Development of obesity can be prevented in rats by chronic icv infusions of AngII but less by Ang(1–7)

  • Martina Winkler
  • Michael Bader
  • Franziska Schuster
  • Ines Stölting
  • Sonja Binder
  • Walter RaaschEmail author
Integrative Physiology
Part of the following topical collections:
  1. Integrative Physiology


Considering that obesity is one of the leading risks for death worldwide, it should be noted that a brain-related mechanism is involved in AngII-induced and AT1-receptor-dependent weight loss. It is moreover established that activation of the Ang(1–7)/ACE2/Mas axis reduces weight, but it remains unclear whether this Ang(1–7) effect is also mediated via a brain-related mechanism. Additionally to Sprague Dawley (SD) rats, we used TGR(ASrAOGEN) selectively lacking brain angiotensinogen, the precursor to AngII, as we speculated that effects are more pronounced in a model with low brain RAS activity. Rats were fed with high-calorie cafeteria diet. We investigated weight regulation, food behavior, and energy balance in response to chronic icv.-infusions of AngII (200 ng•h−1), or Ang(1–7) (200/600 ng•h−1) or artificial cerebrospinal fluid. High- but not low-dose Ang(1–7) slightly decreased weight gain and energy intake in SD rats. AngII showed an anti-obese efficacy in SD rats by decreasing energy intake and increasing energy expenditure and also improved glucose control. TGR(ASrAOGEN) were protected from developing obesity. However, Ang(1–7) did not reveal any effects in TGR(ASrAOGEN) and those of AngII were minor compared to SD rats. Our results emphasize that brain AngII is a key contributor for regulating energy homeostasis and weight in obesity by serving as a negative brain-related feedback signal to alleviate weight gain. Brain-related anti-obese potency of Ang(1–7) is lower than AngII but must be further investigated by using other transgenic models as TGR(ASrAOGEN) proved to be less valuable for answering this question.


Angiotensin II Angiotensin(1–7) Brain Glycemic control Insulin resistance Obesity 



Angiotensin II


Angiotensin I






AT1 receptor blocker

AT1 receptor

Angiotensin II type 1 receptor


Area under the curve


Blood-brain barrier


Body mass index


Body weight


Cafeteria diet


Maximal concentration


Ethylenediaminetetraacetic acid


Glial fibrillary acidic protein


High-density lipoproteins

HPA axis

Hypothalamic-pituitary-adrenal axis


Knock out


Leptin receptor


Leptin resistance test


Magnetic resonance imaging


Oral glucose tolerance test




Peroxisome proliferator-activated receptor delta


Peroxisome proliferator-activated receptor gamma


Renin-angiotensin system


Respiratory exchange rate


Systolic blood pressure


Sprague Dawley rat




Transgenic rat


Type 2 diabetes mellitus



MW, MB, FS, IS, SB, and WR performed the research, WR, MW, and MB designed the research study, WR and MW analyzed the data, and WR, MW, and MB wrote the paper. The authors gratefully acknowledge Sherryl Sundell for improving the English style.

Source(s) of funding

Martina Winkler received funding from the Konrad Adenauer Stiftung (Germany). Franziska Schuster was supported by a grant of the German Research Foundation to the Graduiertenkolleg 1957 ‘Adipocyte-Brain Crosstalk’, University of Lübeck. The study was supported by a grant of the German Centre for Cardiovascular Research (DZHK).

Compliance with ethical standards

Conflict(s) of interest/disclosure(s)

No conflict of interests

Supplementary material

424_2018_2117_MOESM1_ESM.docx (257 kb)
ESM 1 (DOCX 256 kb)


