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

Abstract

Systemic and tissue-specific insulin resistance have been described in , 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 using loss- and gain-of-function. When expression of the sole 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, 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.

Transgenerational inheritance of cold temperature response in Drosophila

“…) gene enrichment together is also in agreement with the well‐established relationship between intestinal bacteria and metabolism in diverse species including fly . As TAG levels were found altered in several of the above metabolic studies , are associated with cold tolerance in D. melanogaster , and, notably, show alterations in the offspring of cold‐exposed mice , we identified altered TAG regulation as a potential trait that might be inherited following cold exposure.…”

Immune Regulation of Intestinal Stem Cell Proliferation and Differentiation in Drosophila

“…At present, we know little about cell-specific aspects of IMD activity in the midgut. For example, several lines of evidence implicate IMD in metabolic homeostasis (17,(51)(52)(53). However, we don't know if these immunemetabolic links are cell-intrinsic, or if they are secondary to IMD-mediated changes to the gut microbiota, with attendant shifts in microbial control of metabolism in the host.…”

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

“…In addition, several studies identified interaction points between immune and insulin responses in the fly. For example, depletion of the insulin receptor from the fat body alters the expression of immune response genes, and alters sensitivity to infection (Musselman et al, 2017). Furthermore, mutations of the IRS homolog chico increase survival after infection with Pseudomonas aeruginosa and Enterococcus faecalis (Libert et al, 2008); challenges with Mycobacterium marinum lower AKT phosphorylation, and diminish systemic insulin activity (Dionne et al, 2006); activation of TOR blocks AMP expression (Varma et al, 2014); infection increases expression of the FOXO-responsive transcript 4E-BP ortholog thor (Bernal and Kimbrell, 2000); and FOXO regulates the expression of intestinal antimicrobial peptides (Becker et al, 2010).…”

“…These observations suggest broad tissue autonomy in IMD responses. In contrast, 29.8% of genes affected by IMD activation are also affected by loss of the insulin receptor in fat tissue (Musselman et al, 2017) (Figure 4D, E). The overlap between the two gene sets includes genes required for fatty acid beta-oxidation, carbohydrate metabolism, and the TCA cycle.…”