Inflammation Improves Glucose Homeostasis through IKKβ-XBP1s Interaction

It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. I kappa B kinase beta (IKK beta) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor a (TNF-alpha) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKK beta-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKK beta phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKK beta activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKK beta-mediated hepatic inflammation in glucose homeostasis.