Abstract
Substantial evidence supports a role for the renin–angiotensin system (RAS) in the regulation of metabolic function, but an apparent paradox exists where genetic or pharmacological inhibition of the RAS occasionally has similar physiological effects as chronic angiotensin infusion. Similarly, while RAS targeting in animal models has robust metabolic consequences, effects in humans are more subtle. Here, we review the data supporting a role for the RAS in metabolic rate regulation and propose a model where the local brain RAS works in opposition to the peripheral RAS, thus helping to explain the paradoxically similar effects of RAS supplementation and inhibition. Selectively modulating the peripheral RAS or brain RAS may thus provide a more effective treatment paradigm for obesity and obesity-related disorders.
Similar content being viewed by others
References
Achard V, Boullu-Ciocca S, Desbriere R, Nguyen G, Grino M (2007) Renin receptor expression in human adipose tissue. Am J Physiol Regul Integr Comp Physiol 292:R274–R282
Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH (1991) Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 324:1098–1104
Alligier M, Meugnier E, Debard C, Lambert-Porcheron S, Chanseaume E, Sothier M, Loizon E, Ait HA, Brozek J, Scoazec JY, Morio B, Vidal H, Laville M (2011) Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. J Clin Endocrinol Metab 97:E183–E192
American Diabates Association (2008) Economic costs of diabetes in the U.S. in 2007. Diabetes Care 31:596–615
Bernstein AM, Willett WC (2010) Trends in 24-h urinary sodium excretion in the United States, 1957–2003: a systematic review. Am J Clin Nutr 92:1172–1180
Bloem LJ, Manatunga AK, Tewksbury DA, Pratt JH (1995) The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest 95:948–953
Boschmann M, Ringel J, Klaus S, Sharma AM (2001) Metabolic and hemodynamic response of adipose tissue to angiotensin II. Obes Res 9:486–491
Brink M, Price SR, Chrast J, Bailey JL, Anwar A, Mitch WE, Delafontaine P (2001) Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I. Endocrinology 142:1489–1496
Carman WJ, Barrett-Connor E, Sowers M, Khaw KT (1994) Higher risk of cardiovascular mortality among lean hypertensive individuals in Tecumseh, Michigan. Circulation 89:703–711
Carter CS, Cesari M, Ambrosius WT, Hu N, Diz D, Oden S, Sonntag WE, Pahor M (2004) Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats. J Gerontol A Biol Sci Med Sci 59:416–423
Cassis LA, Dwoskin LP (1991) Presynaptic modulation of neurotransmitter release by endogenous angiotensin II in brown adipose tissue. J Neural Transm Suppl 34:129–137
Cassis L, Helton M, English V, Burke G (2002) Angiotensin II regulates oxygen consumption. Am J Physiol Regul Integr Comp Physiol 282:R445–R453
Chou CL, Lai YH, Lin TY, Lee TJ, Fang TC (2011) Aliskiren prevents and ameliorates metabolic syndrome in fructose-fed rats. Arch Med Sci 7:882–888
Cole BK, Keller SR, Wu R, Carter JD, Nadler JL, Nunemaker CS (2010) Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of a high-fat diet in mice. Hypertension 55:715–721
Cooper R, McFarlane-Anderson N, Bennett FI, Wilks R, Puras A, Tewksbury D, Ward R, Forrester T (1997) ACE, angiotensinogen and obesity: a potential pathway leading to hypertension. J Hum Hypertens 11:107–111
Crandall DL, Armellino DC, Busler DE, McHendry-Rinde B, Kral JG (1999) Angiotensin II receptors in human preadipocytes: role in cell cycle regulation. Endocrinology 140:154–158
Darimont C, Vassaux G, Ailhaud G, Negrel R (1994) Differentiation of preadipose cells: paracrine role of prostacyclin upon stimulation of adipose cells by angiotensin-II. Endocrinology 135:2030–2036
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:E1081–E1091
Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM (2005) Weight loss and the renin-angiotensin-aldosterone system. Hypertension 45:356–362
English V, Cassis L (1999) Facilitation of sympathetic neurotransmission contributes to angiotensin regulation of body weight. J Neural Transm 106:631–644
