Sympathetic nervous system in obesity-related hypertension: mechanisms and clinical implications

Hypertension Research - Tập 35 Số 1 - Trang 4-16 - 2012
Graziela Z Kalil1, William G. Haynes2
1Division of Endocrinology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2Divisions of Endocrinology and Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

CDC. State-specific prevalence of obesity among adults—United States, 2009. MMWR 2009; 59: 1–5.

Matshushita Y, Takahashi Y, Mizoue T, Inoue M, Noda M, Tsugane S . Overweight and obesity trends among Japanese adults: a 10-year follow-up of the JPHC Study. Int J Obes 2008; 32: 1861–1867.

Lapidus L, Bengtsson C, Bjorntorp P . The quantitative relationship between ‘the metabolic syndrome’ and abdominal obesity in women. Obes Res 1994; 4: 372–377.

Emerging Risk Factors Collaboration Wormser D, Kaptoge S, Di Angelantonio E, Wood AM, Pennells L, Thompson A, Sarwar N, Kizer JR, Lawlor DA, Nordestgaard BG, Ridker P, Salomaa V, Stevens J, Woodward M, Sattar N, Collins R, Thompson SG, Whitlock G, Danesh J . Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet 2011; 377: 1085–1095.

Brown CD, Higgins M, Donato KA, Rohde FC, Garrison R, Obarzanek E, Ernst ND, Horan M . Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res 2000; 8: 605–619.

Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, Granger JP . Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension 1995; 25: 893–897.

Samuelson A, Morris A, Igosheva N, Kirk SL, Pombo JMC, Coen CW, Poston L, Taylor PD . Evidence for sympathetic origins of hypertension in juvenile offspring of obese rats. Hypertension 2010; 55: 76–82.

Tuck ML . Obesity, the sympathetic nervous system and essential hypertension. Hypertension 1992; 19: I67–I77.

Shibao C, Gamboa A, Diedrich A, Ertl AC, Chen KY, Byrne DW, Farley G, Paranjape SY, Davis SN, Biaggioni I . Autonomic contribution to blood pressure and metabolism in obesity. Hypertension 2007; 49: 27–33.

Wofford MR, Anderson Jr DC, Brown CA, Jones DW, Miller ME, Hall JE . Antihypertensive effect of α- and β-adrenergic blockade in obese and lean hypertensive subjects. Am J Hypertens 2001; 14: 694–698.

Grassi G, Seravalle G, Cattaneo BM, Bolla GB, Lanfranchi A, Colombo M, Giannattasio C, Brunani A, Cavagnini F, Mancia G . Sympathetic activation in obese normotensive subjects. Hypertension 1995; 25: 560–563.

Vaz M, Jennings G, Turner A, Cox H, Lambert G, Esler M . Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. Circulation 1997; 96: 3423–3429.

Lambert E, Straznicky N, Schlaich M, Esler M, Dawood T, Hotchkin E, Lambert G . Differing pattern of sympathoexcitation in normal-weight and obesity-related hypertension. Hypertension 2007; 50: 862–868.

Agapitov AV, Correia MLG, Sinkey CA, Haynes WG . Dissociation between sympathetic nerve traffic and sympathetically mediated vascular tone in normotensive human obesity. Hypertension 2008; 52: 687–695.

Correia MLG, Agapitov AV, Siney CA, Mark AL, Haynes WG . Obesity does not increase sympathetic vascular tone in hypertensives. Am J Hypertens 2005; 2: 195A.

Correia M, Agapitov A, Siney C, Mark A, Haynes W . Weight loss does not reduce sympathetic vascular tone I obese hypertensives. Obes Res 2005; 3 (Suppl): A47.

Correia, Marcelo Lima De Gusmao. ‘Sympathetic Vascular Tone in Human Obesity’ PhD diss., University of Iowa, 2007. http://ir.uiowa.edu/etd/134 .

