IKK epsilon is key to induction of insulin resistance in the hypothalamus and its inhibition reverses obesity
- Laís Weissmann1,
- Paula G.F. Quaresma1,
- Andressa C. Santos1,
- Alexandre H. B. de Matos1,
- Vínicius D’Ávila Bittencourt Pascoal1,
- Tamires M. Zanotto1,
- Gisele Castro1,
- Dioze Guadgnini1,
- Joelcimar Martins da Silva3,
- Licio A. Velloso1,
- Jackson C. Bittencourt3,
- Iscia Lopes-Cendes1,
- Mario J.A. Saad1 and
- Patricia O. Prada1,2⇑
- 1Department of Internal Medicine
- 2School of Applied Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil
- 3Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
- Corresponding Author: Patricia O. Prada, PhD., E-mail:
IKK epsilon (IKKε) is induced by the activation of NFκB. Whole body IKKε knockout mice on a high fat diet (HFD) were protected from insulin resistance and showed altered energy balance. Here, 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, using CAYMAN10576 or siRNA, decreased NFκB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1Ser phosphorylation and insulin and leptin resistance by an improvement of IR/IRS-1/Akt and JAK2/STAT3 pathway 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, hypophagia, and 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 and db/db mice, suggesting a reduction on 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.
- Received November 28, 2013.
- Accepted April 27, 2014.
- © 2014 by the American Diabetes Association.
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