Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Anderson SE, Whitaker RC. Prevalence of obesity among US preschool children in different racial and ethnic groups. Arch Pediatr Adolesc Med. 2009;163(4):344–8.
Bauer KW, Marcus MD, El ghormli L, Ogden CL, Foster GD. Cardio-metabolic risk screening among adolescents: understanding the utility of body mass index, waist circumference and waist to height ratio. Pediatr Obes. 2015;10(5):329–37.
Ogden CL, Carroll MD, Flegal KM. Prevalence of obesity in the United States. JAMA. 2014;312(2):189–90.
Hall JE, Crook ED, Jones DW, Wofford MR, Dubbert PM. Mechanisms of obesity-associated cardiovascular and renal disease. Am J Med Sci. 2002;324(3):127–37.
Jones DW, Kim JS, Andrew ME, Kim SJ, Hong YP. Body mass index and blood pressure in Korean men and women: the Korean National Blood Pressure Survey. J Hypertens. 1994;12(12):1433–7.
Wilson PW, D’Agostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med. 2002;162(16):1867–72.
Garrison RJ, Kannel WB, Stokes 3rd J, Castelli WP. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med. 1987;16(2):235–51.
Obarzanek E, Kimm SY, Barton BA, Van Horn LL, Kwiterovich Jr PO, Simons-Morton DG, et al. Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC). Pediatrics. 2001;107(2):256–64.
Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, Smith West D, et al. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med. 2001;134(1):1–11.
Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney disease. Int J Nephrol Renovasc Dis. 2014;7:75–88.
Head GA, Lim K, Barzel B, Burke SL, Davern PJ. Central nervous system dysfunction in obesity-induced hypertension. Curr Hypertens Rep. 2014;16(9):466.
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.
Esler M. The 2009 Carl Ludwig Lecture: Pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol. 2010;108(2):227–37.
Straznicky NE, Grima MT, Eikelis N, Nestel PJ, Dawood T, Schlaich MP, et al. The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components. J Clin Endocrinol Metab. 2011;96(3):E503–8.
Hall JE. The kidney, hypertension, and obesity. Hypertension. 2003;41(3 Pt 2):625–33.
Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, et al. Hypertension: physiology and pathophysiology. Compr Physiol. 2012;2(4):2393–442.
Davy KP, Hall JE. Obesity and hypertension: two epidemics or one? Am J Physiol Regul Integr Comp Physiol. 2004;286(5):R803–13.
McAllen RM. Action and specificity of ventral medullary vasopressor neurones in the cat. Neuroscience. 1986;18(1):51–9.
McAllen RM. Identification and properties of sub-retrofacial bulbospinal neurones: a descending cardiovascular pathway in the cat. J Auton Nerv Syst. 1986;17(2):151–64.
Sugiyama Y, Suzuki T, Yates BJ. Role of the rostral ventrolateral medulla (RVLM) in the patterning of vestibular system influences on sympathetic nervous system outflow to the upper and lower body. Exp Brain Res. 2011;210(3–4):515–27.
Chen QH, Toney GM. In vivo discharge properties of hypothalamic paraventricular nucleus neurons with axonal projections to the rostral ventrolateral medulla. J Neurophysiol. 2010;103(1):4–15.
Dampney RA, Horiuchi J, Tagawa T, Fontes MA, Potts PD, Polson JW. Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone. Acta Physiol Scand. 2003;177(3):209–18.
ter Horst GJ, Luiten PG. The projections of the dorsomedial hypothalamic nucleus in the rat. Brain Res Bull. 1986;16(2):231–48.
Carmichael CY, Wainford RD. Hypothalamic signaling mechanisms in hypertension. Curr Hypertens Rep. 2015;17(5):39.
Hirooka Y, Kishi T, Ito K, Sunagawa K. Potential clinical application of recently discovered brain mechanisms involved in hypertension. Hypertension. 2013;62(6):995–1002.
Kishi T, Hirooka Y, Ogawa K, Konno S, Sunagawa K. Calorie restriction inhibits sympathetic nerve activity via anti-oxidant effect in the rostral ventrolateral medulla of obesity-induced hypertensive rats. Clin Exp Hypertens. 2011;33(4):240–5.