Tappy L, Girardet K, Schwaller N, Vollenweider L, Jequier E, Nodod P, Scherrer U . Metabolic effects of an increase of sympathetic activity in healthy humans. Int J Obesity Metab Dis 1995; 19: 419–422.

Young JB, Weiss J, Boufath N . Effects of dietary monosaccharides on sympathetic nervous system activity in adipose tissues of male rats. Diabetes 2004; 53: 1271–1278.

Serazin V, Dos Santos E, Morot M, Giudicelli Y . Human adipose angiotensinogen gene expression and secretion are stimulated by cyclic AMP via increased DNA cyclic AMP responsive element binding activity. Endocrine 2004; 25: 97–104.

Licata G, Volpe M, Scaglione R, Rubattu S . Salt-regulating hormones in young normotensive obese subjects. Effects of saline load. Hypertension 1994; 23: 1020–1024.

Tuck ML, Sowers J, Dornfeld L, Kledzik G, Maxwell M . The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930–933.

Cooper R, Forrester T, Ogunbiyi O, Muffinda J . Angiotensinogen levels and obesity in four black populations. ICSHIB Investigators. J Hypertens 1998; 16: 571–575.

Engeli S, Sharma AM . The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension. J Mol Med 2001; 79: 21–29.

Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM . Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005; 45: 356–362.

Giacchetti G, Faloia E, Sardu C, Camilloni MA, Mariniello B, Gatti C, Garrapa GG, Guerrieri M, Mantero F . Gene expression of angiotensinogen in adipose tissue of obese patients. Int J Obes Relat Metab Disord 2000; 24 (Suppl 2): S142–S143.

Van Harmelen V, Ariapart P, Hoffstedt J, Lundkvist I, Bringman S, Arner P . Increased adipose angiotensinogen gene expression in human obesity. Obes Res 2000; 8: 337–341.

Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL . Hyperinsulinemia produces both sympathetic neural activation and vasodilatation in normal humans. J Clin Invest 1991; 87: 2246–2252.

Anderson EA, Balon TW, Hoffman RP, Sinkey CA, Mark AL . Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension 1992; 19: 621–627.

Hausberg M, Hoffman RP, Somers VK, Sinkey CA, Mark AL, Anderson EA . Contrasting autonomic and hemodynamic effects of insulin in healthy elderly versus young subjects. Hypertension 1997; 29: 700–705.

Rahmouni K, Morgan DA, Morgan GM, Liu X, Sigmund CD, Mark AL, Haynes WG . Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest 2004; 114: 625–628.

Dallman MF, Strack AM, Akana SF, Bradburry MJ, Hanson ES, Scribner KA, Smith M . Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol 1993; 14: 303–347.

Goodwin JE, Zhang J, Geller DS . A critical role for vascular smooth muscle in acute glucocorticoid-induced hypertension. J Am Soc Nephrol 2008; 19: 1291–1299.

Sato A, Funder JW, Okubo M, Kubota E, Saruta T . Glucocorticoid-induced hypertension in the elderly relation to serum calcium and family history of essential hypertension. Am J Hypertens 1995; 8: 823–828.

Grassi G, Seravalle G, Dell Oro R, Turri C, Pasqualinotto L, Colombo M, Mancia G . Participation of the hypothalamus-hypophysis axis in the sympathetic activation of human obesity. Hypertension 2001; 38: 1316–1320.

Matias I, Di Marzo V . Endocannabinoids and the control of energy balance. Trends Endocrinol Metabol 2007; 18: 27–37.

Jamshidi N, Taylor DA . Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 2001; 134: 1151–1154.

Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, Pacher P, Harvery-White J, Luft FC, Sharma AM, Jordan J . Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005; 54: 2838–2843.

Pacher P, Batkai S, Kunos G . Blood pressure regulation by endocannabinoids and their receptors. Neuropharmacology 2005; 48: 1130–1138.

