Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity

Overnutrition is associated with chronic inflammation in metabolic tissues. Whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Here we show that a mediator of metabolic inflammation, IKKbeta/NF-kappaB,...

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Bibliographic Details
Published in:Cell 2008-10, Vol.135 (1), p.61-73
Main Authors: Zhang, Xiaoqing, Zhang, Guo, Zhang, Hai, Karin, Michael, Bai, Hua, Cai, Dongsheng
Format: Article
Language:English
Subjects:
Agouti-Related Protein - genetics
Agouti-Related Protein - metabolism
Animals
Endoplasmic Reticulum - metabolism
Energy Metabolism
Humans
Hypothalamus - immunology
Hypothalamus - physiopathology
I-kappa B Proteins - metabolism
Immunity, Innate
Insulin Resistance
Mice
Mice, Inbred C57BL
Neurons - metabolism
NF-kappa B - metabolism
Obesity - metabolism
Overnutrition - physiopathology
Signal Transduction
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins - metabolism
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Summary:Overnutrition is associated with chronic inflammation in metabolic tissues. Whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Here we show that a mediator of metabolic inflammation, IKKbeta/NF-kappaB, normally remains inactive although enriched in hypothalamic neurons. Overnutrition atypically activates hypothalamic IKKbeta/NF-kappaB at least in part through elevated endoplasmic reticulum stress in the hypothalamus. While forced activation of hypothalamic IKKbeta/NF-kappaB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKbeta either broadly across the brain or locally within the mediobasal hypothalamus, or specifically in hypothalamic AGRP neurons significantly protects against obesity and glucose intolerance. The molecular mechanisms involved include regulation by IKKbeta/NF-kappaB of SOCS3, a core inhibitor of insulin and leptin signaling. Our results show that the hypothalamic IKKbeta/NF-kappaB program is a general neural mechanism for energy imbalance underlying obesity and suggest that suppressing hypothalamic IKKbeta/NF-kappaB may represent a strategy to combat obesity and related diseases.
ISSN:1097-4172
DOI:10.1016/j.cell.2008.07.043