The increasing prevalence of obesity worldwide has brought with it an epidemic of type 2 diabetes. How an increase in adiposity in obese individuals leads to diabetes is a fundamental, unanswered question. Considerable evidence supports the idea that inflammation of obese adipose tissue impairs insulin action in adipocytes, leading to insulin resistance in muscle and liver. However, it has been difficult to identify additional components that link innate immunity to insulin signaling in humans. In this grant proposal, we describe the use of the genetically-tractable model organism Drosophila melanogaster to employ classical genetics in the identification of such genes. The highly conserved insulin signaling pathway acts in the Drosophila fat body to promote nutrient storage and growth of the whole animal. This organ also serves as th director of the humoral arm of the innate immune response. Remarkably, the interactions between the innate immune and insulin signaling pathways are conserved in Drosophila. Activating innate immune signaling by infection or by transgenic expression of an activated Toll receptor in the fat body leads to decreased phosphorylation of the key downstream component of the insulin signaling pathway, dAkt, and also to decreased growth and viability of the whole animal. The growth impairment and reduced viability resulting frm innate immune suppression of insulin signaling forms the basis for the forward genetic screen proposed here. Already, when performed at a small scale, such an approach has yielded novel regulators of inflammatory and insulin signaling. By performing the proposed genetic screen at a large scale, we aim to identify genes that, when overexpressed or knocked down with the activated Toll receptor in the fat body, reverse the effects of inflammatory signaling on growth. Such genes may encode novel proteins that mediate interactions between the innate immune and insulin signaling pathways, or they may encode molecules that permit the fat body to communicate its nutrient status to the rest of the fly in a manner analogous to the communication between mammalian adipose tissue and peripheral organs. By focusing our studies on genes with clear human orthologues, we hope to identify novel genes that have relevance to human disease.
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 conserved in the fat body of the fruit fly Drosophila melanogaster, leading to decreasd 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.