Brozoski DT, Dean C, Hopp FA, Hillard CJ, Seagard JL . Differential endocannabinoid regulation of baroreflex-evoked sympathoactivation in normotensive versus hypertensive rats. Auton Neurosci 2009; 150: 82–93.

Ruilope LM, Despres JP, Scheen A, Pi-Sunyer X, Mancia G, Zanchetti A, Van Gaal L . Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results. J Hypertens 2008; 26: 357–367.

Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G . Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410: 822–825.

Tschop M, Smiley DL, Heiman ML . Ghrelin induces adiposity in rodents. Nature 2000; 407: 908–913.

Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML . Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707–709.

Langenberg C, Bergstrom J, Laughlin GA, Barrett-Connor E . Ghrelin and the metabolic syndrome in older adults. J Clin Endocrinol Metab 2005; 90: 6448–6453.

Lambert E, Lambert G, Ika-Sari C, Dawood T, Lee K, Chopra R, Straznicky N, Eikelis N, Drew S, Tilbrook A, Dixon J, Esler M, Schlaich MP . Ghrelin modulates sympathetic nervous system activity and stress response in lean and overweight men. Hypertension 2011; 58: 43–50.

Li ZF, Guo ZF, Yang SG, Zheng X, Cao J, Qin YW . Circulating ghrelin and ghrelin to obestatin ration are low in patients with untreated mild-to-moderate hypertension. Regul Pept 2010; 165: 206–209.

Berthold HK, Giannakidou E, Krone W, Tregouet DA, Gouni-Berthold I . Influence of ghrelin gene polymorphisms on hypertension and atherosclerotic disease. Hypertens Res 2010; 33: 155–160.

Haqq AM, Stadler DD, Rosenfeld RG, Pratt KL, Weigle DS, Frayo RS, LaFranchi SH, Cummings DE, Purnell JQ . Circulating ghrelin levels are suppressed by meals and octreotide therapy in Prader-Willi Syndrome. J Clin Endocrinol Metab 2003; 88: 3573–3576.

Vogels A, Fryns JP . Age at diagnosis, body mass index and physical morbidity in children and adults with the Prader-Willi syndrome. Genet Couns 2004; 15: 397–404.

Tanida M, Shen J, Horii Y, Matsuda M, Kihara S, Funahashi T, Shimomura I, Sawai H, Fukuda Y, Matsuzawa Y, Nagai K . Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats. Exp Biol Med 2007; 232: 390–397.

Vasunta RL, Kesaniemi YA, Ukkola O . Plasma adiponectin concentration is associated with ambulatory daytime systolic blood pressure but not with the dipping status. J Hum Hypertens 2010; 24: 545–551.

Celoria BMJ, Genelhu VA, Duarte SFP, Delfraro PAS, Francischetti EA . Hypoadiponectinemia is associated with prehypertension in obese individuals of multiethnic origin. Clin Cardiol 2010; 33: E61–E65.

Lim SY, Davidson SM, Paramanathan AJ, Smith CC, Yellon DM, Hausenloy DJ . The novel adipocytokine visfatin exerts direct cardioprotective effects. J Cell Mol Med 2008; 12: 1395–1403.

Kawamoto R, Tabara Y, Kohara K, Miki T, Kusunoki T, Takayama S, Abe M, Katoh A, Ostsuka N . Relationships between lipid profiles and metabolic syndrome, insulin resistance and serum high molecular adiponectin in Japanese community-dwelling adults. Lipids Health Dis 2011; 10: 79.

Kawamoto R, Tabara Y, Kohara K, Abe M, Kusunoki T, Miki T . Association of serum high molecular weight adiponectin and blood pressure among non-diabetic community dwelling men. Clin Exp Hypertens 2011; 33: 336–344.