Seravalle G, Grassi G. Sympathetic nervous system, hypertension, obesity and metabolic syndrome. High Blood Press Cardiovasc Prev. 2016. [Epub ahead of print].
Gauthier P, Reis DJ, Nathan MA. Arterial hypertension elicited either by lesions or by electrical stimulations of the rostral hypothalamus in the rat. Brain Res. 1981;211(1):91–105.
Valensi P, Doare L, Perret G, Germack R, Paries J, Mesangeau D. Cardiovascular vagosympathetic activity in rats with ventromedial hypothalamic obesity. Obes Res. 2003;11(1):54–64.
Reisin E, Wilson JR, Frohlich ED. Hypertension and obesity in rats with ventromedial-hypothalamic lesions and low salt intake. J Hypertens. 1987;5(2):173–8.
Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012;16(3):296–309.
Rinaman L. Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions. Am J Physiol Regul Integr Comp Physiol. 2011;300(2):R222–35.
Nagae A, Fujita M, Kawarazaki H, Matsui H, Ando K, Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension. Circulation. 2009;119(7):978–86.
Winklewski PJ, Radkowski M, Wszedybyl-Winklewska M, Demkow U. Brain Inflammation and hypertension: the chicken or the egg? J Neuroinflammation. 2015;12:85.
Campese VM, Ku E, Park J. Sympathetic renal innervation and resistant hypertension. Int J Hypertens. 2011;2011:814354.
Campese VM, Ye S, Zhong H, Yanamadala V, Ye Z, Chiu J. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol. 2004;287(2):H695–703.
Stocker SD, Gordon KW. Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol. 2015;113(5):1302–9.
Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G. Mechanisms of obesity-induced hypertension. Hypertens Res. 2010;33(5):386–93.
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86(5):1930–5.
Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension. 2006;47(6):1108–16.
Kawczynska-Drozdz A, Olszanecki R, Jawien J, Brzozowski T, Pawlik WW, Korbut R, et al. Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats. Am J Hypertens. 2006;19(7):764–7.
DeMarco VG, Aroor AR, Sowers JR. The pathophysiology of hypertension in patients with obesity. Nat Rev Endocrinol. 2014;10(6):364–76.
Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res. 2015;116(6):991–1006. Provides a comprehensive review of the neurohumoral mechanisms in obesity-induced hypertension.
de Paula RB, da Silva AA, Hall JE. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension. 2004;43(1):41–7.
Van Vliet BN, Hall JE, Mizelle HL, Montani JP, Smith Jr MJ. Reduced parasympathetic control of heart rate in obese dogs. Am J Physiol. 1995;269(2 Pt 2):H629–37.
Lohmeier TE, Warren S, Cunningham JT. Sustained activation of the central baroreceptor pathway in obesity hypertension. Hypertension. 2003;42(1):96–102.
Dewan NA, Nieto FJ, Somers VK. Intermittent hypoxemia and OSA: implications for comorbidities. Chest. 2015;147(1):266–74.
Mansukhani MP, Kara T, Caples SM, Somers VK. Chemoreflexes, sleep apnea, and sympathetic dysregulation. Curr Hypertens Rep. 2014;16(9):476.
Witkowski A, Prejbisz A, Florczak E, Kadziela J, Sliwinski P, Bielen P, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension. 2011;58(4):559–65.
Lohmeier TE, Iliescu R, Tudorancea I, Cazan R, Cates AW, Georgakopoulos D, et al. Chronic interactions between carotid baroreceptors and chemoreceptors in obesity hypertension. Hypertension. 2016. in press.
Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS. Role of leptin in fat regulation. Nature. 1996;380(6576):677.
Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–71.
Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159(6):1404–16. This study shows that the effects of leptin on blood pressure are mediated by neurons in the dorsomedial hypothalamus.
Mark AL. Selective leptin resistance revisited. Am J Physiol Regul Integr Comp Physiol. 2013;305(6):R566–81. Provides a comprehensive review on the sympathetic and cardiovascular actions of leptin.
Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–84.
Harris RB. Leptin--much more than a satiety signal. Annu Rev Nutr. 2000;20:45–75.
Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997;100(2):270–8.
Machleidt F, Simon P, Krapalis AF, Hallschmid M, Lehnert H, Sayk F. Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans. J Clin Endocrinol Metab. 2013;98(3):E491–6.
