Abstract

Obesity can reduce the body’s responsiveness to insulin, a phenomenon termed “insulin resistance”. Insulin resistance, in turn, drives cells in the pancreas to churn out ever-increasing amounts, a burden that over time, induces diabetes. There are no FDA-approved medicines that specifically restore insulin sensitivity in obesity. Our proposal is based on data indicating that in obesity, insulin-responsive cells in the liver and fat engorged with fats undergo stress in the endoplasmic reticulum, an organelle responsible for making and folding new proteins. Chronic “ER stress” promotes inflammation and cell death. The trigger for this response is governed by a protein called IRE1alpha, and we have developed and used a series of genetic tools and cutting-edge small molecules that precisely targeting IRE1alpha to normalize blood glucose in mouse models of obesity. With these tools in hand, we are poised to fill several important gaps in this field: 1) We will determine the relative contribution of the liver, fat, muscle, and pancreas to the beneficial metabolic effects of systemically inhibiting IRE1alpha. 2) We will determine the role of IRE1alpha’s ability to specifically sense lipid stress in preserving insulin action in mouse and human cells. 3) We will explore how IRE1alpha activation in obesity impacts gene expression networks in the liver, fat, and muscle, and the extent to which pharmacologic interventions can normalize these networks. These studies will validate IRE1alpha as a lynchpin in the ER stress-induced pathophysiology of type 2 diabetes and unveil tools to reverse diabetes with high molecular precision.