title: 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 condition. 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 origin. 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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Sudarshana
authors.initials: S
authors.lastname: Purkayastha
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D007031:Hypothalamus / Q000166:cytology / Q000503:physiopathology*; D051550:I-kappa B Kinase / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D011333:Pro-Opiomelanocortin; D051550:I-kappa B Kinase