Takahashi N, Anan F, Nakagawa M, Yufu K, Shinohara T, Tsubone T, Goto K, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Hara M, Saikawa T, Yoshimatsu H . Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123I-metaiodobenzylguanidine scintigraphy. Metabolism 2007; 56: 919–924.

Leu H-B, Chung C-M, Lin S-J, Jong Y-S, Pan W-H, Chen JW . Adiponectin gene polymorphism is selectively associated with the concomitant presence of metabolic syndrome and essential hypertension. PLoS One 2011; 6: e19999.

Ai M, Otokozawa S, Asztalos BF, White CC, Cupples LA, Nakajima K, Lamon-Fava S, Wilson PW, Matsuzawa Y, Shaefer EJ . Adiponectin: an independent risk factor for coronary heart disease in men in the Framingham offspring Study. Atherosclerosis 2011; 217: 543–548.

Thomopoulos C, Daskalaki M, Papazachou O, Rodolakis N, Bratsas A, Papadopoulos DP, Papavasileiou MV, Perrea D, Makris T . Association of resistin and adiponectin with different clinical blood pressure phenotypes. J Hum Hypertens 2011; 25: 38–46.

Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM . Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546.

Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI . Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997; 100: 270–278.

Correia ML, Morgan DA, Sivitz WI, Mark AL, Haynes WG . Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure. Hypertension 2001; 37: 936–942.

Shek EW, Brands MW, Hall JE . Chronic leptin infusion increases arterial pressure. Hypertension 1998; 31: 409–414.

Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, Matsuoka N, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Nakao K . Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 2000; 105: 1243–1252.

Carlyle M, Jones OK, Kuo JJ, Hall JE . Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 2002; 39: 496–501.

Farooqi SI, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S . Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879–884.

Ozata M, Ozdemir IC, Licino 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: 3686–3695.

Shintani M, Ikegami H, Fujisawa T, Kamaguchi Y, Ohishi M, Katsuya T, Higaki J, Shimmoto K, Ogihara T . Leptin gene polymorphism is associated with hypertension independent of obesity. J Clin Endocrinol Metab 2002; 87: 2909–2912.

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: 918–926.

Shankar A, Xiao J . Positive relationship between plasma leptin level and hypertension. Hypertension 2010; 56: 623–628.

Grøntved A, Steene-Johannessen J, Kynde I, Franks PW, Helge JW, Froberg K, Anderssen SA, Andersen LB . Association between plasma leptin and blood pressure in two population-based samples of children and adolescents. J Hypertens 2011; 29: 1093–1100.

Abramson JL, Lewis C, Murrah NV . Body mass index, leptin, and ambulatory blood pressure variability in healthy adults. Atherosclerosis 2011; 214: 456–461.

Rahmouni K, Haynes WG, Morgan DA, Mark AL . Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 2003; 41: 763–767.

Rahmouni K, Sigmund CD, Haynes WG, Mark AL . Mitogen activated protein kinase: a newly discovered mediator of selective leptin actions. Hypertension 2005; 46: 867.

Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers Jr MG . STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature 2003; 421: 856–859.

Flier JS . Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116: 337–350.

Fruhbeck G . Intracellular signaling pathways activated by leptin. Biochem J 2006; 393: 7–20.

Correia ML, Haynes WG, Rahmouni K, Morgan DA, Sivitz WI, Mark AL . The concept of selective leptin resistance: evidence from agouti yellow obese mice. Diabetes 2002; 51: 439–442.

Rahmouni K, Haynes WG, Morgan DA, Mark AL . Selective resistance to central neural administration of leptin in agouti obese mice. Hypertension 2002; 39: 486–490.

Rahmouni K, Morgan DA, Morgan GM, Mark AL, Haynes WG . Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes 2005; 54: 2012–2018.

Haynes WG, Morgan DA, Djalali A, Sivitz W, Mark AL . Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 1999; 33: 542–547.

