In recent years, the increasing prevalence of obesity worldwide has brought with it an epidemic of type 2 diabetes. How increased fat mass in obese individuals leads to diabetes is a fundamental, unanswered question. There is considerable support for the idea that obesity initiates an innate immune response in adipose tissue that impairs insulin action in adipocytes, leading to insulin resistance in other tissues. Research in this area has been hampered by the difficulty in finding additional components that link innate immunity to insulin signaling in humans. In this grant proposal, we describe the use of a genetically tractable organism to employ classical genetics in the identification of such genes. The highly conserved insulin signaling pathway promotes growth and nutrient storage in animals ranging from fruit flies to humans. Remarkably, the interactions between the innate immune and insulin signaling pathways are also conserved in the genetic model organism Drosophila melanogaster. Activating innate immune signaling by expressing an activated Toll transgene in the Drosophila fat body leads not only to decreased phosphorylation of dAkt, a key downstream kinase of the insulin signaling pathway, but also to decreased growth of the whole organism. The decreased growth resulting from increased immune signaling and decreased insulin signaling in the fat body forms the basis for the forward genetic screen proposed here. We aim to identify genes that, when expressed with the activated Toll transgene, reverse the effects of Toll signaling in the fat body on growth. Such genes may encode novel molecules that mediate interactions between immune signaling and insulin signaling or they may encode molecules that permit the fat body to communicate its nutrient status to other parts of the fly. By focusing our studies on genes with clear human orthologues, we hope to identify novel genes that have relevance to human diabetes. PUBLIC HEALTH RELEVANCE: Obesity almost always precedes the development of type 2 diabetes, and a growing body of evidence indicates that inflammation of obese adipose tissue and signaling between macrophages and adipocytes may underlie insulin resistance. The negative regulation of insulin signaling by the immune system is recapitulated in the fat body of the fruit fly Drosophila melanogaster, leading to decreased growth of the whole animal. The study proposed here will employ an unbiased, forward genetic approach in Drosophila to identify novel genes that link inflammation and insulin signaling, thereby providing new targets for the study and treatment of type 2 diabetes.