Review article: "Discovering signaling mechanisms governing metabolism and metabolic diseases with Drosophila"

Cell Metab. 2021 Jun 11:S1550-4131(21)00269-2. doi: 10.1016/j.cmet.2021.05.018.

Discovering signaling mechanisms governing metabolism and metabolic diseases with Drosophila.

Kim SK, Tsao DD, Suh GSB, Miguel-Aliaga I]

Abstract:

There has been rapid growth in the use of Drosophila and other invertebrate systems to dissect mechanisms governing metabolism. New assays and approaches to physiology have aligned with superlative genetic tools in fruit flies to provide a powerful platform for posing new questions, or dissecting classical problems in metabolism and disease genetics. In multiple examples, these discoveries exploit experimental advantages as-yet unavailable in mammalian systems. Here, we illustrate how fly studies have addressed long-standing questions in three broad areas-inter-organ signaling through hormonal or neural mechanisms governing metabolism, intestinal interoception and feeding, and the cellular and signaling basis of sexually dimorphic metabolism and physiology-and how these findings relate to human (patho)physiology. The imaginative application of integrative physiology and related approaches in flies to questions in metabolism is expanding, and will be an engine of discovery, revealing paradigmatic features of metabolism underlying human diseases and physiological equipoise in health.

Copyright © 2021 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2021.05.018
PMID: 34139200

Drosophila research helps inform hypothesis regarding effects of macrophages on metabolism

Front Cell Dev Biol. 2021 Feb 15;9:629238. doi: 10.3389/fcell.2021.629238.
eCollection 2021.

Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic
Research.

Bajgar A(1), Krejčová G(1), Doležal T(1).

Author information:
(1)Department of Molecular Biology and Genetics, University of South Bohemia,
Ceske Budejovice, Czechia.

From the abstract:

Insulin resistance and cachexia represent severe metabolic syndromes accompanying a variety of human pathological states, from life-threatening cancer and sepsis to chronic inflammatory states, such as obesity and autoimmune disorders. ... Current progress in insect immuno-metabolic research reveals that the induction of insulin resistance might represent an adaptive mechanism during the acute phase of bacterial infection. In Drosophila, insulin resistance is induced by signaling factors released by bactericidal macrophages as a reflection of their metabolic polarization toward aerobic glycolysis. Such metabolic adaptation enables them to combat the invading pathogens efficiently but also makes them highly nutritionally demanding. Therefore, systemic metabolism has to be adjusted upon macrophage activation ... We hypothesize that insulin resistance evoked by macrophage-derived signaling factors represents an adaptive mechanism for the mobilization of sources and their preferential delivery toward the activated immune system. We consider here the validity of the presented model for mammals and human medicine. ... Chronic insulin resistance is at the base of many human metabolically conditioned diseases such as non-alcoholic steatohepatitis, atherosclerosis, diabetes, and cachexia. Therefore, revealing the original biological relevance of cytokine-induced insulin resistance may help to develop a suitable strategy for treating these frequent diseases.

Copyright © 2021 Bajgar, Krejčová and Doležal.

DOI: 10.3389/fcell.2021.629238
PMCID: PMC7917182
PMID: 33659253

Fly model with high uric acid levels established for study of this key risk factor for multiple diseases

Lang S, Hilsabeck TA, Wilson KA, Sharma A, Bose N, Brackman DJ, Beck JN, Chen L, Watson MA, Killilea DW, Ho S, Kahn A, Giacomini K, Stoller ML, Chi T, Kapahi P. A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster. PLoS Genet. 2019 Aug 15;15(8):e1008318. PubMed PMID: 31415568; PubMed Central PMCID: PMC6695094.

From the abstract: "Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. ... In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene ... we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan ..."

Drosophila as model for studying genotype influence on response to high sugar consumption

Branch A, Zhang Y, Shen P. Genetic and Neurobiological Analyses of the Noradrenergic-like System in Vulnerability to Sugar Overconsumption Using a Drosophila Model. Sci Rep. 2017 Dec 15;7(1):17642. PubMed PMID: 29247240; PubMed Central PMCID: PMC5732301.