Hausberg M, Morgan DA, Chapleau MA, Sivitz WI, Mark AL, Haynes WG . Differential modulation of leptin-induced sympathoexcitation by baroreflex activation. J Hypertens 2002; 20: 1633–1641.

Marsh AJ, Fontes MA, Killinger S, Pawlak DB, Polson JW, Dampney RA . Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension 2003; 42: 488–493.

Munzberg H, Myers Jr MG . Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 2005; 8: 566–570.

Munzberg H, Flier JS, Bjorbaek C . Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 2004; 145: 4880–4889.

Rhamouni K, Sigmund CD, Haynes WG, Mark AL . Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes 2009; 58: 536–542.

Lund IK, Hansen JA, Andersen HS, Moller NP, Billestrup N . Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signaling. J Mol Endocrinol 2005; 34: 339–351.

Kaszubska W, Falls HD, Schaefer VG, Haasch D, Frost L, Hessler P, Kroeger PE, White DW, Jirousek MR, Trevillyan JM . Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol Cell Endocrinol 2002; 195: 109–118.

Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy BP, Tremblay ML . Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2002; 4: 497–503.

Morrison CD, White CL, Wang Z, Lee SY, Lawrence DS, Cefaly WT, Zhang ZY, Gettys TW . Increased hypothalamic protein tyrosine phosphatase 1 contributes to leptin resistance with age. Endocrinology 2007; 148: 433–440.

Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Meyers Jr MG, Ozan U . Endoplasmic reticulum plays a central role in development of leptin resistance. Cell Metabolism 2009; 9: 31–51.

Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U . The regulatory subunits of PI3K, p85 alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med 2010; 4: 429–437.

Agata J, Masuda A, Takada M, Hiashura K, Murakami H, Miyazaki Y, Shimamoto K . High plasma immunoreactive leptin level in essential hypertension. Am J Hypertens 1997; 10: 1171–1174.

Matsubara M, Chiba H, Maruoka S, Katayose S . Elevated serum leptin concentrations in women with components of multiple risk factor clustering syndrome. J Atheroscler Thromb 2000; 7: 231–237.

Barba G, Russo O, Siani A, Iacone R, Farinaro E, Gerardi MC, Russo P, Della Valle E, Strazzullo P . Plasma leptin and blood pressure in men: graded association independent of body mass and fat pattern. Obes Res 2003; 11: 160–166.

Alvarez-Aguilar C, Mondragon-Jimenez LI, Ramirez-Enriquez J, Gomez-Garcia A, Paniagua-Sierra R, Amato D . Hyperleptinemia as a risk factor in obesity-related hypertension. Med Clin 2004; 123: 766–769.

Nakamura Y, Ueshima H, Okuda N, Murakami Y, Miura K, Kita Y, Okamura T, Turin TC, Rodriguez B, Curb JD, Stamler J . Relation of serum leptin to blood pressure of Japanese in Japan and Japanese-Americans in Hawaii. Hypertension 2009; 54: 1416–1422.

Kramer CK, von Muhlen D, Barrett-Connor E . Does leptin predict incident hypertension in older adults? Clin Endocrinol 2010; 73: 201–205.

Eikelis N, Schlaich M, Aggarwal A, Kaye D, Esler M . Interactions between leptin and the human sympathetic nervous system. Hypertension 2003; 41: 1072–1079.

Mackintosh RM, Hirsch J . The effects of leptin administration in non-obese human subjects. Obes Res 2001; 9: 462–469.

Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL . Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005; 115: 3579–3586.

Banglore S, Parkar S, Grossman E, Messerli F . A meta-analysis of 94 492 patients with hypertension treated with beta-blockers to determine the risk of new-onset diabetes mellitus. J Am Coll Cardiol 2007; 100: 1254–1262.

Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Ledeballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H . Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 995–1003.

Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Östergren J, for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required, in the Anglo-Scandinavian Cardiac Outcomes Trial Blood-Pressure Lowering Arm (ASCOT-BPLA): a multicenter randomized controlled trial. Lancet 2005; 366: 895–906.

