Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Insulin action in the fat cell (#238)

David James 1 , Sean Humphrey , Guang Yang , Rima Chaudhuri , Daniel Fazakerley
  1. Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia

Insulin plays a fundamental role in regulating many important physiological processes and dysfunctional insulin action is at the heart of many metabolic diseases.  We have utilised global unbiased phosphoproteomic analysis to map pathways that are regulated by insulin in various insulin responsive cell types.  This has revealed a surprisingly large insulin regulated phosphorylation network comprising thousands of regulated phosphosites.  While some of these can be linked to known insulin regulated kinases such as Akt and mTOR most remain unchartered and so represent the ‘dark phosphoproteome’.  By performing a detailed kinetic analysis of insulin signaling combined with machine learning we have begun to develop more accurate methods for assigning kinase substrate relationships.  This has led to the identification of novel Akt substrates underpinning new actions of insulin.  We have 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 rewiring of the insulin signaling network rather than simply aberrant flux through the existing network as is often assumed.  Phosphoproteomic analysis is a powerful method for assessing cellular and tissue function and future efforts probing deeper into this network will likely yield novel insights into important biological processes.