Ernsberger P, Koletsky RJ (2006) Metabolic effects of antihypertensive agents: role of sympathoadrenal and renin-angiotensin systems. Naunyn Schmiedebergs Arch Pharmacol 373:245–258
Faloia E, Gatti C, Camilloni MA, Mariniello B, Sardu C, Garrapa GG, Mantero F, Giacchetti G (2002) Comparison of circulating and local adipose tissue renin-angiotensin system in normotensive and hypertensive obese subjects. J Endocrinol Invest 25:309–314
Ferguson AV, Washburn DL, Latchford KJ (2001) Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function. Exp Biol Med (Maywood) 226:85–96
Flegal KM, Graubard BI, Williamson DF, Gail MH (2005) Excess deaths associated with underweight, overweight, and obesity. JAMA 293:1861–1867
Fleming I, Kohlstedt K, Busse R (2006) The tissue renin-angiotensin system and intracellular signalling. Curr Opin Nephrol Hypertens 15:8–13
Fowler JD, Krueth SB, Bernlohr DA, Katz SA (2009) Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations. Am J Physiol Endocrinol Metab 296:E343–E350
Galvez-Prieto B, Bolbrinker J, Stucchi P, de Las Heras AI, Merino B, Arribas S, Ruiz-Gayo M, Huber M, Wehland M, Kreutz R, Fernandez-Alfonso MS (2008) Comparative expression analysis of the renin-angiotensin system components between white and brown perivascular adipose tissue. J Endocrinol 197:55–64
Giacchetti G, Faloia E, Mariniello B, Sardu C, Gatti C, Camilloni MA, Guerrieri M, Mantero F (2002) Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens 15:381–388
Goossens GH, Blaak EE, van Baak MA (2003) Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Obes Rev 4:43–55
Gratze P, Boschmann M, Dechend R, Qadri F, Malchow J, Graeske S, Engeli S, Janke J, Springer J, Contrepas A, Plehm R, Klaus S, Nguyen G, Luft FC, Muller DN (2009) Energy metabolism in human renin-gene transgenic rats: does renin contribute to obesity? Hypertension 53:516–523
Grobe JL, Buehrer BA, Hilzendeger AM, Liu X, Davis DR, Xu D, Sigmund CD (2011) Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice. Hypertension 57:600–607
Grobe JL, Grobe CL, Beltz TG, Westphal SG, Morgan DA, Xu D, de Lange WJ, Li H, Sakai K, Thedens DR, Cassis LA, Rahmouni K, Mark AL, Johnson AK, Sigmund CD (2010) The brain renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance. Cell Metab 12:431–442
Grobe JL, Xu D, Sigmund CD (2008) An intracellular renin-angiotensin system in neurons: fact, hypothesis, or fantasy. Physiology (Bethesda) 23:187–193
Hammond RA, LeVine R (2010) The economic impact of obesity in the United States. Diabetes Metab Syndr Obes 3:285–295
Idelevich E, Kirch W, Schindler C (2009) Current pharmacotherapeutic concepts for the treatment of obesity in adults. Ther Adv Cardiovasc Dis 3:75–90
Itaya Y, Suzuki H, Matsukawa S, Kondo K, Saruta T (1986) Central renin-angiotensin system and the pathogenesis of DOCA-salt hypertension in rats. Am J Physiol 251:H261–H268
Iwai M, Tomono Y, Inaba S, Kanno H, Senba I, Mogi M, Horiuchi M (2009) AT2 receptor deficiency attenuates adipocyte differentiation and decreases adipocyte number in atherosclerotic mice. Am J Hypertens 22:784–791
Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM (2002) Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes 51:1699–1707
Jayasooriya AP, Mathai ML, Walker LL, Begg DP, Denton DA, Cameron-Smith D, Egan GF, McKinley MJ, Rodger PD, Sinclair AJ, Wark JD, Weisinger HS, Jois M, Weisinger RS (2008) Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. Proc Natl Acad Sci USA 105:6531–6536
Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM (1998) Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 83:3925–3929
Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556
Kouyama R, Suganami T, Nishida J, Tanaka M, Toyoda T, Kiso M, Chiwata T, Miyamoto Y, Yoshimasa Y, Fukamizu A, Horiuchi M, Hirata Y, Ogawa Y (2005) Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor. Endocrinology 146:3481–3489
Krysiak R, Sierant M, Marek B, Bienek R, Okopien B (2010) The effect of angiotensin-converting enzyme inhibitors on plasma adipokine levels in normotensive patients with coronary artery disease. Endokrynol Pol 61:280–287
