Obesity is often associated with hypertension, which increases the risk of developing cardiovascular disease (see commentary by Humphreys). Noting that the transcription factor nuclear factor κB (NF-κB) and its activator IKKβ (inhibitor of NF-κB kinase β) mediate obesity-associated inflammation and that the hypothalamus plays a role in the pathogenesis of obesity, Purkayastha et al. investigated a potential role for hypothalamic NF-κB signaling in linking obesity and hypertension. Retroviral expression of a constitutively active mutant of IKKβ (to activate NF-κB signaling) in the mediobasal hypothalamus of mice induced hypertension after 7 days (without inducing weight gain), which was not observed in mice infected with a control retrovirus. Conversely, retroviral expression in the mediobasal hypothalamus of a dominant-negative form of the NF-κB inhibitor IκBα (to suppress NF-κB activation) reduced obesity-related hypertension in mice fed a high-fat diet compared with that in control mice fed a high-fat diet; both sets of mice became similarly obese. Exposure of mice fed normal chow to the proinflammatory, obesity-related cytokine tumor necrosis factor–α (TNF-α) triggered hypertension in a dose-dependent manner. Immunohistochemical analysis showed that TNF-α triggered the activation of IKKβ and NF-κB in pro-opiomelanocortin (POMC) neurons in the hypothalamus. Mice in which the gene encoding IKKβ was deleted specifically in POMC neurons failed to exhibit hypertension when either exposed to TNF-α or fed a high-fat diet, although in response to a high-fat diet, both the knockout mice and the wild-type mice became similarly obese. Together, these data suggest that NF-κB signaling in POMC neurons in the hypothalamus forms a bridge between obesity and the induction of hypertension, providing a potential therapeutic target for the treatment of hypertension without needing to control obesity.
S. Purkayastha, G. Zhang, D. Cai, Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17, 883–887 (2011). [PubMed]
M. H. Humphreys, The brain splits obesity and hypertension. Nat. Med. 17, 782–783 (2011). [PubMed]