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Control of Energy Balance by the Brain Renin-Angiotensin System

  • Hypertension and the Brain (S Stocker, Section Editor)
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Abstract

The renin-angiotensin system (RAS) exists as a circulating hormone system but it is also used by various tissues of the body, including the brain, as a paracrine signaling mechanism. The local brain version of the RAS is mechanistically involved in fluid balance and blood pressure control, and there is growing appreciation for a role of the brain RAS in the control of energy balance. Here, we review major evidence for the control of energy balance by the brain RAS; outline the current understanding of the RAS components, targets, and mechanisms involved; and highlight some major questions that currently face the field.

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References

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

  1. Jung RT. Obesity as a disease. Br Med Bull. 1997;53(2):307–21.

    Article  CAS  PubMed  Google Scholar 

  2. Huffman MD, Capewell S, Ning H, Shay CM, Ford ES, Lloyd-Jones DM. Cardiovascular health behavior and health factor changes (1988–2008) and projections to 2020: results from the National Health and Nutrition Examination Surveys. Circulation. 2012;125(21):2595–602. doi:https://doi.org/10.1161/CIRCULATIONAHA.111.070722.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Massiera F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu A, Gasc JM, et al. Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. Faseb J. 2001;15(14):2727–9. doi:https://doi.org/10.1096/fj.01-0457fje.

    Article  CAS  PubMed  Google Scholar 

  4. Faloia E, Gatti C, Camilloni MA, Mariniello B, Sardu C, Garrapa GG, et al. Comparison of circulating and local adipose tissue renin-angiotensin system in normotensive and hypertensive obese subjects. J Endocrinol Investig. 2002;25(4):309–14.

    Article  CAS  Google Scholar 

  5. Goossens GH, Blaak EE, van Baak MA. Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Obes Rev: Off J Int Assoc Study Obes. 2003;4(1):43–55.

    Article  CAS  Google Scholar 

  6. Messerli FH, Nunez BD, Ventura HO, Snyder DW. Overweight and sudden death. Increased Ventri Ectopy Cardiopathy Obes Archives Int Med. 1987;147(10):1725–8.

    Article  CAS  Google Scholar 

  7. Bloem LJ, Manatunga AK, Tewksbury DA, Pratt JH. The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest. 1995;95(3):948–53. doi:https://doi.org/10.1172/JCI117803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cooper R, McFarlane-Anderson N, Bennett FI, Wilks R, Puras A, Tewksbury D, et al. ACE, angiotensinogen and obesity: a potential pathway leading to hypertension. J Hum Hypertens. 1997;11(2):107–11.

    Article  CAS  PubMed  Google Scholar 

  9. Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 2005;45(3):356–62. doi:https://doi.org/10.1161/01.HYP.0000154361.47683.d3.

    Article  CAS  PubMed  Google Scholar 

  10. Takahashi N, Li F, Hua K, Deng J, Wang CH, Bowers RR, et al. Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin. Cell Metab. 2007;6(6):506–12. doi:https://doi.org/10.1016/j.cmet.2007.10.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Massiera F, Seydoux J, Geloen A, Quignard-Boulange A, Turban S, Saint-Marc P, et al. Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity. Endocrinology. 2001;142(12):5220–5. doi:https://doi.org/10.1210/endo.142.12.8556.

    Article  CAS  PubMed  Google Scholar 

  12. Jayasooriya AP, Mathai ML, Walker LL, Begg DP, Denton DA, Cameron-Smith D, et al. Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. Proc Natl Acad Sci U S A. 2008;105(18):6531–6. doi:https://doi.org/10.1073/pnas.0802690105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kouyama R, Suganami T, Nishida J, Tanaka M, Toyoda T, Kiso M, et al. Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor. Endocrinology. 2005;146(8):3481–9. doi:https://doi.org/10.1210/en.2005-0003.

    Article  CAS  PubMed  Google Scholar 

  14. Weisinger RS, Stanley TK, Begg DP, Weisinger HS, Spark KJ, Jois M. Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet. Physiol Behav. 2009;98(1–2):192–7. doi:https://doi.org/10.1016/j.physbeh.2009.05.009.

