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

IKK epsilon is key to induction of insulin resistance in the hypothalamus and its inhibition reverses obesity.
Diabetes. 2014 May 8;
Authors: Weissmann L, Quaresma PG, Santos AC, de Matos AH, D'Ávila Bittencourt Pascoal V, Zanotto TM, Castro G, Guadgnini D, Martins da Silva J, Velloso LA, Bittencourt JC, Lopes-Cendes I, Saad MJ, Prada PO
Abstract
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-1(Ser) 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 ...

Source: Diabetes - May 8, 2014 Category: Endocrinology Authors: Weissmann L, Quaresma PG, Santos AC, de Matos AH, D'Ávila Bittencourt Pascoal V, Zanotto TM, Castro G, Guadgnini D, Martins da Silva J, Velloso LA, Bittencourt JC, Lopes-Cendes I, Saad MJ, Prada PO Tags: Diabetes Source Type: research