IKKε is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity.

Autor:	Weissmann L; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Quaresma PG; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Santos AC; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., de Matos AH; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Pascoal VD; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Zanotto TM; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Castro G; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Guadagnini D; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., da Silva JM; Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Velloso LA; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Bittencourt JC; Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Lopes-Cendes I; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Saad MJ; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil., Prada PO; Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil School of Applied Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil pprada@fcm.unicamp.br.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2014 Oct; Vol. 63 (10), pp. 3334-45. Date of Electronic Publication: 2014 May 08.
DOI:	10.2337/db13-1817
Abstrakt:	IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-κB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism. (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
Databáze:	MEDLINE
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