Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB

Abstract

Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition1,2,3. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin4,5,6,7,8,9,10,11,12,13. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor κB (NF-κB) and its upstream activator IκB kinase-β (IKK-β, encoded by Ikbkb) in the mediobasal hypothalamus rapidly elevated blood pressure in mice independently of obesity. This form of hypothalamic inflammation-induced hypertension involved the sympathetic upregulation of hemodynamics and was reversed by sympathetic suppression. Loss-of-function studies further showed that NF-κB inhibition in the mediobasal hypothalamus counteracted obesity-related hypertension in a manner that was dissociable from changes in body weight. In addition, we found that pro-opiomelanocortin (POMC) neurons were crucial for the hypertensive effects of the activation of hypothalamic IKK-β and NF-κB, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-β and NF-κB in the mediobasal hypothalamus—particularly in the hypothalamic POMC neurons—is a primary pathogenic link between obesity and hypertension. Breaking this pathogenic link may represent an avenue for controlling obesity-related hypertension and CVD without requiring obesity control.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Effects of manipulating hypothalamic IKK-β and NF-κB on blood pressure in C57BL/6 mice.
Figure 2: Effects of TNF-α injection via the third ventricle on blood pressure in C57BL/6 mice.
Figure 3: Activation of IKK-β and NF-κB by TNF-α in POMC neurons.
Figure 4: Hypotensive effect of POMC neuron-specific IKK-β ablation.

References

  1. Schwartz, M.W. & Porte, D. Jr. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).

    Article  CAS  Google Scholar 

  2. Münzberg, H. & Myers, M.G. Jr. Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8, 566–570 (2005).

    Article  Google Scholar 

  3. Howard, J.K. & Flier, J.S. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 17, 365–371 (2006).

    Article  CAS  Google Scholar 

  4. Osborn, J.W., Fink, G.D., Sved, A.F., Toney, G.M. & Raizada, M.K. Circulating angiotensin II and dietary salt: converging signals for neurogenic hypertension. Curr. Hypertens. Rep. 9, 228–235 (2007).

    Article  CAS  Google Scholar 

  5. Veerasingham, S.J. & Raizada, M.K. Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br. J. Pharmacol. 139, 191–202 (2003).

    Article  CAS  Google Scholar 

  6. Veerasingham, S.J., Sellers, K.W. & Raizada, M.K. Functional genomics as an emerging strategy for the investigation of central mechanisms in experimental hypertension. Prog. Biophys. Mol. Biol. 84, 107–123 (2004).

    Article  CAS  Google Scholar 

  7. Campese, V.M. et al. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am. J. Physiol. Heart Circ. Physiol. 287, H695–H703 (2004).

    Article  CAS  Google Scholar 

  8. Guyenet, P.G. The sympathetic control of blood pressure. Nat. Rev. Neurosci. 7, 335–346 (2006).

    Article  CAS  Google Scholar 

  9. Wofford, M.R. & Hall, J.E. Pathophysiology and treatment of obesity hypertension. Curr. Pharm. Des. 10, 3621–3637 (2004).

    Article  CAS  Google Scholar 

  10. Dampney, R.A. et al. Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. Clin. Exp. Pharmacol. Physiol. 32, 419–425 (2005).

    Article  CAS  Google Scholar 

  11. Haynes, W.G. Role of leptin in obesity-related hypertension. Exp. Physiol. 90, 683–688 (2005).

    Article  CAS  Google Scholar 

  12. Rahmouni, K., Correia, M.L., Haynes, W.G. & Mark, A.L. Obesity-associated hypertension: new insights into mechanisms. Hypertension 45, 9–14 (2005).

    Article  CAS  Google Scholar 

  13. Hall, J.E. et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J. Biol. Chem. 285, 17271–17276 (2010).

    Article  CAS  Google Scholar 

  14. Shoelson, S.E. & Goldfine, A.B. Getting away from glucose: fanning the flames of obesity-induced inflammation. Nat. Med. 15, 373–374 (2009).

    Article  CAS  Google Scholar 

  15. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  Google Scholar 

  16. Lehrke, M. & Lazar, M.A. Inflamed about obesity. Nat. Med. 10, 126–127 (2004).

    Article  CAS  Google Scholar 

  17. Petersen, K.F. & Shulman, G.I. Etiology of insulin resistance. Am. J. Med. 119, S10–S16 (2006).

    Article  Google Scholar 

  18. Berg, A.H. & Scherer, P.E. Adipose tissue, inflammation and cardiovascular disease. Circ. Res. 96, 939–949 (2005).

    Article  CAS  Google Scholar 

  19. Muoio, D.M. & Newgard, C.B. Obesity-related derangements in metabolic regulation. Annu. Rev. Biochem. 75, 367–401 (2006).