Simone G, Wachtell K, Palmieri V, Hille DA, Beevers G, Dhlof B, Faire U, Fyhrquist F, Ibsen H, Julius S, Kjeldsen SE, Laderballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Devereux RB . Body build and risk of cardiovascular events in hypertension and left ventricular hypertrophy: the LIFE (Losartan Intervention for Endpoint reduction in hypertension) Study. Circulation 2005; 111: 1924–1931.

UKPDS. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications of type 2 diabetes: UKPDS 39. BMJ 1998; 317: 713–720.

Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH . Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension a randomized controlled trial. JAMA 2004; 292: 2227–2236.

Grassi G, Trevano FQ, Facchini A, Toutouzas T, Chanu B, Mancia G . Efficacy and tolerability profile of nebivolol vs atenolol in mid-to-moderate essential hypertension: results of a double-blind randomized multicentre trial. Blood Press Suppl 2003; 2: 35–40.

Correia ML, Haynes WG . Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs 2005; 10: 643–660.

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Diuretics versus beta-blocker as first-step antihypertensive therapy: the final results from the antihypertensive therapy. The final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 2003; 42: 239–246.

Cushman WC, Ford CE, Einhorn PT, Wright JT, Preston RA, Davis BR, Basile JN, Whelton PK, Weiss RJ, Bastien A, Courtney DL, Hamilton BP, Kirchner K, Louis GT, Retta TM, Vidt DG, for the ALLHAT Collaborative Research Group. Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2008; 10: 751–760.

Wright JT, Harris-Haywood S, Pressel S, Barzilay J, Baimbridge C, Bareis CJ, Basile JN, Black HR, Dart R, Gupta AK, Hamilton BP, Einhorn PT, Haywood J, Jafri SZA, Lois GT, Whelton PK, Scott CL, Simmons DL, Stanford C, Davis BR . Clinical outcomes by race in patients with or without the metabolic syndrome ALLHAT. Arch Intern Med 2008; 168: 207–217.

Barzilay JI, Davis BR, Bettencourt J, Margolis KL, Goff DC, Black H, Habib G, Ellsworth A, Force RW, Wiegman T, Ciocon JO, Basile JN . Cardiovascular outcomes using doxazosin vs chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT Study. J Clin Hypertens 2004; 6: 116–125.

Topal E, Cikim AS, Cikim K, Temel I, Ozdemir R . The effect of moxonidine on endothelial dysfunction in metabolic syndrome. Am J Cardiovasc Drugs 2006; 6: 343–348.

Reisin E, Weir MR, Falkner B . Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) Study Group. Hypertension 1997; 30 (1 Part 1): 140–145.

Jordan J, Engeli S, Boye SW, Le Breton S, Keefe DL . Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 2007; 49: 1047–1055.

Sowers JR, Raij L, Jiall I, Egan BM, Ofili EO, Zappe DH, Purkayastha D, Deedwanis PC . Angiotensin receptor blocker/diuretic combination preserves insulin responses in obese hypertensives. J Hypertens 2010; 28: 1761–1799.

Jordan J, Engeli S, Boschmann M, Weidinger G, Luft FC, Sharma AM, Kreuzberg U . Hemodynamic and metabolic responses to valsartan and atenolol in obese hypertensive patients. J Hypertens 2005; 23: 2313–2318.

Elliott WJ, Meyer PM . Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369: 201–207.

Jansen PM, Danser JAH, Spiering W, Meiracket AH . Drug mechanisms to help in managing resistant hypertension in obesity. Curr Hypertens Rep 2010; 12: 220–225.

de Souza F, Muxfeldt E, Fiszman R, Salles G . Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension 2010; 55: 147–152.

Ernst ME, Carter BL, Goerdt C, Steffensmeir JJG, Philips BB, Zimmerman MB, Bergus GR . Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006; 47: 352–358.