From the abstract: "Regular overconsumption of sugar is associated with obesity and type-2 diabetes, but how genetic factors contribute to variable sugar preferences and intake levels remains mostly unclear. Here we provide evidence for the usefulness of a Drosophila larva model to investigate genetic influence on vulnerability to sugar overconsumption. ..."

High-sugar diet, diabetes and the innate immune system

Yu S, Zhang G, Jin LH. A high-sugar diet affects cellular and humoral immune responses in Drosophila. Exp Cell Res. 2018 Jul 15;368(2):215-224. PMID: 29727694.

From the abstract: "A high-sugar diet (HSD) induces Type 2 diabetes (T2D) and obesity, which severely threaten human health. ... few studies have focused on the relationship between a HSD and the innate immune response in Drosophila. In this study, we fed flies a high-sucrose diet and observed defects in the phagocytosis of latex beads and B. bassiana spores. The actin cytoskeleton was also disrupted in hemocytes from HSD-fed larvae. Furthermore, HSD induced the differentiation of lamellocytes in the lymph gland and circulating hemolymph, which rarely occurs in healthy bodies, via JNK signaling. In addition, the Toll and JNK pathways were excessively activated in the fat bodies of HSD-fed larvae, and a large number of dead cells were observed. Finally, HSD induced the aberrant activation of the innate immune system, including inflammation. Our results have established a connection between T2D and the innate immune response."

Diet and the gut

Pereira MT, Malik M, Nostro JA, Mahler GJ, Musselman LP. Effect of dietary additives on intestinal permeability in both Drosophila and a human cell co-culture. Dis Model Mech. 2018 Nov 28;11(12). pii: dmm034520. PMID: 30504122.

From the abstract: "Increased intestinal barrier permeability has been correlated with aging and disease, including type 2 diabetes, Crohn's disease, celiac disease, multiple sclerosis and irritable bowel syndrome. The prevalence of these ailments has risen together with an increase in industrial food processing and food additive consumption. Additives, including sugar, metal oxide nanoparticles, surfactants and sodium chloride, have all been suggested to increase intestinal permeability. We used two complementary model systems to examine the effects of food additives on gut barrier function: a Drosophila in vivo model and an in vitro human cell co-culture model. ... This study extends previous work in flies and humans showing that diet can play a role in the health of the gut barrier. ..."

Drosophila as "providing an unparalleled opportunity to combine dietary manipulation with models of human metabolic disease and cancer" (Review Article)

Warr CG, Shaw KH, Azim A, Piper MDW, Parsons LM. Using Mouse and Drosophila Models to Investigate the Mechanistic Links between Diet, Obesity, Type II Diabetes, and Cancer. Int J Mol Sci. 2018 Dec 18;19(12). pii: E4110. PMID: 30567377.

The abstract: "Many of the links between diet and cancer are controversial and over simplified. To date, human epidemiological studies consistently reveal that patients who suffer diet-related obesity and/or type II diabetes have an increased risk of cancer, suffer more aggressive cancers, and respond poorly to current therapies. However, the underlying molecular mechanisms that increase cancer risk and decrease the response to cancer therapies in these patients remain largely unknown. Here, we review studies in mouse cancer models in which either dietary or genetic manipulation has been used to model obesity and/or type II diabetes. These studies demonstrate an emerging role for the conserved insulin and insulin-like growth factor signaling pathways as links between diet and cancer progression. However, these models are time consuming to develop and expensive to maintain. As the world faces an epidemic of obesity and type II diabetes we argue that the development of novel animal models is urgently required. We make the case for Drosophila as providing an unparalleled opportunity to combine dietary manipulation with models of human metabolic disease and cancer. Thus, combining diet and cancer models in Drosophila can rapidly and significantly advance our understanding of the conserved molecular mechanisms that link diet and diet-related metabolic disorders to poor cancer patient prognosis."