  1. 1.
    Andrade JM, Lemos FO, da Fonseca PS, Millan RD, de Sousa FB, Guimaraes AL, Qureshi M, Feltenberger JD, de Paula AM, Neto JT, Lopes MT, Andrade HM, Santos RA, Santos SH (2014) Proteomic white adipose tissue analysis of obese mice fed with a high-fat diet and treated with oral angiotensin-(1-7). Peptides 60:56–62. CrossRefPubMedGoogle Scholar
  2. 2.
    Baltatu O, Janssen BJ, Bricca G, Plehm R, Monti J, Ganten D, Bader M (2001) Alterations in blood pressure and heart rate variability in transgenic rats with low brain angiotensinogen. Hypertension 37(2):408–413. CrossRefPubMedGoogle Scholar
  3. 3.
    Banks WA (2010) Blood-brain barrier as a regulatory interface. Forum Nutr 63:102–110CrossRefPubMedGoogle Scholar
  4. 4.
    Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, Morley JE (2004) Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53(5):1253–1260. CrossRefPubMedGoogle Scholar
  5. 5.
    Brink M, Wellen J, Delafontaine P (1996) Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. J Clin Invest 97(11):2509–2516. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bustin SA (2002) Quantification of mRNA using real-time reverse transcription PCR (RT-PCR): trends and problems. J Mol Endocrinol 29(1):23–39. CrossRefPubMedGoogle Scholar
  7. 7.
    Cabassi A, Coghi P, Govoni P, Barouhiel E, Speroni E, Cavazzini S, Cantoni AM, Scandroglio R, Fiaccadori E (2005) Sympathetic modulation by carvedilol and losartan reduces angiotensin II-mediated lipolysis in subcutaneous and visceral fat. J Clin Endocrinol Metab 90(5):2888–2897. CrossRefPubMedGoogle Scholar
  8. 8.
    Cantley J (2014) The control of insulin secretion by adipokines: current evidence for adipocyte-beta cell endocrine signalling in metabolic homeostasis. Mamm Genome 25(9-10):442–454. CrossRefPubMedGoogle Scholar
  9. 9.
    Claflin KE, Sandgren JA, Lambertz AM, Weidemann BJ, Littlejohn NK, Burnett CM, Pearson NA, Morgan DA, Gibson-Corley KN, Rahmouni K, Grobe JL (2017) Angiotensin AT1A receptors on leptin receptor-expressing cells control resting metabolism. J Clin Invest 127(4):1414–1424. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    de Kloet AD, Krause EG, Scott KA, Foster MT, Herman JP, Sakai RR, Seeley RJ, Woods SC (2011) Central angiotensin II has catabolic action at white and brown adipose tissue. Am J Physiol Endocrinol Metab 301(6):E1081–E1091. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    de Kloet AD, Pati D, Wang L, Hiller H, Sumners C, Frazier CJ, Seeley RJ, Herman JP, Woods SC, Krause EG (2013) Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J Neurosci 33(11):4825–4833. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Di NR, Mendelsohn FA, Hutchinson JS, Takata Y, Doyle AE (1982) Dissociation of dipsogenic and pressor responses to chronic central angiotensin II in rats. Am J Phys 242:R498–R504Google Scholar
  13. 13.
    Dos-Santos RC, Monteiro L, Paes-Leme B, Lustrino D, Antunes-Rodrigues J, Mecawi AS, Reis LC (2017) Central angiotensin-(1-7) increases osmotic thirst. Exp Physiol 102(11):1397–1404. CrossRefPubMedGoogle Scholar
  14. 14.
    Engeli S, Negrel R, Sharma AM (2000) Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 35(6):1270–1277. CrossRefPubMedGoogle Scholar
  15. 15.
    Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, Speth RC, Sigmund CD, Lazartigues E (2010) Brain-selective overexpression of human angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 106(2):373–382. CrossRefPubMedGoogle Scholar
  16. 16.
    Guimaraes PS, Santiago NM, Xavier CH, Velloso EP, Fontes MA, Santos RA, Campagnole-Santos MJ (2012) Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats. Am J Physiol Heart Circ Physiol 303(3):H393–H400. CrossRefPubMedGoogle Scholar
  17. 17.