    Article  CAS  Google Scholar 

  20. Schenk, S., Saberi, M. & Olefsky, J.M. Insulin sensitivity: modulation by nutrients and inflammation. J. Clin. Invest. 118, 2992–3002 (2008).

    Article  CAS  Google Scholar 

  21. Duan, S.Z., Usher, M.G. & Mortensen, R.M. PPARs: the vasculature, inflammation and hypertension. Curr. Opin. Nephrol. Hypertens. 18, 128–133 (2009).

    Article  CAS  Google Scholar 

  22. Harrison, D.G., Guzik, T.J., Goronzy, J. & Weyand, C. Is hypertension an immunologic disease? Curr. Cardiol. Rep. 10, 464–469 (2008).

    Article  Google Scholar 

  23. Savoia, C. & Schiffrin, E.L. Inflammation in hypertension. Curr. Opin. Nephrol. Hypertens. 15, 152–158 (2006).

    CAS  PubMed  Google Scholar 

  24. Shoelson, S.E., Lee, J. & Goldfine, A.B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    Article  CAS  Google Scholar 

  25. Cai, D. NFkappaB-mediated metabolic inflammation in peripheral tissues versus central nervous system. Cell Cycle 8, 2542–2548 (2009).

    Article  CAS  Google Scholar 

  26. Zhang, X. et al. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008).

    Article  CAS  Google Scholar 

  27. Kleinridders, A. et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10, 249–259 (2009).

    Article  CAS  Google Scholar 

  28. Posey, K.A. et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 296, E1003–E1012 (2009).

    Article  CAS  Google Scholar 

  29. Goncalves, A.C. et al. Diabetic hypertensive leptin receptor-deficient db/db mice develop cardioregulatory autonomic dysfunction. Hypertension 53, 387–392 (2009).

    Article  Google Scholar 

  30. Hayden, M.S. & Ghosh, S. Shared principles in NF-κB signaling. Cell 132, 344–362 (2008).

    Article  CAS  Google Scholar 

  31. Hoffmann, A. & Baltimore, D. Circuitry of nuclear factor κB signaling. Immunol. Rev. 210, 171–186 (2006).

    Article  Google Scholar 

  32. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

    Article  CAS  Google Scholar 

  33. Li, Q. & Verma, I.M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).

    Article  CAS  Google Scholar 

  34. Faustman, D. & Davis, M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat. Rev. Drug Discov. 9, 482–493 (2010).

    Article  CAS  Google Scholar 

  35. Xu, A.W. et al. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115, 951–958 (2005).

    Article  CAS  Google Scholar 

  36. Kuo, J.J., da Silva, A.A., Tallam, L.S. & Hall, J.E. Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation. Hypertension 43, 370–375 (2004).

    Article  CAS  Google Scholar 

  37. Greenfield, J.R. et al. Modulation of blood pressure by central melanocortinergic pathways. N. Engl. J. Med. 360, 44–52 (2009).

    Article  CAS  Google Scholar 

  38. Tallam, L.S., Stec, D.E., Willis, M.A., da Silva, A.A. & Hall, J.E. Melanocortin-4 receptor–deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension 46, 326–332 (2005).

    Article  CAS  Google Scholar 

  39. Farah, V.M., Joaquim, L.F., Bernatova, I. & Morris, M. Acute and chronic stress influence blood pressure variability in mice. Physiol. Behav. 83, 135–142 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Barsh and A. Xu for Pomc-Cre and Agrp-Cre mice. This study was supported by US National Institutes of Health grants (RO1 DK078750 and RO1 AG 031774) (D.C.) and by an American Diabetes Association Junior Faculty Award (1-07-JF-09) (D.C.).

Author information

Authors and Affiliations

Authors

Contributions

D.C. conceived and designed the study; S.P. did experiments shown in Figures 1, 2 and 4 with assistance from G.Z. and D.C.; and G.Z. also carried out experiments shown in Figure 3. All authors did data analysis and interpretation. D.C. wrote the paper.

Corresponding author

Correspondence to Dongsheng Cai.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 756 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Purkayastha, S., Zhang, G. & Cai, D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat Med 17, 883–887 (2011). https://doi.org/10.1038/nm.2372

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2372

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing