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. Although the origin of these metabolic syndromes has not been fully comprehended yet, a growing body of evidence indicates their possible interconnection with the acute and chronic activation of an innate immune response. 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 to provide them with nutrients and thus support the immune function. That anticipates the involvement of macrophage-derived systemic factors mediating the inter-organ signaling between macrophages and central energy-storing organs. Although it is crucial to coordinate the macrophage cellular metabolism with systemic metabolic changes during the acute phase of bacterial infection, the action of macrophage-derived factors may become maladaptive if chronic or in case of infection by an intracellular pathogen. 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. The adoption of aerobic glycolysis by bactericidal macrophages as well as the induction of insulin resistance by macrophage-derived factors are conserved between insects and mammals. 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.

Department of Molecular Biology and Genetics University of South Bohemia Ceske Budejovice Czechia

Zobrazit více v PubMed

Agaisse H., Petersen U.-M., Boutros M., Mathey-Prevot B., Perrimon N. (2003). Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev. Cell 5 441–450. 10.1016/S1534-5807(03)00244-2 PubMed DOI

Alam M., Costales M., Cavanaugh C., Williams K. (2015). Extracellular adenosine generation in the regulation of pro-inflammatory responses and pathogen colonization. Biomolecules 5 775–792. 10.3390/biom5020775 PubMed DOI PMC

Allee J. P. (2011). ImpL2 Represses Insulin Signaling in Response to Hypoxia, Thesis, University of Oregon, Eugene, OR.

Almajwal A., Alam I., Zeb F., Fatima S. (2019). Energy metabolism and allocation in selfish immune system and brain: a beneficial role of insulin resistance in aging. Food Nutr. Sci. 10 64–80. 10.4236/fns.2019.101006 DOI

Álvarez-Rendón J. P., Salceda R., Riesgo-Escovar J. R. (2018). Drosophila melanogaster as a model for diabetes type 2 progression. Biomed Res. Int. 2018 1–16. 10.1155/2018/1417528 PubMed DOI PMC

Anderson R. S., Holmes B., Good R. A. (1973). Comparative biochemistry of phagocytizing insect hemocytes. Comp. Biochem. Physiol. Part B Comp. Biochem. 46 595–602. 10.1016/0305-0491(73)90099-0 PubMed DOI

Arab S., Hadjati J. (2019). Adenosine blockage in tumor microenvironment and improvement of cancer immunotherapy. Immune Netw. 19:e23. 10.4110/in.2019.19.e23 PubMed DOI PMC

Aymerich I., Foufelle F., Ferré P., Casado F. J., Pastor-Anglada M. (2006). Extracellular adenosine activates AMP-dependent protein kinase (AMPK). J. Cell Sci. 119 1612–1621. 10.1242/jcs.02865 PubMed DOI

Bailey P., Nathan J. (2018). Metabolic regulation of hypoxia-inducible transcription factors: the role of small molecule metabolites and iron. Biomedicines 6:60. 10.3390/biomedicines6020060 PubMed DOI PMC

Bajgar A., Dolezal T. (2018). Extracellular adenosine modulates host-pathogen interactions through regulation of systemic metabolism during immune response in Drosophila. PLoS Pathog. 14:e1007022. 10.1371/journal.ppat.1007022 PubMed DOI PMC

Bajgar A., Kucerova K., Jonatova L., Tomcala A., Schneedorferova I., Okrouhlik J., et al. (2015). Extracellular adenosine mediates a systemic metabolic switch during immune response. PLoS Biol. 13:e1002135. 10.1371/journal.pbio.1002135 PubMed DOI PMC

Banerjee U., Girard J. R., Goins L. M., Spratford C. M. (2019). Drosophila as a genetic model for hematopoiesis. Genetics 211 367–417. 10.1534/genetics.118.300223 PubMed DOI PMC

Bartolomé N., Arteta B., Martínez M. J., Chico Y., Ochoa B. (2008). Kupffer cell products and interleukin 1? directly promote VLDL secretion and apoB mRNA up-regulation in rodent hepatocytes. Innate Immun. 14 255–266. 10.1177/1753425908094718 PubMed DOI

Bekkering S., Arts R. J. W., Novakovic B., Kourtzelis I., van der Heijden C. D. C. C., Li Y., et al. (2018). Metabolic induction of trained immunity through the mevalonate pathway. Cell 172 135–146.e9. 10.1016/j.cell.2017.11.025 PubMed DOI

Bellucci P. N., González Bagnes M. F., Di Girolamo G., González C. D. (2017). Potential effects of nonsteroidal anti-inflammatory drugs in the prevention and treatment of type 2 diabetes mellitus. J. Pharm. Pract. 30 549–556. 10.1177/0897190016649551 PubMed DOI

Benoit M., Desnues B., Mege J.-L. (2008). Macrophage polarization in bacterial infections. J. Immunol. 181 3733–3739. 10.4049/jimmunol.181.6.3733 PubMed DOI

Bernal W. (2016). The liver in systemic disease: sepsis and critical illness. Clin. Liver Dis. 7 88–91. 10.1002/cld.543 PubMed DOI PMC