Carlyle M, Jones OB, Kuo JJ, Hall JE. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension. 2002;39(2 Pt 2):496–501.
Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998;31(1 Pt 2):409–14.
Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy S, et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J Biol Chem. 2010;285(23):17271–6.
Kuo JJ, Jones OB, Hall JE. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension. 2001;37(2 Pt 2):670–6.
Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice with agouti yellow obese mice. J Hypertens. 1999;17(12 Pt 2):1949–53.
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.
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(4):758–62.
Vong L, Ye C, Yang Z, Choi B, Chua Jr S, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron. 2011;71(1):142–54.
Harlan SM, Morgan DA, Agassandian K, Guo DF, Cassell MD, Sigmund CD, et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res. 2011;108(7):808–12.
do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JE. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension. 2011;57(5):918–26.
Young CN, Morgan DA, Butler SD, Mark AL, Davisson RL. The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects. Hypertension. 2013;61(3):737–44.
Mark AL, Agassandian K, Morgan DA, Liu X, Cassell MD, Rahmouni K. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension. 2009;53(2):375–80.
Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, 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.
do Carmo JM, da Silva AA, Sessums PO, Ebaady SH, Pace BR, Rushing JS, 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.
do Carmo JM, da Silva AA, Ebaady SE, Sessums PO, Abraham RS, Elmquist JK, 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. This study shows that Shp2 signaling in POMC neurons contributes to the long-term blood pressure and antidiabetic effects of leptin but has only a modest role in body weight regulation.
Rahmouni K, Morgan DA, Morgan GM, Liu X, Sigmund CD, Mark AL, et al. Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest. 2004;114(5):652–8.
do Carmo JM, da Silva AA, Wang Z, Freeman NJ, Alsheik AJ, Adi A, et al. Regulation of blood pressure, appetite, and glucose by leptin after inactivation of insulin receptor substrate 2 signaling in the entire brain or in proopiomelanocortin neurons. Hypertension. 2016;67(2):378–86.
Tallam LS, da Silva AA, Hall JE. Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Hypertension. 2006;48(1):58–64.
Aslan IR, Ranadive SA, Valle I, Kollipara S, Noble JA, Vaisse C. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes (Lond). 2014;38(1):148–51.
Farooqi IS. Genetic aspects of severe childhood obesity. Pediatr Endocrinol Rev. 2006;3 Suppl 4:528–36.
Greenfield JR. Melanocortin signalling and the regulation of blood pressure in human obesity. J Neuroendocrinol. 2011;23(2):186–93.
Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360(1):44–52.
da Silva AA, do Carmo JM, Dubinion JH, Bassi M, Mokhtarpouriani K, Hamza SM, et al. Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion. Hypertension. 2015;65(1):171–7.
da Silva AA, do Carmo JM, Wang Z, Hall JE. The brain melanocortin system, sympathetic control, and obesity hypertension. Physiology (Bethesda). 2014;29(3):196–202.
da Silva AA, do Carmo JM, Kanyicska B, Dubinion J, Brandon E, Hall JE. Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats. Hypertension. 2008;51(4):884–90.
do Carmo JM, da Silva AA, Rushing JS, Hall JE. Activation of the central melanocortin system contributes to the increased arterial pressure in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol. 2012;302(5):R561–7.
We thank Sydney P. Moak, Jackson Browning, and Calvin Torrey for technical assistance with our experimental studies cited in this review.
Sources of Funding
This research was supported by National Heart, Lung and Blood Institute Grant (PO1HL-51971), the National Institute of General Medical Sciences (P20GM104357), and by an American Heart Association Scientist Development Grant to Jussara M. do Carmo.
Conflict of Interest
Dr. do Carmo reports grants from National Institutes of Health, American Heart Association, and Palatin Technologies. Dr. Hall reports grants from National Institutes of Health and Palatin Technologies. Drs. da Silva, Wang, Fang, Aberdein, and de Lara Rodriguez report no conflicts 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.
This article is part of the Topical Collection on Secondary Hypertension: Nervous System Mechanisms
About this article
Cite this article
do Carmo, J.M., da Silva, A.A., Wang, Z. et al. Obesity-Induced Hypertension: Brain Signaling Pathways. Curr Hypertens Rep 18, 58 (2016). https://doi.org/10.1007/s11906-016-0658-1