Insulin Action in the Fat Cell (#22)
The adipocyte has emerged as a central choreographer of whole body metabolism. One of the reasons for this is that in the hierarchy of insulin responsive cells in the body, the fat cell is possibly the most insulin responsive of all and so it is well designed to play a role in the first line of defense to manage metabolic perturbations. To begin to better understand the behavior of the fat cell we have utilized global unbiased phosphoproteomic analysis to construct a large scale map of the insulin regulated signaling network in this important cell. This has revealed key regulatory nodes together with novel substrates of major insulin regulated kinases such as Akt. Using machine learning we have discovered several new Akt substrates that have revealed novel aspects of insulin action, several of which will be discussed. We have also applied similar approaches to examine changes in insulin signaling and the total proteome in adipocytes rendered insulin resistant using a range of physiological perturbations. These studies have revealed novel insights into the mechanism of insulin resistance, which appears to involve the induction of an insulin sensitive pathway in adipocytes that impairs insulin regulated glucose metabolism.