humans. Am J Physiol 1991, 261:R1418-R1423.

    PubMed  CAS  Google Scholar 

  51. Hausberg M, Hoffman RP, Somers VK, et al.: Contrasting autonomic and hemodynamic effects of insulin in health elderly versus young subjects. Hypertension 1997, 29:700–705.

    PubMed  CAS  Google Scholar 

  52. Anderson EA, Balon TW, Hoffman RP, et al.: Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension 1992, 19:621–627.

    PubMed  CAS  Google Scholar 

  53. Wollenweider P, Tappy L, Randin D, et al.: Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 1993, 92:147–154.

    Google Scholar 

  54. Monroe MB, Van Pelt RE, Schiller BC, et al.: Relation of leptin and inslin to adiposity-associated elevations in sympathetic activity with age in humans. Int J Obes 2000, 24:1183–1187. Leptin and insulin are able to activate the sympathetic nervous system and both peptides tend to cosegregate. This study used MSNA and multivariate analysis in an attempt to separate the individual contributions of leptin and insulin on sympathetic activity and found evidence for the predominance of leptin.

    Article  CAS  Google Scholar 

  55. Jensen MD, Haymond MW, Rizza RA, et al.: Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest 1989, 83:1168–1173.

    PubMed  CAS  Google Scholar 

  56. Reaven GM, Hollenbeck C, Jeng CY, et al.: Measurement of plasma glucose, free fatty acids, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes 1988, 37:1020–1024.

    Article  PubMed  CAS  Google Scholar 

  57. Ferrannini E, Barrett EJ, Bevilacqua S: Effects of fatty acids on glucose production and utilization in man. J Clin Invest 1983, 72:1737–1747.

    PubMed  CAS  Google Scholar 

  58. Cabezas MC, deBruin TWA, deValk HW, et al.: Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating apolipoprotein B overproduction and insulin resistance. J Clin Invest 1993, 92:160–168.

    Article  CAS  Google Scholar 

  59. Bülow J, Madsen J, Hojgaard L: Reversibility of the effects on local circulation of high lipid concentrations in blood. Scand J Clin Lab Invest 1990, 50:291–296.

    PubMed  Google Scholar 

  60. Grekin RJ, Dumont CJ, Vollmer AP, et al.: Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Am J Physiol 1997, 273:R324-R330.

    PubMed  CAS  Google Scholar 

  61. Hildebrandt DA, Kirk D, Hall JE: Renal and cardiovascular responses to chronic increases in cerebrovascular free fatty acids. Fed Proc 1999, 13:780.

    Google Scholar 

  62. Stojiljkovic MP, Zhang D, Lopes HF, et al.: Hemodynamic effects of lipids in humans. Am J Physiol 2001, R280:1674–1679.

    Google Scholar 

  63. Steinberg HO, Tarshoby M, Monestel R, et al.: Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997, 100:1230–1239.

    PubMed  CAS  Google Scholar 

  64. Haastrup T, Stepniakowski KT, Goodfriend TL, Egan BM: Lipids enhance a1-adrenergic receptor mediated pressor reactivity. Hypertension 1998, 32:693–698.

    PubMed  CAS  Google Scholar 

  65. Thomas GD, Sander M, Lau KS, et al.: Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci U S A 1998, 95:15090–15095.

    Article  PubMed  CAS  Google Scholar 

  66. Fagot-Campagna A, Balkau B, Simon D, et al.: High free fatty acid concentration: An independent risk factor for hypertension in the Paris Prospective Study. Int J Epidemiol 1998, 27:808–813.

    Article  PubMed  CAS  Google Scholar 

  67. Gadegbeku CA, Dhandayuthapani A, Sadler JE, Egan BM: Raising lipids acutely reduces baroreflex sensitivity. Am J Hypertens 2002, 15:479–485.

    Article  PubMed  CAS  Google Scholar 

  68. Paolisso G, Manzella D, Rosaria MR, et al.: Elevated plasma fatty acid concentrations stimulate the cardiac autonomic nervous system in healthy subjects. Am J Clin Nutr 2000, 72:723–730. This paper summarizes a thoughtfully designed study that shows that a rise in plasma NEFAs alters the neural control of heart rate variability. These findings may provide one link between elevated fatty acids and sudden death.

    PubMed  CAS  Google Scholar 

  69. Jouven X, Charles M-A, Desnos M, Ducimetière P: Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation 2001, 104:756–761.

    PubMed  CAS  Google Scholar 

  70. Chan JC, Cheung JC, Stehouwer CD, et al.: The central roles of obesity-associated dyslipidaemia, endothlelial activation and cytokines in the metabolic syndrome—an analysis by structural equation modeling. Int J Obes 2002, 26:994–1008.

