Hypothalamic IKKβ/NF-κB 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, IKKβ/NF-κB, normally remains inactive although enriched in hypothalamic neurons. Overnutrition atypically activates hypothalamic IKKβ/NF-κB at least in part through elevated endoplasmic reticulum stress in the hypothalamus. While forced activation of hypothalamic IKKβ/NF-κB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKβ 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 IKKβ/NF-κB of SOCS3, a core inhibitor of insulin and leptin signaling. Our results show that the hypothalamic IKKβ/NF-κB program is a general neural mechanism for energy imbalance underlying obesity and suggest that suppressing hypothalamic IKKβ/NF-κB may represent a strategy to combat obesity and related diseases.