    Huber G, Schuster F, Raasch W (2017) Brain renin-angiotensin system in the pathophysiology of cardiovascular diseases. Pharmacol Res 125(Pt A):72–90. CrossRefPubMedGoogle Scholar
  18. 18.
    Jezova D, Ochedalski T, Kiss A, Brain AG (1998) Angiotensin II modulates sympathoadrenal and hypothalamic pituitary adrenocortical activation during stress. J Neuroendocrinol 10(1):67–72CrossRefPubMedGoogle Scholar
  19. 19.
    Kadoguchi T, Kinugawa S, Takada S, Fukushima A, Furihata T, Homma T, Masaki Y, Mizushima W, Nishikawa M, Takahashi M, Yokota T, Matsushima S, Okita K, Tsutsui H (2015) Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle. Exp Physiol 100(3):312–322. CrossRefPubMedGoogle Scholar
  20. 20.
    Kangussu LM, Guimaraes PS, Nadu AP, Melo MB, Santos RA, Campagnole-Santos MJ (2015) Activation of angiotensin-(1-7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats. Neuropharmacology 97:58–66. CrossRefPubMedGoogle Scholar
  21. 21.
    Kasper SO, Carter CS, Ferrario CM, Ganten D, Ferder LF, Sonntag WE, Gallagher PE, Diz DI (2005) Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems. Physiol Genomics 23(3):311–317. CrossRefPubMedGoogle Scholar
  22. 22.
    King VL, English VL, Bharadwaj K, Cassis LA (2013) Angiotensin II stimulates sympathetic neurotransmission to adipose tissue. Physiol Rep 1(2):
  23. 23.
    May CN (1996) Prolonged systemic and regional haemodynamic effects of intracerebroventricular angiotensin II in conscious sheep. Clin Exp Pharmacol Physiol 23(10-11):878–884. CrossRefPubMedGoogle Scholar
  24. 24.
    McKinley MJ, Evered M, Mathai M, Coghlan JP (1994) Effects of central losartan on plasma renin and centrally mediated natriuresis. Kidney Int 46(6):1479–1482. CrossRefPubMedGoogle Scholar
  25. 25.
    McKinley MJ, McBurnie MI, Mathai ML (2001) Neural mechanisms subserving central angiotensinergic influences on plasma renin in sheep. Hypertension 37(6):1375–1381. CrossRefPubMedGoogle Scholar
  26. 26.
    Metzger R, Bader M, Ludwig T, Berberich C, Bunnemann B, Ganten D (1995) Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues. FEBS Lett 357(1):27–32. CrossRefPubMedGoogle Scholar
  27. 27.
    Miesel A, Müller H, Thermann M, Heidbreder M, Dominiak P, Raasch W (2010) Overfeeding-induced obesity in spontaneously hypertensive rats: an animal model of the human metabolic syndrome. Ann Nutr Metab 56(2):127–142. CrossRefPubMedGoogle Scholar
  28. 28.
    Müller-Fielitz H, Hübel N, Mildner M, Vogt FM, Barkhausen J, Raasch W (2014) Chronic blockade of angiotensin AT(1) receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats. Br J Pharmacol 171(3):746–760. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Müller-Fielitz H, Landolt J, Heidbreder M, Werth S, Vogt FM, Jöhren O, Raasch W (2012) Improved insulin sensitivity after long-term treatment with AT1 blockers is not associated with PPARgamma target gene regulation. Endocrinology 153(3):1103–1115. CrossRefPubMedGoogle Scholar
  30. 30.
    Müller-Fielitz H, Lau M, Geissler C, Werner L, Winkler M, Raasch W (2015) Preventing leptin resistance by blocking angiotensin II AT1 receptors in diet-induced obese rats. Br J Pharmacol 172(3):857–868. CrossRefPubMedGoogle Scholar
  31. 31.
    Müller-Fielitz H, Lau M, Jöhren O, Stellmacher F, Schwaninger M, Raasch W (2012) Blood pressure response to angiotensin II is enhanced in obese Zucker rats and is attributed to an aldosterone-dependent mechanism. Br J Pharmacol 166(8):2417–2429. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Müller-Fielitz H, Raasch W (2013) Angiotensin II impairs glucose utilization in obese Zucker rats by increasing HPA activity via an adrenal-dependent mechanism. Horm Metab Res 45(2):173–180. PubMedCrossRefGoogle Scholar
  33. 33.
