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

Cell 135, 61–73, October 3, 2008

Speaker: Peihua Wu (吳佩樺)                                  Time: 13:10-14:00, Sep 23, 2009

Commentator: Dr. Yau-Sheng Tsai (蔡曜聲)          Place: Room 601

Abstract:

Obesity is characterized by chronic activation of inflammatory pathway which is causally linked to insulin resistance and type 2 diabetes (T2D)(1). Research revealed activation of both c-JUN N-terminal kinase (JNK) and inhibitor of kappa B kinase (IKKβ) pathways in the liver leads to systemic insulin resistance(2). In peripheral tissues, the endoplasmic reticulum (ER), when under stress, interferes with insulin action and promotes weight gain and T2D(3). In this study, the authors found that IKKβ was enriched but normally inactive in mediobasal hypothalamus (MBH), where is the primary site of integration and regulation of energy homeostasis. The activation of IKKβ/NF-κB in hypothalamus was induced by overnutrition. Targeting to IKKβ in MBH by virus-carried dominant negative IKKβ or genetic suppression, decreased high fat diet (HFD)-induced weight gain. They further found that HFD or IKKβ/NF-κB activation elevated ER stress in hypothalamus. When they provided a chronic intra-third ventricle treatment of ER stress inhibitor, TUDCA, on mice with HFD, the degree of obesity was significantly decreased. After delivery of constitutively active IKKβ, insulin and leptin signalings, as reported function together to control energy balance in hypothalamus, were impaired. Furthermore, the leptin or insulin-mediated reduction in food intake was reversed by activation of IKKβ/NF-κB. They disrupted IKKβ in the orexigenic AGRP neurons, a critical source of hypothalamic insulin and leptin signaling, by breeding floxed IKKβ (IKKβ^lox/lox) mice with AGRP-specific Cre (AGRP-Cre) mice. The body weight and food intake of AGRP/IKKβ^lox/lox mice were less than controls after 12 weeks of the HFD. Since recent research indicated SOCS3 is a critical inhibitor for both insulin and leptin signaling in the hypothalamus, they further examined whether SOCS3 was involved in the effects of hypothalamic IKKβ/NF-κB on energy balance. Their results revealed that a HFD significantly induced SOCS3 in the MBH. The exogenous expression of SOCS3 in the MBH neurons significantly decreased the reductions in weight gain and food intake of AGRP/IKKβ^lox/lox mice. In summary, these results provide a link between ER stress and metabolic dysfunction of the hypothalamus through activation of IKKβ. Therefore, hypothalamic IKKβ may be a potential target to counter obesity and T2D.

References:

1.         M. Lehrke, M. A. Lazar, Nat Med 10, 126 (Feb, 2004).

2.         D. Cai et al., Nat Med 11, 183 (Feb, 2005).

3.         U. Ozcan et al., science 306, 457 (Oct 15, 2004).