    Article  CAS  Google Scholar 

  71. Maguri SR, Hauser R, Schwartz J, et al.: Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 2001, 104:986–991.

    Google Scholar 

  72. Vgontzas AN, Papanicolaou DA, Bixler EO, et al.: Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000, 85:1151–1158.

    Article  PubMed  CAS  Google Scholar 

  73. O’Dea K, Esler M, Leonard P, et al.: Noradrenaline turnover during under- and over-eating in normal weight subjects. Metabolism 1982, 31:896–899.

    Article  PubMed  CAS  Google Scholar 

  74. Engeli S, Sharma AM: Role of adipose tissue for cardiovascular-renal regulation in health and disease. Horm Metab Res 2000, 21:485–499.

    Google Scholar 

  75. Brody MJ, Kadowitz PJ: Prostaglandins as modulators of autonomic nervous system. Fed Proc 1974, 33:48–60.

    PubMed  CAS  Google Scholar 

  76. Stjärne L: Enhancement by indomethacin of cold-induced hypersecretion of noradrenaline in the rat in vivo by suppression of PGE mediated feedback control? Acta Physiol Scand 1972, 86:388–397.

    Article  PubMed  Google Scholar 

  77. Qadri F, Carretero OA, Scicli AG: Centrally produced nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and hypertensive spontaneously hypertensive rats. Jpn J Pharmacol 1999, 81:279–285.

    Article  PubMed  CAS  Google Scholar 

  78. Tanioka H, Nakamura K, Fujimura S, et al.: Facilitatory role of NO in neural norepinephrine release in the rat kidney. Am J Physiol 2002, 282:R1436-R1442.

    CAS  Google Scholar 

  79. Kuo JJ, Jones OB, Hall JE: Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 2001, 37(part 2):670–676.

    PubMed  CAS  Google Scholar 

  80. Konishi S, Tsunoo A, Otsuka M: Enkephalins presynaptically inhibit cholinergic transmission in sympathetic ganglia. Nature 1979, 282:515–516.

    Article  PubMed  CAS  Google Scholar 

  81. Paquali R, Cantobelli S, Casimirri F, et al.: The role of opioid peptides in the development of hyperinsulinemia in obese women with abdominal fat distribution. Metabolism 1992, 41:763–767.

    Article  Google Scholar 

  82. McCubbin JA, Survit RS, Williams RB, et al.: Altered pituitary hormone response to naloxone in hypertension development. Hypertension 1989, 14:636–644.

    PubMed  CAS  Google Scholar 

  83. Ramirez-Gonzalez MD, Tchakarov L, Garcia RM, Kunos G: bendorphin acting on the brainstem is involved in the antihypertensive action of clonidine and a-methyldopa in rats. Circ Res 1983, 53:150–157.

    PubMed  CAS  Google Scholar 

  84. Bouloux P-M, Grossman A, Al-Damluji S, et al.: Enhancement of the sympathoadrenal response to the cold-pressor test by naloxone in man. Clin Sci 1985, 69:365–368.

    PubMed  CAS  Google Scholar 

  85. Rothman RB, Xu H, Char GU, et al.: Phenylpiperidine opioid antagonists that promote weight loss in rats have high affinity for the k2B (enkephalin-sensitive) binding site. Peptides 1993, 14:17–20.

    Article  PubMed  CAS  Google Scholar 

  86. Balasubramaniam A: Clinical potential of neuropeptide Y family of hormones. Am J Surg 2002, 183:430–434.

    Article  PubMed  CAS  Google Scholar 

  87. Silverberg DS, Oksenberg A: Are sleep-related breathing disorders important contributing factors to the production of essential hypertension? Curr Hypertens Rep 2001, 3:209–215.

    PubMed  CAS  Google Scholar 

  88. Roux F, D’Ambrosio C, Mohsenin V: Sleep-related breathing disorders and cardiovascular disease. Am J Med 2000, 108:396–402.

    Article  PubMed  CAS  Google Scholar 

  89. Fletcher EC, Lesske J, Behm R, et al.: Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 1992, 72:1978–1984.

    PubMed  CAS  Google Scholar 

  90. Ries DJ, Morrison S, Ruggiero DA: The C1 area of the brainstem in tonic and reflex control of blood pressure: state of the art lecture. Hypertension 1988, 11(Suppl 1):I8-I13.

    Google Scholar 

  91. Johnson EH: Interrelationships between psychological factors, overweight, and blood pressure in adolescents. J Adolesc Health Care 1990, 11:310–318.

    Article  PubMed  CAS  Google Scholar 

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Egan, B.M. Insulin resistance and the sympathetic nervous system. Current Science Inc 5, 247–254 (2003). https://doi.org/10.1007/s11906-003-0028-7

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