Metabolism Separating Obesity from Hypertension

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

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 B (NF-B) and its activator IKKβ (inhibitor of NF-B 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-B signaling in linking obesity and hypertension. Retroviral expression of a constitutively active mutant of IKKβ (to activate NF-B 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-B inhibitor IBα (to suppress NF-B 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-B 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-B 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-B. Nat. Med. 17, 883–887 (2011). [PubMed]

M. H. Humphreys, The brain splits obesity and hypertension. Nat. Med. 17, 782–783 (2011). [PubMed]

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