Drosophila, diabetes, and kidney disease

Rani L, Gautam NK. Drosophila renal system as an in-vivo tool for target identification and screening of potential therapeutics for the diabetic nephropathy. Curr Drug Targets. 2018 Aug 7. PMID: 30088447.

From the abstract: "... This review provides evidence for the use of Drosophila renal system as an in-vivo tool for identifying drug target against the disease. ... It also illustrates the use of Drosophila based tools for pre-screening of a potential drug for the disease."

Review article -- Drosophila as a model to study diabetes

Murillo-Maldonado JM, Riesgo-Escovar JR. Development and diabetes on the fly. Mech Dev. 2017 Apr;144(Pt B):150-155. PMID: 27702607.

From the abstract: "... Genetic model organisms, like the common fruit fly, Drosophila melanogaster, offer the possibility of studying the panoply of life processes in normal and diseased states like diabetes mellitus, from a plethora of different perspectives. ..."

Detailed molecular mechanistic study related to insulin resistance

Fischer Z, Das R, Shipman A, Fan JY, Pence L, Bouyain S, Dobens LL. A Drosophila model of insulin resistance associated with the human Trib3 Q/R polymorphism. Dis Model Mech. 2017 Oct 12. pii: dmm.030619. doi: 10.1242/dmm.030619. PMID: 29025897.

From the abstract: "Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to Akt kinase to block its phosphorylation-activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human Trib3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding resulting in reduced Akt phosphorylation and is associated with a predisposition to Type II diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis. Here we used a Drosophila model to understand the importance of the conserved R residue in several Trbl functions. ..."

Fly data as confidence filter -- Drosophila in diabetes-related research

awasaki K, Yamada S, Ogata K, Saito Y, Takahama A, Yamada T, Matsumoto K, Kose H. Use of Drosophila as an evaluation method reveals imp as a candidate gene for type 2 diabetes in rat locus Niddm22. J Diabetes Res. 2015;2015:758564. PMID: 25821834; PMCID: PMC4363715.

From the abstract: "Type 2 diabetes (T2D) is one of the most common human diseases. QTL analysis of the diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats has identified numerous hyperglycemic loci. However, molecular characterization and/or gene identification largely remains to be elucidated ... Here we utilized Drosophila melanogaster as a secondary model organism for functional evaluation of the candidate gene. We demonstrate that the tissue specific knockdown of a homologue of igf2bp2 RNA binding protein leads to increased sugar levels similar to that found in the OLETF rat. ..."

Effects on transcriptome of genotype and diet on metabolic phenotypes in Drosophila--relevance to understanding human obesity

Williams S, Dew-Budd K, Davis K, Anderson J, Bishop R, Freeman K, Davis D, Bray K, Perkins L, Hubickey J, Reed LK. Metabolomic and Gene Expression Profiles Exhibit Modular Genetic and Dietary Structure Linking Metabolic Syndrome Phenotypes in Drosophila. G3 (Bethesda). 2015 Nov 3;5(12):2817-29. PMID: 26530416; PMCID: PMC4683653.

From the abstract: "Genetic and environmental factors influence complex disease in humans, such as metabolic syndrome, and Drosophila melanogaster serves as an excellent model in which to test these factors experimentally. Here we explore the modularity of endophenotypes with an in-depth reanalysis of a previous study by Reed et al. (2014), where we raised 20 wild-type genetic lines of Drosophila larvae on four diets and measured gross phenotypes of body weight, total sugar, and total triglycerides, as well as the endophenotypes of metabolomic and whole-genome expression profiles. We then perform new gene expression experiments to test for conservation of phenotype-expression correlations across different diets and populations. We find that transcript levels correlated with gross phenotypes were enriched for puparial adhesion, metamorphosis, and central energy metabolism functions. ... This study demonstrates that variation for disease traits within a population is acquired through a multitude of physiological mechanisms, some of which transcend genetic and environmental influences, and others that are specific to an individual's genetic and environmental context."

Review of fly research related to type 2 diabetes

Alfa RW, Kim SK. Using Drosophila to discover mechanisms underlying type 2 diabetes. Dis Model Mech. 2016 Apr 1;9(4):365-76. PMID: 27053133.

From the abstract: "Mechanisms of glucose homeostasis are remarkably well conserved between the fruit fly Drosophila melanogaster and mammals. From the initial characterization of insulin signaling in the fly came the identification of downstream metabolic pathways for nutrient storage and utilization. Defects in these pathways lead to phenotypes that are analogous to diabetic states in mammals. These discoveries have stimulated interest in leveraging the fly to better understand the genetics of type 2 diabetes mellitus in humans. ... Here, we examine results from studies modeling metabolic disease in the fruit fly and compare findings to proposed mechanisms for diabetic phenotypes in mammals. We provide a systematic framework for assessing the contribution of gene candidates to insulin-secretion or insulin-resistance pathways relevant to diabetes pathogenesis."

Flies, podocytes and diabetic nephropathy

Na J, Sweetwyne MT, Park AS, Susztak K, Cagan RL. Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. Cell Rep. 2015 Jul 28;12(4):636-47. PMID: 26190114; PMCID: PMC4532696.

From the abstract: "Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly specialized component of the glomerular filtration barrier. Here, we demonstrate that the Drosophila nephrocyte, a cell analogous to the mammalian podocyte, displays defects that phenocopy aspects of diabetic nephropathy in animals fed chronic high dietary sucrose. Through functional studies, we identify an OGT-Polycomb-Knot-Sns pathway that links dietary sucrose to loss of the Nephrin ortholog Sns ..."

New study in flies and mammals related to diabetic nephropathy

Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. http://t.co/JJpcdLzpRA

— flypapers (@fly_papers) July 21, 2015

Diabetes-related fly study: from human GWAS data to fly disease model

He BZ, Ludwig MZ, Dickerson DA, Barse L, Arun B, Vilhjálmsson BJ, Jiang P, Park SY, Tamarina NA, Selleck SB, Wittkopp PJ, Bell GI, Kreitman M. Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin. Genetics. 2014 Feb;196(2):557-67. PMID: 24281155; PMCID: PMC3914626.

From the abstract: "The identification and validation of gene-gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. ... In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, and validate its contribution to disease with available genetic resources and the potential to experimentally link the variant to a molecular mechanism demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease."

Review looks at Drososophila models of metabolism-related diseases including diabetes

Padmanabha D, Baker KD. Drosophila gains traction as a repurposed tool to investigate metabolism. Trends Endocrinol Metab. 2014 Apr 22. pii: S1043-2760(14)00058-7. PMID: 24768030.

From the abstract: "... the Drosophila system is being used to identify human disease genes and has the potential to model successfully human disorders that center on excessive caloric intake and metabolic dysfunction, including diet-induced lipotoxicity and type 2 diabetes. ..."

Fly and human studies related to Wolfram syndrome

Jones MA, Amr S, Ferebee A, Huynh P, Rosenfeld JA, Miles MF, Davies AG, Korey CA, Warrick JM, Shiang R, Elsea SH, Girirajan S, Grotewiel M. Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease. Biol Open. 2014 Apr 4. pii: bio.20147559v1. PMID: 24705017.

Drosophila included in vitamin B study

Marzio A, Merigliano C, Gatti M, Vernì F. Sugar and chromosome stability: clastogenic effects of sugars in vitamin b6-deficient cells. PLoS Genet. 2014 Mar 20;10(3):e1004199. PMID: 24651653; PMCID: PMC3961173.

Review: Modeling obesity in flies.

Trinh I, Boulianne GL. Modeling obesity and its associated disorders in Drosophila. Physiology (Bethesda). 2013 Mar;28(2):117-24. PMID: 23455770.