    Article  CAS  PubMed  Google Scholar 

  15. Zorad S, Dou JT, Benicky J, Hutanu D, Tybitanclova K, Zhou J, et al. Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma. Eur J Pharmacol. 2006;552(1–3):112–22. doi:https://doi.org/10.1016/j.ejphar.2006.08.062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stucchi P, Cano V, Ruiz-Gayo M, Fernandez-Alfonso MS. Aliskiren reduces body-weight gain, adiposity and plasma leptin during diet-induced obesity. Br J Pharmacol. 2009;158(3):771–8. doi:https://doi.org/10.1111/j.1476-5381.2009.00355.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mathai ML, Naik S, Sinclair AJ, Weisinger HS, Weisinger RS. Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats. Int J Obes. 2008;32(10):1576–84. doi:https://doi.org/10.1038/ijo.2008.126.

    Article  CAS  Google Scholar 

  18. Santos EL, de Picoli SK, Guimaraes PB, Reis FC, Silva SM, Costa-Neto CM, et al. Effect of angiotensin converting enzyme inhibitor enalapril on body weight and composition in young rats. Int Immunopharmacol. 2008;8(2):247–53. doi:https://doi.org/10.1016/j.intimp.2007.07.021.

    Article  CAS  PubMed  Google Scholar 

  19. Gratze P, Boschmann M, Dechend R, Qadri F, Malchow J, Graeske S, et al. Energy metabolism in human renin-gene transgenic rats: does renin contribute to obesity? Hypertension. 2009;53(3):516–23. doi:https://doi.org/10.1161/HYPERTENSIONAHA.108.124966.

    Article  CAS  PubMed  Google Scholar 

  20. Laragh JH. Biochemical profiling and the natural history of hypertensive diseases: low-renin essential hypertension, a benign condition. Circulation. 1971;44(6):971–4.

    Article  CAS  PubMed  Google Scholar 

  21. Jamerson KA. Rationale for angiotensin II receptor blockers in patients with low-renin hypertension. Am J Kidney Dis: Off J Ntnl Kidney Foundation. 2000;36(3 Suppl 1):S24–30.

    Article  CAS  Google Scholar 

  22. Karlberg BE, Asplund J, Wettre S, Ohman KP, Nilsson OR. Long-term experience of captopril in the treatment of primary (essential) hypertension. Br J Clin Pharmacol. 1982;14 Suppl 2:133S–7.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mizuno K, Haruyama K, Gotoh M, Matsui J, Fukuchi S. Evidence for the role of kinins in the acute antihypertensive effect of captopril in low-renin hypertension. Jpn Heart J. 1984;25(3):379–86.

    Article  CAS  PubMed  Google Scholar 

  24. Gomez HJ, Smith 3rd SG, Moncloa F. Efficacy and safety of lisinopril in older patients with essential hypertension. Am J Med. 1988;85(3B):35–7.

    Article  CAS  PubMed  Google Scholar 

  25. Gohlke P, Ganten D, Lang RE, Unger T. The renin-angiotensin system: systemic and local function. Z Kardiol. 1988;77 Suppl 3:1–12.

    CAS  PubMed  Google Scholar 

  26. Gwathmey TM, Alzayadneh EM, Pendergrass KD, Chappell MC. Novel roles of nuclear angiotensin receptors and signaling mechanisms. Am J Physiol Regul Integrat Comparat Physiol. 2012;302(5):R518–30. doi:https://doi.org/10.1152/ajpregu.00525.2011.

    Article  CAS  Google Scholar 

  27. Buckley RBJ. Evidence for a central mechanism in angiotensin-induced hypertension. Proc Soc Exp Biol Med. 1961;106:834–7.

    Article  Google Scholar 

  28. Booth D. Mechanisms of action of norepinephrine in eliciting an eating response on injection into the rat hypothalamus. J Pharmacol Exp Ther. 1968;160:336–48.

    CAS  PubMed  Google Scholar 

  29. Epstein AN, Fitzsimons JT, Rolls BJ. Drinking induced by injection of angiotensin into the rain of the rat. J Physiol. 1970;210(2):457–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cassis LA, Marshall DE, Fettinger MJ, Rosenbluth B, Lodder RA. Mechanisms contributing to angiotensin II regulation of body weight. Am J Physiol. 1998;274(5 Pt 1):E867–76.

    CAS  PubMed  Google Scholar 

  31. Porter JP, Anderson JM, Robison RJ, Phillips AC. Effect of central angiotensin II on body weight gain in young rats. Brain Res. 2003;959(1):20–8.

