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

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(1-3). 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 origin4-13. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor kB (NF-kappa B) and its upstream activator I kappa B kinase-beta (IKK-beta, 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-kappa B 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-beta and NF-kappa B, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-beta and NF-kappa B 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.