A Complex Relationship between Immunity and Metabolism in Drosophila Diet-Induced Insulin Resistance

ABSTRACT

Both systemic insulin resistance and tissue-specific insulin resistance have been described in Drosophila and are accompanied by many indicators of metabolic disease. The downstream mediators of insulin-resistant pathophysiology remain unclear. We analyzed insulin signaling in the fat body studying loss and gain of function. When expression of the sole Drosophila insulin receptor (InR) was reduced in larval fat bodies, animals exhibited developmental delay and reduced size in a diet-dependent manner. Fat body InR knockdown also led to reduced survival on high-sugar diets. To look downstream of InR at potential mediators of insulin resistance, transcriptome sequencing (RNA-seq) studies in insulin-resistant fat bodies revealed differential expression of genes, including those involved in innate immunity. Obesity-associated insulin resistance led to increased susceptibility of flies to infection, as in humans. Reduced innate immunity was dependent on fat body InR expression. The peptidoglycan recognition proteins (PGRPs) PGRP-SB2 and PGRP-SC2 were selected for further study based on differential expression studies. Downregulating PGRP-SB2 selectively in the fat body protected animals from the deleterious effects of overnutrition, whereas downregulating PGRP-SC2 produced InR-like phenotypes. These studies extend earlier work linking the immune and insulin signaling pathways and identify new targets of insulin signaling that could serve as potential drug targets to treat type 2 diabetes.

KEYWORDS:

• Drosophila
• diabetes
• innate immunity
• insulin receptor
• metabolism

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Article of Significant Interest Selected from This Issue by the Editors

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00259-17.

ACKNOWLEDGMENTS

We thank Ross Cagan for helpful discussions, Cláudia Nogueira Hora Marques for assistance with microbiology, and Diego Rincon-Limas for UAS-Xbp1s flies. We thank Washington University's Genome Technology Access Center for producing the RNA-seq data from our RNA. We also thank the Bloomington Drosophila Stock Center and Vienna Drosophila Resource Center for reagents.

We appreciate funding support for this project from the NIH's Diabetes Complications Consortium (P60 DK076169 to L.P.M.), BIRCWH (K12 HD00145912 to L.P.M.), the Washington University Diabetes Research and Training Center (NIH P60 DK02057934 to L.P.M.), and Binghamton University startup funds (L.P.M.).