    Article  CAS  PubMed  Google Scholar 

  32. Porter JP, Potratz KR. Effect of intracerebroventricular angiotensin II on body weight and food intake in adult rats. Am J Physiol Regulat, Integrat Comparat Physiol. 2004;287(2):R422–8. doi:https://doi.org/10.1152/ajpregu.00537.2003.

    Article  CAS  Google Scholar 

  33. Ferguson AV, Washburn DL, Latchford KJ. Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function. Exp Biol Med (Maywood, NJ). 2001;226(2):85–96.

    Article  CAS  Google Scholar 

  34. Ferguson AV. Angiotensinergic regulation of autonomic and neuroendocrine outputs: critical roles for the subfornical organ and paraventricular nucleus. Neuroendocrinology. 2009;89(4):370–6. doi:https://doi.org/10.1159/000211202.

    Article  CAS  PubMed  Google Scholar 

  35. Coble JP, Grobe JL, Johnson AK, Sigmund CD. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regulaty, Integrat Comparat Physiol. 2014. doi:https://doi.org/10.1152/ajpregu.00486.2014.

    Article  CAS  PubMed  Google Scholar 

  36. Fischer-Ferraro C, Nahmod VE, Goldstein DJ, Finkielman S. Angiotensin and renin in rat and dog brain. J Exp Med. 1971;133(2):353–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ganten D, Boucher R, Genest J. Renin activity in brain tissue of puppies and adult dogs. Brain Res. 1971;33(2):557–9.

    Article  CAS  PubMed  Google Scholar 

  38. Ganten D, Marquez-Julio A, Granger P, Hayduk K, Karsunky KP, Boucher R, et al. Renin in dog brain. Am J Physiol. 1971;221(6):1733–7.

    Article  CAS  PubMed  Google Scholar 

  39. Lavoie JL, Sigmund CD. Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology. 2003;144(6):2179–83. doi:https://doi.org/10.1210/en.2003-0150.

    Article  CAS  PubMed  Google Scholar 

  40. Yang HY, Neff NH. Distribution and properties of angiotensin converting enzyme of rat brain. J Neurochem. 1972;19(10):2443–50.

    Article  CAS  PubMed  Google Scholar 

  41. Poth MM, Heath RG, Ward M. Angiotensin-converting enzyme in human brain. J Neurochem. 1975;25(1):83–5.

    Article  CAS  PubMed  Google Scholar 

  42. Cushman DW, Cheung HS. Concentrations of angiotensin-converting enzyme in tissues of the rat. Biochim Biophys Acta. 1971;250(1):261–5.

    Article  CAS  PubMed  Google Scholar 

  43. Fuxe K, Ganten D, Hokfelt T, Bolme P. Immunohistochemical evidence for the existence of angiotensin II-containing nerve terminals in the brain and spinal cord in the rat. Neurosci Lett. 1976;2(4):229–34.

    Article  CAS  PubMed  Google Scholar 

  44. Healy DP, Printz MP. Distribution of immunoreactive angiotensin II, angiotensin I, angiotensinogen and nephrectomized rats. Hypertension. 1984;6(2 Pt 2):I130–6.

    CAS  PubMed  Google Scholar 

  45. Davisson RL, Oliverio MI, Coffman TM, Sigmund CD. Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest. 2000;106(1):103–6. doi:https://doi.org/10.1172/JCI10022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mimee A, Smith PM, Ferguson AV. Circumventricular organs: targets for integration of circulating fluid and energy balance signals? Physiol Behav. 2013;121:96–102. doi:https://doi.org/10.1016/j.physbeh.2013.02.012.

    Article  CAS  PubMed  Google Scholar 

  47. Mangiapane ML, Simpson JB. Subfornical organ: forebrain site of pressor and dipsogenic action of angiotensin II. Am J Physiol. 1980;239(5):R382–9.

    CAS  PubMed  Google Scholar 

  48. Simpson JB, Routtenberg A. Subfornical organ: site of drinking elicitation by angiotensin II. Science. 1973;181(4105):1172–5.

    Article  CAS  PubMed  Google Scholar 

  49. Coble JP, Cassell MD, Davis DR, Grobe JL, Sigmund CD. Activation of the renin-angiotensin system, specifically in the subfornical organ is sufficient to induce fluid intake. Am J Physiol Regulat, Integrat comparat Physiol. 2014;307(4):R376–86. doi:https://doi.org/10.1152/ajpregu.00216.2014.

