Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity

By Xiaoqing Zhang, Guo Zhang, Hai Zhang, Michael Karin, Hua Bai, D. Cai. Cell, 2008

842 citations recorded by the source corpus.

SUMMARY Overnutrition is associated with chronic inflammation in metabolic tissues; however, whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Our results demonstrate that a mediator of metabolic inflammation, IKKβ/NF-κB, normally remains inactive although enriched in the hypothalamic neurons; however, overnutrition atypically activates hypothalamic IKKβ/NF-κB at least 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 involved molecular mechanisms include the control of IKKβ/NF-κB over SOCS3, a core inhibitor of insulin and leptin signaling. In conclusion, the hypothalamic IKKβ/NF-κB program is a general neural mechanism for energy imbalance underlying obesity; suppressing hypothalamic IKKβ/NF-κB represents a new strategy to combat obesity and related diseases.

Subfields: Endocrine and Autonomic Systems, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/e9f815c49c218343c26db0abf28b825504a6de6b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrine and Autonomic Systems

1. Haiming Cao
2. Jerrold M. Olefsky
3. M. Donath
4. G. Hotamışlıgil

In Epidemiology

1. Jerrold M. Olefsky
2. Haiming Cao
3. G. Hotamışlıgil
4. M. Donath
5. O. Osborn
6. S. Shoelson
7. J. Pessin
8. H. Kwon

In Physiology

1. Haiming Cao
2. Jerrold M. Olefsky
3. G. Hotamışlıgil
4. J. Pessin
5. H. Kwon
6. O. Osborn
7. S. Shoelson
8. M. Donath

Citations in the corpus

• Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease (2010, positive): “Activation of IKK-b in the brain causes ER stress and interfereswith leptin signaling (Zhang et al., 2008).”
• Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile (2013, positive): “In the central nervous system obesity-associated inflammation can disrupt leptin hypothalamic action through IKKβ/NFkβ regulation of SOCS-3 (suppressor of cytokine signaling-3), a key inhibitor of leptin signaling [67].”
• Endoplasmic reticulum stress plays a central role in development of leptin resistance. (2009, neutral): “Indeed, a recent publication has also demonstrated that PERK phosphorylation is increased in the hypothalamus of the obese mice (Zhang et al., 2008).”
• Adipokines Mediate Inflammation and Insulin Resistance (2013, positive): “More recently, amlexanox, an inhibitor of the non-canonical IκB kinases IKK-ε and TANKbinding kinase 1 (TBK1) was shown to not only improve sensitivity but to also increase energy expenditure and weight loss in obese mice (Reilly et al., 2013).”
• Type 2 diabetes as an inflammatory disease (2011, positive): “, whereas in the hypothalamus it seems that the IKKβ–NF-κB pathway affects feeding behaviour and the leptin signalling axi”
• The cellular and signaling networks linking the immune system and metabolism in disease (2012, positive): “Indeed, recent studies have demonstrated that activators of IKK-β and NF-κB in the hypothalamus can mediate leptin resistanc”