Ikkε Is Key To Induction Of Insulin Resistance In The Hypothalamus, And Its Inhibition Reverses Obesity.


Autoria(s): Weissmann, Laís; Quaresma, Paula G F; Santos, Andressa C; de Matos, Alexandre H B; Pascoal, Vínicius D'Ávila Bittencourt; Zanotto, Tamires M; Castro, Gisele; Guadagnini, Dioze; da Silva, Joelcimar Martins; Velloso, Licio A; Bittencourt, Jackson C; Lopes-Cendes, Iscia; Saad, Mario J A; Prada, Patricia O
Contribuinte(s)

UNIVERSIDADE DE ESTADUAL DE CAMPINAS

Data(s)

01/10/2014

27/11/2015

27/11/2015

Resumo

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.

63

3334-45

Identificador

Diabetes. v. 63, n. 10, p. 3334-45, 2014-Oct.

1939-327X

10.2337/db13-1817

http://www.ncbi.nlm.nih.gov/pubmed/24812431

http://repositorio.unicamp.br/jspui/handle/REPOSIP/201387

24812431

Idioma(s)

eng

Relação

Diabetes

Diabetes

Direitos

fechado

© 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.

Fonte

PubMed

Palavras-Chave #Animals #Body Weight #Diet, High-fat #Hypothalamus #I-kappa B Kinase #Insulin #Insulin Resistance #Leptin #Liver #Male #Mice #Mice, Obese #Neurons #Obesity #Phosphorylation #Signal Transduction #Up-regulation
Tipo

Artigo de periódico