    Article  CAS  Google Scholar 

  50. Oka Y, Ye M, Zuker CS. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature. 2015. doi:https://doi.org/10.1038/nature14108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hilzendeger AM, Cassell MD, Davis DR, Stauss HM, Mark AL, Grobe JL, et al. Angiotensin type 1a receptors in the subfornical organ are required for deoxycorticosterone acetate-salt hypertension. Hypertension. 2013;61(3):716–22. doi:https://doi.org/10.1161/HYPERTENSIONAHA.111.00356.

    Article  CAS  PubMed  Google Scholar 

  52. Braga VA, Medeiros IA, Ribeiro TP, Franca-Silva MS, Botelho-Ono MS, Guimaraes DD. Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: implications in neurogenic hypertension. Brazilian J Med Biol Res = Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica. 2011;44(9):871–6.

    CAS  Google Scholar 

  53. Muratani H, Ferrario CM, Averill DB. Ventrolateral medulla in spontaneously hypertensive rats: role of angiotensin II. Am J Physiol. 1993;264(2 Pt 2):R388–95.

    CAS  PubMed  Google Scholar 

  54. Zhu DN, Moriguchi A, Mikami H, Higaki J, Ogihara T. Central amino acids mediate cardiovascular response to angiotensin II in the rat. Brain Res Bull. 1998;45(2):189–97.

    Article  CAS  PubMed  Google Scholar 

  55. Konno S, Hirooka Y, Kishi T, Sunagawa K. Sympathoinhibitory effects of telmisartan through the reduction of oxidative stress in the rostral ventrolateral medulla of obesity-induced hypertensive rats. J Hypertens. 2012;30(10):1992–9. doi:https://doi.org/10.1097/HJH.0b013e328357fa98.

    Article  CAS  PubMed  Google Scholar 

  56. Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, et al. Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest. 2007;117(4):1088–95. doi:https://doi.org/10.1172/jci31242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Grobe JL, Grobe CL, Beltz TG, Westphal SG, Morgan DA, Xu D, et al. The brain renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance. Cell Metab. 2010;12(5):431–42. doi:https://doi.org/10.1016/j.cmet.2010.09.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Littlejohn NK, Siel Jr RB, Ketsawatsomkron P, Pelham CJ, Pearson NA, Hilzendeger AM, et al. Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. Am J Physiol Regulat, Integrat comparat Physiol. 2013;304(10):R818–28. doi:https://doi.org/10.1152/ajpregu.00082.2013.

    Article  CAS  Google Scholar 

  59. Boschmann M, Engeli S, Adams F, Franke G, Luft FC, Sharma AM, et al. Influences of AT1 receptor blockade on tissue metabolism in obese men. Am J Physiol Regulat, Integrat comparat Physiol. 2006;290(1):R219–23. doi:https://doi.org/10.1152/ajpregu.00341.2005.

    Article  CAS  Google Scholar 

  60. Shimabukuro M, Tanaka H, Shimabukuro T. Effects of telmisartan on fat distribution in individuals with the metabolic syndrome. J Hypertens. 2007;25(4):841–8. doi:https://doi.org/10.1097/HJH.0b013e3280287a83.

    Article  CAS  PubMed  Google Scholar 

  61. Hsueh W, Davidai G, Henry R, Mudaliar S. Telmisartan effects on insulin resistance in obese or overweight adults without diabetes or hypertension. J Clin Hypertens. 2010;12(9):746–52. doi:https://doi.org/10.1111/j.1751-7176.2010.00335.x.

    Article  CAS  Google Scholar 

  62. Marinik EL, Frisard MI, Hulver MW, Davy BM, Rivero JM, Savla JS, et al. Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure. Ther Adv Cardiovasc Dis. 2013;7(1):11–20. doi:https://doi.org/10.1177/1753944712471740. This report revealed that administration of angiotensin receptor blockers does not reduce body weight or BMI in obese human patients.

    Article  PubMed  CAS  Google Scholar 

  63. Mori Y, Itoh Y, Tajima N. Telmisartan improves lipid metabolism and adiponectin production but does not affect glycemic control in hypertensive patients with type 2 diabetes. Adv Ther. 2007;24(1):146–53.