    Müller H, Kroger J, Jöhren O, Szymczak S, Bader M, Dominiak P, Raasch W (2010) Stress sensitivity is increased in transgenic rats with low brain angiotensinogen. J Endocrinol 204(1):85–92. CrossRefPubMedGoogle Scholar
  34. 34.
    Müller H, Schweitzer N, Jöhren O, Dominiak P, Raasch W (2007) Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization. Am J Physiol Endocrinol Metab 293(3):E802–E810. CrossRefPubMedGoogle Scholar
  35. 35.
    Nakamura K, Velho G, Bouby N (2017) Vasopressin and metabolic disorders: translation from experimental models to clinical use. J Intern Med 282(4):298–309. CrossRefPubMedGoogle Scholar
  36. 36.
    Nautiyal M, Shaltout HA, de Lima DC, do NK, Chappell MC, Diz DI (2012) Central angiotensin-(1-7) improves vagal function independent of blood pressure in hypertensive (mRen2)27 rats. Hypertension 60(5):1257–1265. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Oliveira Andrade JM, Paraiso AF, Garcia ZM, Ferreira AV, Sinisterra RD, Sousa FB, Guimaraes AL, de Paula AM, Campagnole-Santos MJ, dos Santos RA, Santos SH (2014) Cross talk between angiotensin-(1-7)/Mas axis and sirtuins in adipose tissue and metabolism of high-fat feed mice. Peptides 55:158–165. CrossRefPubMedGoogle Scholar
  38. 38.
    Paxinos GWC (1998) The Rat Brain in Stereotaxic Coordinates. Academic Press, San DiegoGoogle Scholar
  39. 39.
    Porter JP, Anderson JM, Robison RJ, Phillips AC (2003) Effect of central angiotensin II on body weight gain in young rats. Brain Res 959(1):20–28. CrossRefPubMedGoogle Scholar
  40. 40.
    Raasch W, Bartels T, Schwartz C, Häuser W, Rütten H, Dominiak P (2002) Regression of ventricular and vascular hypertrophy: are there differences between structurally different angiotensin-converting enzyme inhibitors? J Hypertens 20(12):2495–2504. CrossRefPubMedGoogle Scholar
  41. 41.
    Raasch W, Dominiak P, Ziegler A, Dendorfer A (2004) Reduction of vascular noradrenaline sensitivity by AT1 antagonists depends on functional sympathetic innervation. Hypertension 44(3):346–351. CrossRefPubMedGoogle Scholar
  42. 42.
    Santos SH, Fernandes LR, Mario EG, Ferreira AV, Porto LC, Alvarez-Leite JI, Botion LM, Bader M, Alenina N, Santos RA (2008) Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes 57(2):340–347. CrossRefPubMedGoogle Scholar
  43. 43.
    Schinke M, Baltatu O, Bohm M, Peters J, Rascher W, Bricca G, Lippoldt A, Ganten D, Bader M (1999) Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. Proc Natl Acad Sci U S A 96(7):3975–3980. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Schuchard J, Winkler M, Stolting I, Schuster F, Vogt FM, Barkhausen J, Thorns C, Santos RA, Bader M, Raasch W (2015) Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1-7)/Mas-dependent pathway. Br J Pharmacol 172(15):3764–3778. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Schulz C, Paulus K, Lobmann R, Dallman M, Lehnert H (2010) Endogenous ACTH, not only alpha-melanocyte-stimulating hormone, reduces food intake mediated by hypothalamic mechanisms. Am J Physiol Endocrinol Metab 298(2):E237–E244. CrossRefPubMedGoogle Scholar
  46. 46.
    Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671. CrossRefPubMedGoogle Scholar
  47. 47.
    Sigmund CD (2012) Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 302(3):R313–R320. CrossRefPubMedGoogle Scholar
  48. 48.
    Skurk T, van Harmelen V, Blum WF, Hauner H (2005) Angiotensin II promotes leptin production in cultured human fat cells by an ERK1/2-dependent pathway. Obes Res 13(6):969–973. CrossRefPubMedGoogle Scholar
  49. 49.
    Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P (2005) Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 115(2):451–458. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Tabony AM, Yoshida T, Sukhanov S, Delafontaine P (2014) Protein phosphatase 2C-alpha knockdown reduces angiotensin II-mediated skeletal muscle wasting via restoration of mitochondrial recycling and function. Skelet Muscle 4(1):20. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wang YK, Shen D, Hao Q, Yu Q, Wu ZT, Deng Y, Chen YF, Yuan WJ, Hu QK, Su DF, Wang WZ (2014) Overexpression of angiotensin-converting enzyme 2 attenuates tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats. Am J Physiol Heart Circ Physiol 307(2):H182–H190. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Winkler M, Schuchard J, Stolting I, Vogt FM, Barkhausen J, Thorns C, Bader M, Raasch W (2016) The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats. Br J Pharmacol 173(10):1602–1617. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wright JW, Harding JW (2013) The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. Pflugers Arch 465(1):133–151. CrossRefPubMedGoogle Scholar
  54. 54.
    Wu J, Zhao D, Wu S, Wang D (2015) Ang-(1-7) exerts protective role in blood-brain barrier damage by the balance of TIMP-1/MMP-9. Eur J Pharmacol 748:30–36. CrossRefPubMedGoogle Scholar
  55. 55.
    Xia H, Sriramula S, Chhabra KH, Lazartigues E (2013) Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension. Circ Res 113(9):1087–1096. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Xiao L, Gao L, Lazartigues E, Zucker IH (2011) Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure. Hypertension 58(6):1057–1065. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Xu P, Sriramula S, Lazartigues E (2011) ACE2/ANG-(1-7)/Mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol 300(4):R804–R817. CrossRefPubMedGoogle Scholar
  58. 58.
    Yamazato M, Ferreira AJ, Yamazato Y, Diez-Freire C, Yuan L, Gillies R, Raizada MK (2011) Gene transfer of angiotensin-converting enzyme 2 in the nucleus tractus solitarius improves baroreceptor heart rate reflex in spontaneously hypertensive rats. J Renin-Angiotensin-Aldosterone Syst 12(4):456–461. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Yamazato M, Yamazato Y, Sun C, Diez-Freire C, Raizada MK (2007) Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats. Hypertension 49(4):926–931. CrossRefPubMedGoogle Scholar
  60. 60.
    Yoshida T, Semprun-Prieto L, Wainford RD, Sukhanov S, Kapusta DR, Delafontaine P (2012) Angiotensin II reduces food intake by altering orexigenic neuropeptide expression in the mouse hypothalamus. Endocrinology 153(3):1411–1420. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zhang L, Du J, Hu Z, Han G, Delafontaine P, Garcia G, Mitch WE (2009) IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting. J Am Soc Nephrol 20(3):604–612. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Zheng H, Liu X, Patel KP (2011) Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure. Am J Physiol Heart Circ Physiol 301(6):H2402–H2412. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Martina Winkler
    • 1
  • Michael Bader
    • 2
    • 3
    • 4
    • 5
    • 6
  • Franziska Schuster
    • 1
    • 7
  • Ines Stölting
    • 1
  • Sonja Binder
    • 1
  • Walter Raasch
    • 1
    • 7
    • 8
    Email author
  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity of LübeckLübeckGermany
  2. 2.National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological SciencesFederal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Max-Delbrück-Center for Molecular Medicine (MDC)BerlinGermany
  4. 4.DZHK (German Centre for Cardiovascular Research)partner site BerlinGermany
  5. 5.Center for Structural and Cell Biology in Medicine, Institute for BiologyUniversity of LübeckLübeckGermany
  6. 6.Charité – University Medicine BerlinBerlinGermany
  7. 7.CBBM (Center of Brain, Behavior and Metabolism)LübeckGermany
  8. 8.DZHK (German Centre for Cardiovascular Research)LübeckGermany

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