Electrolyte Blood Press.  2013 Dec;11(2):46-52. 10.5049/EBP.2013.11.2.46.

Obesity Associated Hypertension: New Insights into Mechanism

Affiliations
  • 1Division of Nephrology, Department of Internal Medicine, Medical College of Korea University, Ansan Hospital, Ansan-city, Gyeonggi, Korea. starch70@korea.ac.kr

Abstract

With excess nutrition, the burden of obesity is a growing problem worldwide. The imbalance between energy intake and expenditure leads to variable disorders as all major risk factors for cardiovascular disease. There are many hypothetical mechanisms to explain obesity-associated hypertension. Activation of the RAAS is a key contributing factor in obesity. Particularly, the RAAS in adipose tissue plays a crucial role in adipose tissue dysfunction and obesity-induced inflammation. The phenotypic changes of adipocytes occur into hypertrophy and an inflammatory response in an autocrine and paracrine manner to impair adipocyte function, including insulin signaling pathway. Adipose tissue produce and secretes several molecules such as leptin, resistin, adiponectin, and visfatin, as well as cytokines such as TNF-alpha, IL-6, MCP-1, and IL-1. These adipokines are stimulated via the intracellular signaling pathways that regulate inflammation of adipose tissue. Inflammation and oxidative stress in adipose tissue are important to interact with the microvascular endothelium in the mechanisms of obesity-associated hypertension. Increased microvascular resistance raises blood pressure. Therefore, a regulatory link between microvascular and perivascular adipose tissue inflammation and adipokine synthesis are provided to explain the mechanism of obesity-associated hypertension.

Keyword

Obesity; Hypertension; Renin-angiotensin-aldosterone system (RAAS); Microvascular dysfunction; Insulin resistance

MeSH Terms

Adipocytes
Adipokines
Adiponectin
Adipose Tissue
Blood Pressure
Cardiovascular Diseases
Cytokines
Endothelium
Energy Intake
Health Expenditures
Hypertension*
Hypertrophy
Inflammation
Insulin
Insulin Resistance
Interleukin-1
Interleukin-6
Leptin
Nicotinamide Phosphoribosyltransferase
Obesity*
Oxidative Stress
Resistin
Risk Factors
Tumor Necrosis Factor-alpha
Adipokines
Adiponectin
Cytokines
Insulin
Interleukin-1
Interleukin-6
Leptin
Nicotinamide Phosphoribosyltransferase
Resistin
Tumor Necrosis Factor-alpha

Figure

  • Fig. 1 The energy balance of human body.

  • Fig. 2 Putative mechanisms of obesity-associated hypertension including the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system(SNS), and metabolic dysregulation.

  • Fig. 3 The components of renin-angiotensin-aldosterone (RAAS) and its metabolites established in adipose tissue (*: angiotensinogen, angiotensin converting enzyme, renin, renin receptor, AT1 receptor, AT2 receptor, and Mas receptor produced from adipose tissue).

  • Fig. 4 The new therapeutic target of obesity and hypertension focusing on both adipokines and neuropeptides.