    Article  CAS  PubMed  Google Scholar 

  64. Grassi G, Seravalle G, Dell’Oro R, Trevano FQ, Bombelli M, Scopelliti F, et al. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J Hypertens. 2003;21(9):1761–9. doi:https://doi.org/10.1097/01.hjh.0000084718.53355.69.

    Article  CAS  PubMed  Google Scholar 

  65. Cassis L, Helton M, English V, Burke G. Angiotensin II regulates oxygen consumption. Am J Physiol Regulat, Integrat comparat Physiol. 2002;282(2):R445–53. doi:https://doi.org/10.1152/ajpregu.00261.2001.

    Article  CAS  Google Scholar 

  66. Yoshida T, Semprun-Prieto L, Wainford RD, Sukhanov S, Kapusta DR, Delafontaine P. Angiotensin II reduces food intake by altering orexigenic neuropeptide expression in the mouse hypothalamus. Endocrinology. 2012;153(3):1411–20. doi:https://doi.org/10.1210/en.2011-1764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. de Kloet AD, Krause EG, Scott KA, Foster MT, Herman JP, Sakai RR, et al. Central angiotensin II has catabolic action at white and brown adipose tissue. Am J Physiol Endocrinol Metab. 2011;301(6):E1081–91. doi:https://doi.org/10.1152/ajpendo.00307.2011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Ohinata K, Fujiwara Y, Fukumoto S, Iwai M, Horiuchi M, Yoshikawa M. Angiotensin II and III suppress food intake via angiotensin AT(2) receptor and prostaglandin EP(4) receptor in mice. FEBS Lett. 2008;582(5):773–7. doi:https://doi.org/10.1016/j.febslet.2008.01.054.

    Article  CAS  PubMed  Google Scholar 

  69. Yvan-Charvet L, Even P, Bloch-Faure M, Guerre-Millo M, Moustaid-Moussa N, Ferre P, et al. Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance. Diabetes. 2005;54(4):991–9.

    Article  CAS  PubMed  Google Scholar 

  70. de Kloet AD, Wang L, Ludin JA, Smith JA, Pioquinto DJ, Hiller H, et al. Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system. Brain Struct Funct. 2014. doi:https://doi.org/10.1007/s00429-014-0943-1.

    Article  PubMed  CAS  Google Scholar 

  71. Itaya Y, Suzuki H, Matsukawa S, Kondo K, Saruta T. Central renin-angiotensin system and the pathogenesis of DOCA-salt hypertension in rats. Am J Physiol. 1986;251(2 Pt 2):H261–8.

    CAS  PubMed  Google Scholar 

  72. Kubo T, Yamaguchi H, Tsujimura M, Hagiwara Y, Fukumori R. Blockade of angiotensin receptors in the anterior hypothalamic preoptic area lowers blood pressure in DOCA-salt hypertensive rats. Hypertens Res: Off J Jpn Soc Hypertens. 2000;23(2):109–18.

    Article  CAS  Google Scholar 

  73. Park CG, Leenen FH. Effects of centrally administered losartan on deoxycorticosterone-salt hypertension rats. J Korean Med Sci. 2001;16(5):553–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Grobe JL, Buehrer BA, Hilzendeger AM, Liu X, Davis DR, Xu D, et al. Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice. Hypertension. 2011;57(3):600–7. doi:https://doi.org/10.1161/HYPERTENSIONAHA.110.165829.

    Article  CAS  PubMed  Google Scholar 

  75. de Kloet AD, Pati D, Wang L, Hiller H, Sumners C, Frazier CJ, et al. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J Neurosci: Off J Soc Neurosci. 2013;33(11):4825–33. doi:https://doi.org/10.1523/JNEUROSCI.3806-12.2013. This study used mouse models to selectively delete the AT1A receptor from any cell expressing the Sim1 promoter and revealed that deletion of the brain RAS in these specific brain regions increased sensitivity to diet-induced obesity.

    Article  CAS  Google Scholar 

  76. Thatcher S, Yiannikouris F, Gupte M, Cassis L. The adipose renin-angiotensin system: role in cardiovascular disease. Mol Cell Endocrinol. 2009;302(2):111–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Boustany CM, Bharadwaj K, Daugherty A, Brown DR, Randall DC, Cassis LA. Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension. Am J Physiol Regulat, Integrat comparat Physiol. 2004;287(4):R943–9. doi:https://doi.org/10.1152/ajpregu.00265.2004.

