Editors' ChoiceMetabolism

Stressing the Response to an Inflamed Hypothalamus

Science Signaling  07 Oct 2008:
Vol. 1, Issue 40, pp. ec349
DOI: 10.1126/scisignal.140ec349

Overnutrition—in which energy consumption exceeds energy expenditure—is associated with inflammatory signaling in peripheral metabolic tissues, which can lead to metabolic changes associated with obesity and diabetes. For instance, activation of the IKKβ-NF-κB pathway in liver leads to systemic insulin resistance (see Yang and Hotamisligil). Noting that overnutrition interferes with central sensitivity to leptin and insulin signaling, and that disruption of hormonal signaling to the hypothalamus itself promotes obesity and diabetes, Zhang et al. investigated the role of hypothalamic IKKβ-NF-κB signaling in the metabolic consequences of overnutrition. Although IKKβ was abundant in neurons of the mediobasal hypothalamus (MBH, a region involved in nutrient sensing) of mice fed standard chow, it was inactive and NF-κB activity was low. A high-fat diet (HFD) increased NF-κB activity; indeed, even acute administration of glucose or oleic acid into the third cerebral ventricle (near the hypothalamus) activated hypothalamic NF-κB. Exogenous stimulation of MBH IKKβ-NF-κB signaling with a constitutively active form of IKKβ (IKKβCA) enhanced food intake and weight gain in mice fed a HFD, whereas inhibition of MBH IKKβ-NF-κB signaling with a dominant-negative form of IKKβ reduced them, as did genetic ablation of IKKβ in brain, MBH, or AGRP neurons (a group of hypothalamic neurons involved in central metabolic signaling). Expression of IKKβCAin the MBH impaired hypothalamic sensitivity to insulin and leptin, whereas IKKβ ablation in AGRP neurons protected against induction of central insulin and leptin resistance by HFD. HFD induced hypothalamic endoplasmic reticulum (ER) stress [assessed by phosphorylation of PERK (PKR-like ER kinase)], and ventricular administration of an inhibitor of ER stress attenuated HFD activation of NF-κB, whereas an ER stress inducer activated NF-κB. Indeed, chronic administration of the ER stress inhibitor protected against HFD-induced obesity. Expression of IKKβCAin the MBH of chow-fed mice elicited an increase in hypothalamic SOCS3 (suppressor of cytokine signaling-3, an inhibitor of insulin and leptin signaling) mRNA and protein. HFD also increased hypothalamic SOCS3 mRNA, an increase blocked in mice lacking IKKβ in AGRP neurons. Moreover, expression of exogenous SOCS3 in MBH neurons partially overcame the obesity-resistant phenotype of these mice. Thus, the authors conclude that hypothalamic IKKβ-NF-κB signaling—and ER stress—play a critical role in the metabolic response to overnutrition.

X. Zhang, G. Zhang, H. Zhang, M. Karin, H. Bai, D. Cai, Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61-73 (2008). [Online Journal]

L. Yang, G. S. Hotamisligil, Stressing the brain, fattening the body. Cell 135, 20-22 (2008). [Online Journal]