Cooper-Dehoff RM, Wen S, Beitelshees AL, Zineh I, Gums JG, Turner ST, Gong Y, Hall K, Parekh V, Chapman AB, Boerwinkle E, Johnson JA . Impact of abdominal obesity on incidence of adverse metabolic effects associated with antihypertensive medications. Hypertension 2010; 55: 61–68.

Gentille CL, Orr JS, Davy BM, Davy KP . Modest weight gain is associated with sympathetic neural activation in non-obese humans. Am J Physiology Regal Integra Comp Physiology 2007; 292: R1834–R1838.

Andersson B, Elam M, Wallin BG, Bjorntorp P, Andersson OK . Effect of energy-restricted diet on sympathetic muscle nerve activity in obese women. Hypertension 1991; 18: 783–789.

Grassi G, Seravalle G, Colombo M, Bolla G, Cattaneo BM, Cavagnini F, Mancia G . Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans. Circulation 1998; 97: 2037–2042.

Trombetta IC, Batalha LT, Rondon MUPB, Laterza MC, Kuniyoshi FHS, Gowdak MMG, Barretto ACP, Halpern A, Villares SMF, Negrao CE . Weight loss improves neurovascular muscle metaboreflex control in obesity. Am J Physiol Heart Circ Physiol 2003; 285: H974–H982.

Straznicky NE, Lambert EA, Lambert GW, Masuo K, Esler MD, Nestel PJ . Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome. J Clin Endocrinol Metab 2005; 90: 5998–6005.

Neter JE, Stam BE, Kok FJ, Robbee DE, Geleijnse JM . Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2003; 42: 878–884.

Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR, and the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010; 363: 245–256.

Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett S, Kaplan RA, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J . Role of orlistat in the treatment of obese patients with type 2 diabetes. Diabetes Care 1998; 21: 1288–1294.

Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M . A randomized double-blind placebo-controlled study of the long term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Metab Disord 2004; 28: 1399–1410.

Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW . Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese (CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet 2011; 377: 1341–1352.

Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD, Dunayevich E . Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomized, double-blind, placebo-controlled, phase 5 trial. Lancet 2010; 376: 595–605.

The Look AHEAD Research Group. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus. Arch Intern Med 2010; 170: 1566–1575.

Sjostrom L, Narbro K, Sjostrom D, Karason K, Larrsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, Dahlgreen S, Gummesson A, Jacobson P, Karlsson J, Lindroos AK, Lonroth H, Naslund I, Olbers T, Senlof K, Torgerson J, Agren G . Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357: 741–752.

James WPT, Caterson ID, Coutinho W, Finer N, Van Gaal L, Maggioni AP, Torp-Pedrsen C, Sharma AM, Shepherd GM, Rode RA, Renz CL, SCOUT Investigator Group. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363: 905–917.

Agapitov AV, Correia ML, Sinkey CA, Phillips BG, Haynes WG . Weight loss does not alter sympathetically-mediated vascular tone in normotensive obese humans. Pharmacotherapy 2002; 22: 1329–1330.

Correia ML, Agapitov A, Sinkey CA, Haynes WG . Vasodilatation induced by beta2 adrenergic receptor activation is impaired in obese hypertensives before and after weight loss. J Hypertens 2010; 28: e437.

Nogueiras R, Perez D, Christelle VD, Varela L, Haynes WG, Patterson JT, Disse E, Pfluger PT, Lopez M, Woods SC, DiMarchi R, Diegues C, Rahmouni K, Rohner-Jeanrenaud F, Tschop MH . Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet induced obesity. J Neurosci 2009; 29: 5916–5925.

Astrup A, Bosser S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME . Efffects of liraglutide in the treatment of obesity: a randomized, double-blind, placebo-controlled stud. Lancet 2009; 374: 1606–1616.