    Article  CAS  Google Scholar 

  78. Farooqi IS, O’Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutrit. 2009;89(3):980S–4. doi:https://doi.org/10.3945/ajcn.2008.26788C.

    Article  CAS  PubMed  Google Scholar 

  79. 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. doi:https://doi.org/10.1016/j.cell.2014.10.058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, et al. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest. 2000;105(9):1243–52. doi:https://doi.org/10.1172/JCI8341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. da Silva AA, do Carmo JM, Hall JE. Role of leptin and central nervous system melanocortins in obesity hypertension. Curr Opin Nephrol Hypertens. 2013;22(2):135–40. doi:https://doi.org/10.1097/MNH.0b013e32835d0c05.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. 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. doi:https://doi.org/10.1172/JCI119532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Swoap SJ. Altered leptin signaling is sufficient, but not required, for hypotension associated with caloric restriction. Am J Physiol Heart Circulat Physiol. 2001;281(6):H2473–9.

    Article  CAS  Google Scholar 

  84. Hilzendeger AM, Morais RL, Todiras M, Plehm R, da Costa GA, Qadri F, et al. Leptin regulates ACE activity in mice. J Mol Med. 2010;88(9):899–907. doi:https://doi.org/10.1007/s00109-010-0649-7.

    Article  CAS  PubMed  Google Scholar 

  85. McKinley MJ, Allen AM, Clevers J, Paxinos G, Mendelsohn FA. Angiotensin receptor binding in human hypothalamus: autoradiographic localization. Brain Res. 1987;420(2):375–9.

    Article  CAS  PubMed  Google Scholar 

  86. Arakawa H, Chitravanshi VC, Sapru HN. The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II. Am J Physiol Heart Circulat Physiol. 2011;300(3):H951–60. doi:https://doi.org/10.1152/ajpheart.01144.2010.

    Article  CAS  Google Scholar 

  87. Hilzendeger AM, Morgan DA, Brooks L, Dellsperger D, Liu X, Grobe JL, et al. A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity. Am J Physiol Heart Circulat Physiol. 2012;303(2):H197–206. doi:https://doi.org/10.1152/ajpheart.00974.2011.

    Article  CAS  Google Scholar 

  88. Young CN, Morgan DA, Butler SD, Rahmouni K, Gurley SB, Coffman TM, et al. Angiotensin type 1a receptors in the forebrain subfornical organ facilitate leptin-induced weight loss through brown adipose tissue thermogenesis. Mol Metab. 2015. doi:https://doi.org/10.1016/j.molmet.2015.01.007. These studies demonstrate that angiotensin signaling mediated by the AT1A receptor is required for leptin-mediated sympathetic activation of brown adipose tissue supporting a role for the interaction between leptin and angiotensin signaling in metabolic rate control.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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. doi:https://doi.org/10.1161/HYPERTENSIONAHA.111.00405.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

KEC was supported by a predoctoral fellowship from the American Heart Association’s Midwest Affiliate (14PRE20380401). JLG was supported by grants from the National Institutes of Health (HL098276, HL084207), American Heart Association (14IRG18710013, 15SFRN23730000), American Diabetes Association (1-14-BS-079), University of Iowa Office of the Vice President for Research & Economic Development, and the Fraternal Order of Eagles’ Diabetes Research Center.

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  1. Department of Pharmacology, Center for Hypertension Research, Obesity Research & Education Initiative, François M. Abboud Cardiovascular Research Center, and Fraternal Order of Eagles’ Diabetes Research Center, University of Iowa, 51 Newton Rd., 2-307 BSB, Iowa City, IA, 52242, USA

    Kristin E. Claflin & Justin L. Grobe

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  1. Kristin E. Claflin
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  2. Justin L. Grobe
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Correspondence to Justin L. Grobe.

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Conflict of Interest Justin L. Grobe reports grants from NIH, the American Heart Association, and the American Diabetes Association. Kristin E. Claflin reports grants from the American Heart Association.

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.

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This article is part of the Topical Collection on Hypertension and the Brain

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Claflin, K.E., Grobe, J.L. Control of Energy Balance by the Brain Renin-Angiotensin System. Curr Hypertens Rep 17, 38 (2015). https://doi.org/10.1007/s11906-015-0549-x

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