IKK epsilon Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

Author(s):Show less -

Weissmann, Lais ^[1] ; Quaresma, Paula G. F. ^[1] ; Santos, Andressa C. ^[1] ; de Matos, Alexandre H. B. ^[1] ; Pascoal, Vinicius D'Avila Bittencourt ^[1] ; Zanotto, Tamires M. ^[1] ; Castro, Gisele ^[1] ; Guadagnini, Dioze ^[1] ; da Silva, Joelcimar Martins ^[2] ; Velloso, Licio A. ^[1] ; Bittencourt, Jackson C. ^[2] ; Lopes-Cendes, Iscia ^[1] ; Saad, Mario J. A. ^[1] ; Prada, Patricia O. ^{[1, 3]}

Affiliation

^[1] State Univ Campinas UNICAMP, Dept Internal Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil

^[3] State Univ Campinas UNICAMP, Sch Appl Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: Diabetes; v. 63, n. 10, p. 3334-3345, OCT 2014.
• Web of Science Citations: 20

Abstract

IKK epsilon (IKK epsilon) is induced by the activation of nuclear factor-kappa B (NF-kappa B). Whole-body IKK epsilon knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKK epsilon is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKK epsilon in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-kappa B activation in this tissue, relieving the inflammatory environment. Inhibition of IKK epsilon 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 IKK epsilon may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism. (AU)

• FAPESP's process: 10/52068-0 - The putative envolvement of melanin-concentrating hormone in the control of lactation
• Grantee: Jackson Cioni Bittencourt
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/10338-6 - The regulation of Clk2 and IKK epsilon in the hypothalamus of obese mice
• Grantee: Patrícia de Oliveira Prada
• Support Opportunities: Regular Research Grants