Kubo T, Yamaguchi H, Tsujimura M, Hagiwara Y, Fukumori R (2000) Blockade of angiotensin receptors in the anterior hypothalamic preoptic area lowers blood pressure in DOCA-salt hypertensive rats. Hypertens Res 23:109–118
Lavoie JL, Sigmund CD (2003) Minireview: overview of the renin-angiotensin system–an endocrine and paracrine system. Endocrinology 144:2179–2183
Lee-Kirsch MA, Gaudet F, Cardoso MC, Lindpaintner K (1999) Distinct renin isoforms generated by tissue-specific transcription initiation and alternative splicing. Circ Res 84:240–246
Massiera F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu A, Gasc JM, Quignard-Boulange A, Negrel R, Ailhaud G, Seydoux J, Meneton P, Teboul M (2001) Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J 15:2727–2729
Massiera F, Seydoux J, Geloen A, Quignard-Boulange A, Turban S, Saint-Marc P, Fukamizu A, Negrel R, Ailhaud G, Teboul M (2001) Angiotensinogen-deficient mice exhibit impairment of diet induced weight gain with alteration in adipose tissue development and increased locomotor activity. Endocrinology 142:5220–5225
Masuo K, Mikami H, Ogihara T, Tuck ML (2001) Weight reduction and pharmacologic treatment in obese hypertensives. Am J Hypertens 14:530–538
Mathai ML, Chen N, Cornall L, Weisinger RS (2011) The role of angiotensin in obesity and metabolic disease. Endocr Metab Immune Disord Drug Targets 11:198–205
Mathai ML, Naik S, Sinclair AJ, Weisinger HS, Weisinger RS (2008) Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats. Int J Obes (Lond) 32:1576–1584
Matsushita K, Wu Y, Okamoto Y, Pratt RE, Dzau VJ (2006) Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes. Hypertension 48:1095–1102
McClendon KS, Riche DM, Uwaifo GI (2009) Orlistat: current status in clinical therapeutics. Expert Opin Drug Saf 8:727–744
Messerli FH, Nunez BD, Ventura HO, Snyder DW (1987) Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity. Arch Int Med 147:1725–1728
Mogi M, Iwai M, Horiuchi M (2006) Emerging concept of adipogenesis regulation by the renin-angiotensin system. Hypertension 48:1020–1022
Morimoto S, Cassell MD, Sigmund CD (2002) Glial- and neuronal-specific expression of the renin-angiotensin system in brain alters blood pressure, water intake, and salt preference. J Biol Chem 277:33235–33241
Morrison SF, Nakamura K, Madden CJ (2008) Central control of thermogenesis in mammals. Exp Physiol 93:773–797
Park CG, Leenen FH (2001) Effects of centrally administered losartan on deoxycorticosterone-salt hypertension rats. J Korean Med Sci 16:553–557
Porter JP, Anderson JM, Robison RJ, Phillips AC (2003) Effect of central angiotensin II on body weight gain in young rats. Brain Res 959:20–28
Porter JP, Potratz KR (2004) Effect of intracerebroventricular angiotensin II on body weight and food intake in adult rats. Am J Physiol Regul Integr Comp Physiol 287:R422–R428
Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, Sigmund CD (2007) Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest 117:1088–1095
Santos EL, de Picoli SK, Guimaraes PB, Reis FC, Silva SM, Costa-Neto CM, Luz J, Pesquero JB (2008) Effect of angiotensin converting enzyme inhibitor enalapril on body weight and composition in young rats. Int Immunopharmacol 8:247–253
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 57:340–347
Satin M (2011) The salt debate–more salacious than salubrious. Nutrition 27:759–760
Saye JA, Ragsdale NV, Carey RM, Peach MJ (1993) Localization of angiotensin peptide-forming enzymes of 3T3-F442A adipocytes. Am J Physiol 264:C1570–C1576
Sinn PL, Sigmund CD (2000) Identification of three human renin mRNA isoforms from alternative tissue-specific transcriptional initiation. Physiol Genom 3:25–31
Stec DE, Davisson RL, Haskell RE, Davidson BL, Sigmund CD (1999) Efficient liver-specific deletion of a floxed human angiotensinogen transgene by adenoviral delivery of cre-recombinase in vivo. J Biol Chem 274:21285–21290
Stec DE, Keen HL, Sigmund CD (2002) Lower blood pressure in floxed angiotensinogen mice after adenoviral delivery of cre-recombinase. Hypertension 39:629–633