Reference

1. Kramer H. Obesity and chronic kidney disease. Contrib Nephrol. 2006; 151:1–18. PMID: 16929130.
Article
2. Landsberg L, Aronne LJ, Beilin LJ, Burke V, Igel LI, Lloyd-Jones D, et al. Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment: a position paper of The Obesity Society and the American Society of Hypertension. J Clin Hypertens (Greenwich). 2013; 15:14–33. PMID: 23282121.
3. Aghamohammadzadeh R, Heagerty AM. Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue. Ann Med. 2012; 44(Suppl 1):S74–S84. PMID: 22713152.
Article
4. Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Jarvinen H. Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes. 1999; 48:821–827. PMID: 10102699.
Article
5. Matsuzawa Y. The metabolic syndrome and adipocytokines. FEBS Lett. 2006; 580:2917–2921. PMID: 16674947.
Article
6. Ferrante AW Jr. Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med. 2007; 262:408–414. PMID: 17875176.
Article
7. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259:87–91. PMID: 7678183.
8. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996; 271:665–668. PMID: 8571133.
9. Schaffler A, Scholmerich J. Innate immunity and adipose tissue biology. Trends Immunol. 2010; 31:228–235. PMID: 20434953.
10. Majdalawieh A, Ro HS. Regulation of Ikappa Balpha function and NF-kappaB signaling: AEBP1 is a novel proinflammatory mediator in macrophages. Mediators Inflamm. 2010; 2010:823821. PMID: 20396415.
11. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009; 15:914–920. PMID: 19633658.
12. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009; 15:930–939. PMID: 19633656.
Article
13. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007; 117:175–184. PMID: 17200717.
Article
14. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11:183–190. PMID: 15685173.
15. Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes. 2010; 59:1648–1656. PMID: 20357360.
Article
16. Zeyda M, Gollinger K, Kriehuber E, Kiefer FW, Neuhofer A, Stulnig TM. Newly identified adipose tissue macrophage populations in obesity with distinct chemokine and chemokine receptor expression. Int J Obes (Lond). 2010; 34:1684–1694. PMID: 20514049.
Article
17. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999; 353:611–616. PMID: 10030325.
Article
18. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342:145–153. PMID: 10639539.
Article
19. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359:995–1003. PMID: 11937178.
20. Engeli S. Role of the renin-angiotensin-aldosterone system in the metabolic syndrome. Contrib Nephrol. 2006; 151:122–134. PMID: 16929137.
21. Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension. 2000; 35:1270–1277. PMID: 10856276.
Article
22. Campbell DJ, Habener JF. Cellular localization of angiotensinogen gene expression in brown adipose tissue and mesentery: quantification of messenger ribonucleic acid abundance using hybridization in situ. Endocrinology. 1987; 121:1616–1626. PMID: 3665835.
Article
23. 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; 15:2727–2729. PMID: 11606482.
24. Hainault I, Nebout G, Turban S, Ardouin B, Ferre P, Quignard-Boulange A. Adipose tissue-specific increase in angiotensinogen expression and secretion in the obese (fa/fa) Zucker rat. Am J Physiol Endocrinol Metab. 2002; 282:E59–E66. PMID: 11739084.
25. 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. PMID: 10933310.
Article
26. Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin-angio tensin-aldosterone system. Hypertension. 2005; 45:356–362. PMID: 15630041.
27. Thatcher S, Yiannikouris F, Gupte M, Cassis L. The adipose renin-angiotensin system: role in cardiovascular disease. Mol Cell Endocrinol. 2009; 302:111–117. PMID: 19418627.
Article
28. 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; 54:991–999. PMID: 15793237.
Article
29. 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; 146:3481–3489. PMID: 15878965.
Article
30. Santos SH, Fernandes LR, Mario EG, Ferreira AV, Porto LC, Alvarez-Leite JI, et al. Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes. 2008; 57:340–347. PMID: 18025412.
Article
31. 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; 6:506–512. PMID: 18054319.
Article
32. 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 USA. 2008; 105:6531–6536. PMID: 18443281.
Article
33. Yvan-Charvet L, Quignard-Boulange A. Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity. Kidney Int. 2011; 79:162–168. PMID: 20944545.
Article
34. Lee MH, Song HK, Ko GJ, Kang YS, Han SY, Han KH, et al. Angiotensin receptor blockers improve insulin resistance in type 2 diabetic rats by modulating adipose tissue. Kidney Int. 2008; 74:890–900. PMID: 18596725.
Article
35. Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol. 2011; 57:1511–1522. PMID: 21453829.
36. Aroor AR, Demarco VG, Jia G, Sun Z, Nistala R, Meininger GA, et al. The Role of Tissue Renin-Angio-tensin-Aldosterone System in the Development of Endothelial Dysfunction and Arterial Stiffness. Front Endocrinol (Lausanne). 2013; 4:161. PMID: 24194732.
Article
37. De Boer MP, Meijer RI, Wijnstok NJ, Jonk AM, Houben AJ, Stehouwer CD, et al. Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Microcirculation. 2012; 19:5–18. PMID: 21883642.
Article
Full Text Links
  • EBP
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2023 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr