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 ..."

Fly research contributes to studies related to obesity -- 2 reports

Guida MC, Birse RT, Dall'Agnese A, Toto PC, Diop SB, Mai A, Adams PD, Puri PL, Bodmer R. Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila. Nat Commun. 2019 Jan 14;10(1):193. PMID: 30643137; PMCID: PMC6331650.

From the abstract: "Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure and thus mortality. ... and increasing evidence suggests that the parents' nutritional status may predispose their offspring to lipotoxic cardiomyopathy. ... Here we report that cardiac dysfunction induced by high-fat-diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1. We provide evidence that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, we find that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations."

Justice AE, Karaderi T, Highland HM, et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nat Genet. 2019 Feb 18. PMID: 30778226.

Abstract: "Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants."

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 research a highlight in a review article about obesity-related research

Mirth CK, Piper MD. Matching complex dietary landscapes with the signalling pathways that regulate life history traits. Curr Opin Genet Dev. 2017 Dec;47:9-16. doi: 10.1016/j.gde.2017.08.001. PMID: 28822885.

From the abstract: "The rise in obesity in human populations has reinvigorated research focused on how nutrition impacts life history traits, including body size, lifespan, reproductive success, stress resistance and propensity for disease. ... Here, we offer our perspective on how to integrate insights from the cellular to the whole organism to understand the regulation of life history traits."

Cactus-feeding flies provide opportunity for study of metabolic syndrome

Cázarez-García D, Ramírez Loustalot-Laclette M, Ann Markow T, Winkler R. Lipidomic profiles of Drosophila melanogaster and cactophilic fly species: models of human metabolic diseases. Integr Biol (Camb). 2017 Nov 13;9(11):885-891. doi: 10.1039/c7ib00155j. PubMed PMID: 29043354.

Abstract: "The metabolic syndrome (MetS) is associated with serious diseases and represents an important threat for global public health. The common fruit fly (Drosophila melanogaster) has served as a model organism to study physiological processes of the MetS, because central metabolic pathways are conserved among species, and because the flies are easy to cultivate in a laboratory. In nature, D. melanogaster is a fruit generalist, feeding on diets rich in simple carbohydrates. Other Drosophilids, however, have specialized on distinct resources. Drosophila mojavensis, for example, is endemic to the Sonoran Desert, where it feeds on necrotic cacti which are low in carbohydrates. Its close relative Drosophila arizonae is cactophilic as well, but is also found breeding in fruits containing simple sugars. Previous studies have shown that high-sugar diets negatively affect the larval development of D. mojavensis and increase their triglyceride content, compared to D. melanogaster. More general metabolic profiles, in response to these different diets, however, have yet to be produced for any of the species. In addition, because D. arizonae appears somewhat intermediate between D. melanogaster and D. mojavensis in its development times and survival under the above mentioned diets, its general metabolic profiles are also of interest. Thus, in the present study we ask to what extent the general metabolism of these three different Drosophila species is affected by diets of distinct protein-sugar ratios. To obtain an un-biased view on possibly novel phenomena, we combined untargeted metabolomics with Random Forest data mining."

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 includes contribution of model systems to understanding lipodystrophies and dyslipidemias

Prieur X, Le May C, Magré J, Cariou B. Congenital lipodystrophies and dyslipidemias. Curr  Atheroscler Rep. 2014 Sep;16(9):437. PMID: 25047893.

From the abstract:  "... The precise mechanisms by which the lack of adipose tissue causes dyslipidemia remain largely unknown. In recent years, new insights have arisen from data obtained in vitro in adipocytes, yeast, drosophila, and very recently in several genetically modified mouse models of generalized lipodystrophy. ..."

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. ..."

Mini-review on fly models of obesity

Smith WW, Thomas J, Liu J, Li T, Moran TH. From fat fruitfly to human obesity. Physiol Behav. 2014 Feb 5. pii: S0031-9384(14)00034-1. PMID: 24508822.

From GWAS to functional genetics--fly study related to diabetes and metabolism

Pendse J, Ramachandran PV, Na J, Narisu N, Fink JL, Cagan RL, Collins FS, Baranski TJ. A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX. BMC Genomics. 2013 Feb 27;14:136. PMID: 23445342; PMCID: PMC3608171.

Flies & aging. Recent review.

Demontis F, Piccirillo R, Goldberg AL, Perrimon N. The influence of skeletal muscle on systemic aging and lifespan. Aging Cell. 2013 Jun 26. PMID: 23802635.

From the abstract: "... we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging ..."

Identification of "a previously unknown causative factor for metabolic syndrome in humans" using flies. Recent report.

Subramanian M, Metya SK, Sadaf S, Kumar S, Schwudke D, Hasan G. Altered lipid homeostasis in Drosophila InsP3 receptor mutants leads to obesity and hyperphagia. Dis Model Mech. 2013 Mar 15. PubMed PMID: 23471909.