Stucchi P, Cano V, Ruiz-Gayo M, Fernandez-Alfonso MS (2009) Aliskiren reduces body-weight gain, adiposity and plasma leptin during diet-induced obesity. Br J Pharmacol 158:771–778
Sui Y, Zhao HL, Fan RR, Guan J, He L, Lee HM, Chan JC, Tong PC (2010) Renin-angiotensin system activation in renal adipogenesis. Am J Physiol Renal Physiol 298:F391–F400
Takahashi N, Li F, Hua K, Deng J, Wang CH, Bowers RR, Bartness TJ, Kim HS, Harp JB (2007) Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin. Cell Metab 6:506–512
Thatcher S, Yiannikouris F, Gupte M, Cassis L (2009) The adipose renin-angiotensin system: role in cardiovascular disease. Mol Cell Endocrinol 302:111–117
Vetter ML, Faulconbridge LF, Webb VL, Wadden TA (2010) Behavioral and pharmacologic therapies for obesity. Nat Rev Endocrinol 6:578–588
Wang P, Holst C, Wodzig WK, Andersen MR, Astrup A, van Baak MA, Larsen TM, Jebb SA, Kafatos A, Pfeiffer AF, Martinez JA, Handjieva-Darlenska T, Kunesova M, Viguerie N, Langin D, Saris WH, Mariman EC (2012) Circulating ACE is a predictor of weight loss maintenance not only in overweight and obese women, but also in men. Int J Obes (Lond) (in press)
Weiland F, Verspohl EJ (2008) Variety of angiotensin receptors in 3T3-L1 preadipose cells and differentiated adipocytes. Horm Metab Res 40:760–766
Weisinger RS, Stanley TK, Begg DP, Weisinger HS, Spark KJ, Jois M (2009) Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet. Physiol Behav 98:192–197
Xu D, Borges GR, Davis DR, Agassandian K, Sequeira Lopez ML, Gomez RA, Cassell MD, Grobe JL, Sigmund CD (2011) Neuron- or glial-specific ablation of secreted renin does not affect renal renin, baseline arterial pressure or metabolism. Physiol Genom 43:286–294
Xu D, Borges GR, Grobe JL, Pelham CJ, Yang B, Sigmund CD (2009) Preservation of intracellular renin expression is insufficient to compensate for genetic loss of secreted renin. Hypertension 54:1240–1247
Yang G, Merrill DC, Thompson MW, Robillard JE, Sigmund CD (1994) Functional expression of the human angiotensinogen gene in transgenic mice. J Biol Chem 269:32497–32502
Yiannikouris F, Karounos M, Charnigo R, English VL, Rateri DL, Daugherty A, Cassis LA (2012) Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice. Am J Physiol Regul Integr Comp Physiol 302:R244–R251
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. doi:10.1210/en.2011-1764
Yvan-Charvet L, Even P, Bloch-Faure M, Guerre-Millo M, Moustaid-Moussa N, Ferre P, Quignard-Boulange A (2005) Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance. Diabetes 54:991–999
Yvan-Charvet L, Massiera F, Lamande N, Ailhaud G, Teboul M, Moustaid-Moussa N, Gasc JM, Quignard-Boulange A (2009) Deficiency of angiotensin type 2 receptor rescues obesity but not hypertension induced by overexpression of angiotensinogen in adipose tissue. Endocrinology 150:1421–1428
Yvan-Charvet L, Quignard-Boulange A (2011) Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity. Kidney Int 79:162–168
Zanchi A, Dulloo AG, Perregaux C, Montani JP, Burnier M (2007) Telmisartan prevents the glitazone-induced weight gain without interfering with its insulin-sensitizing properties. Am J Physiol Endocrinol Metab 293:E91–E95
Zorad S, Dou JT, Benicky J, Hutanu D, Tybitanclova K, Zhou J, Saavedra JM (2006) Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma. Eur J Pharmacol 552:112–122
Acknowledgments
This work was supported by research grants from the US National Institutes of Health including HL098276 to JLG, HL014388 to KR, HL084207 to CDS and KR, and HL048058 and HL061446 to CDS. KR was also supported by a grant (1-11-BS-127) from the American Diabetes Association. The authors also gratefully acknowledge the generous support of the Roy J. Carver Trust.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published as part of the special issue on the Renin-Angiotensin System.
Rights and permissions
About this article
Cite this article
Grobe, J.L., Rahmouni, K., Liu, X. et al. Metabolic rate regulation by the renin–angiotensin system: brain vs. body. Pflugers Arch - Eur J Physiol 465, 167–175 (2013). https://doi.org/10.1007/s00424-012-1096-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-012-1096-9