Toplak H, Haman A, Moore A, Masson E, Gorska M, Vercryusse F, Sun X, Fitchet M . Efficacy and safety of topiramate in combination with metformin in the treatment of the obese subject with type 2 diabetes: a randomized, double-blind, placebo controlled study. Int J Obes 2007; 31: 138–146.

Roth JD, Hughes H, Kendall E, Baron AD, Anderson CM . Antiobesity effects of the beta-cell hormone amylin in diet-induced obese rats: effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology 2006; 147: 5855–5864.

Roth JD, Roland BL, Cole R, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD . Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA 2008; 105: 7257–7262.

Amylin Pharmaceuticals USA. Pramlintide Acetate Prescribing Information. Revised July 2008. Amylin Pharmaceuticals USA: San Diego, CA, 2008.

Aronne LJ, Halseth AE, Burns CM, Miller S, Shen LZ . Enhanced weight loss following coadministration of pramlintide with sibutramine or phentermine in a multicenter trial. Obesity 2010; 18: 1739–1746.

Wulffelé MG, Kooy A, Zeeuw D, Stehouwer CDA, Gansevoort RT . The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med 2004; 256: 1–14.

Holman RR, Paul SK, Bethel A, Matthews DR, Neil HAW . 10-year follow-up of intensive glucose control in Type 2 diabetes. N Engl J Med 2008; 359: 1–13.

Diabetes Prevention Program Research Group. Intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care 2005; 28: 888–894.

O’brien PE, Dixon JB, Laurie C, Skinner S, Rioretto J, Mcneil JM . Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding. Ann Intern Med 2006; 144: 625–633.

Hofso D, Nordtrand N, Johnson LK, Karlsen TI, Hager H, Jenssen T, Bollersev J, Godang K, Sandbu R, Roilsien J, Hjelmeseth J . Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention. Eur J Endocrinol 2010; 163: 735–745.

Erondu N, Addy C, Kaifeng L, Mallick M, Musser B, Gantz I, Prioretto J, Astrup A, Toubro S, Rissannen A, Tonstad S, Haynes WG, Gottesdiener K, Kaufan KD, Amatruda JM, Heymsfield SB . NPY5R Antagonism does not augment the weight loss efficacy of orlistat vs sibutramine. Obesity 2007; 15: 2027–2042.

United States Food and Drug Administration (FDA) NDA 22580 Briefing Documents. Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Gaithersburg, MD 2010.

Kang JG, Park CY, Kang JH, Park YW, Park SW . Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity. Diabetes Obes Metab 2010; 12: 876–882.

Cercato C, Roizenblatt VA, Leanca CC, Segal A, Lopes Filho AP, Mancini MC, Halpern A . A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes 2009; 33: 857–865.

Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKenney J, O’Neil PM . Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res 2002; 10: 633–641.

Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Kempf M . Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998; 352: 167–172.

Torgerson JS, Boldrin MN, Hauptman J, Sjostrom L . Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: a randomize study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27: 155–161.

Miles JM, Leiter L, Hollander P, Wadden T, Anderson JW, Doyle M, Forey T, Aronne L, Klein S . Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes Care 2002; 25: 11123–11128.

Buse JB, Rosenstock J, Sesti G, Schimidt WE, Montanya E, Brett JH, Zychma M, Blonde L, LaEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 10: 633–641.

Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M, Perry BH . A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003; 11: 722–733.

Tonstad S, Tykarski A, Weissgarten J, Ivleva A, Levy B, Fitchet M . Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am J Cardiol 2005; 96: 243–251.

Stenlof K, Rossner S, Verruysse F, Kumar A, Fitchet M, Sjostrom L . Topiramate in the treatment of obese subjects with drug-naïve type 2 diabetes. Diabetes Obes Metab 2007; 9: 360–368.

Gadde KM, Franciscy DM, Wagner II HR, Krishnan KR . Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 2003; 289: 1820–1825.