Biddinger S. B., Hernandez-Ono A., Rask-Madsen C., Haas J. T., Alemán J. O., Suzuki R., et al. (2008). Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to Atherosclerosis. Cell Metab. 7 125–134. 10.1016/j.cmet.2007.11.013 PubMed DOI PMC

Bobryshev Y. V., Ivanova E. A., Chistiakov D. A., Nikiforov N. G., Orekhov A. N. (2016). Macrophages and their role in atherosclerosis: pathophysiology and transcriptome analysis. Biomed Res. Int. 2016 1–13. 10.1155/2016/9582430 PubMed DOI PMC

Boison D., Yegutkin G. G. (2019). Adenosine metabolism: emerging concepts for cancer therapy. Cancer Cell 36 582–596. 10.1016/j.ccell.2019.10.007 PubMed DOI PMC

Bowser J. L., Lee J. W., Yuan X., Eltzschig H. K. (2017). The hypoxia-adenosine link during inflammation. J. Appl. Physiol. 123 1303–1320. 10.1152/japplphysiol.00101.2017 PubMed DOI PMC

Browne N., Heelan M., Kavanagh K. (2013). An analysis of the structural and functional similarities of insect hemocytes and mammalian phagocytes. Virulence 4 597–603. 10.4161/viru.25906 PubMed DOI PMC

Bunker B. D., Nellimoottil T. T., Boileau R. M., Classen A. K., Bilder D. (2015). The transcriptional response to tumorigenic polarity loss in Drosophila. eLife 4:e03189. 10.7554/eLife.03189 PubMed DOI PMC

Burns J., Manda G. (2017). Metabolic pathways of the warburg effect in health and disease: perspectives of choice, chain or chance. Int. J. Mol. Sci. 18:2755. 10.3390/ijms18122755 PubMed DOI PMC

Castellano J., Aledo R., Sendra J., Costales P., Juan-Babot O., Badimon L., et al. (2011). Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 31 1411–1420. 10.1161/ATVBAHA.111.225490 PubMed DOI

Castoldi A., Naffah de Souza C., Câmara N. O. S., Moraes-Vieira P. M. (2016). The macrophage switch in obesity development. Front. Immunol. 6:637. 10.3389/fimmu.2015.00637 PubMed DOI PMC

Cattenoz P. B., Sakr R., Pavlidaki A., Delaporte C., Riba A., Molina N., et al. (2020). Temporal specificity and heterogeneity of Drosophila immune cells. EMBO J. 39:e104486. 10.15252/embj.2020104486 PubMed DOI PMC

Chakrabarti S., Dudzic J. P., Li X., Collas E. J., Boquete J.-P., Lemaitre B. (2016). Remote control of intestinal stem cell activity by haemocytes in Drosophila. PLoS Genet. 12:e1006089. 10.1371/journal.pgen.1006089 PubMed DOI PMC

Chen C., Pore N., Behrooz A., Ismail-Beigi F., Maity A. (2001). Regulation of glut1 mRNA by Hypoxia-inducible Factor-1. J. Biol. Chem. 276 9519–9525. 10.1074/jbc.M010144200 PubMed DOI

Cheng L., Baonza A., Grifoni D. (2018). Drosophila models of human disease. Biomed. Res. Int. 2018:7214974. 10.1155/2018/7214974 PubMed DOI PMC

Cho B., Spratford C. M., Yoon S., Cha N., Banerjee U., Shim J. (2018). Systemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila. Nat. Commun. 9:2679. 10.1038/s41467-018-04990-3 PubMed DOI PMC

Cho Y.-R., Ann S. H., Won K.-B., Park G.-M., Kim Y.-G., Yang D. H., et al. (2019). Association between insulin resistance, hyperglycemia, and coronary artery disease according to the presence of diabetes. Sci. Rep. 9:6129. 10.1038/s41598-019-42700-1 PubMed DOI PMC

Corcoran S. E., O’Neill L. A. J. (2016). HIF1α and metabolic reprogramming in inflammation. J. Clin. Invest. 126 3699–3707. 10.1172/JCI84431 PubMed DOI PMC

Cui P., Shao W., Huang C., Wu C.-J., Jiang B., Lin D. (2019). Metabolic derangements of skeletal muscle from a murine model of glioma cachexia. Skelet. Muscle 9:3. 10.1186/s13395-018-0188-4 PubMed DOI PMC

Davis J. M., Zhao Z., Stock H. S., Mehl K. A., Buggy J., Hand G. A. (2003). Central nervous system effects of caffeine and adenosine on fatigue. Am. J. Physiol. Integr. Comp. Physiol. 284 R399–R404. 10.1152/ajpregu.00386.2002 PubMed DOI

de Deken R. H. (1966). The crabtree effect: a regulatory system in yeast. J. Gen. Microbiol. 44, 149–156. 10.1099/00221287-44-2-149 PubMed DOI

De Gregorio E. (2002). The Toll and Imd pathways are the major regulators of the immune response in Drosophila. EMBO J. 21 2568–2579. 10.1093/emboj/21.11.2568 PubMed DOI PMC

de Luca C., Olefsky J. M. (2008). Inflammation and insulin resistance. FEBS Lett. 582 97–105. 10.1016/j.febslet.2007.11.057 PubMed DOI PMC

Del Fabbro E., Hui D., Dalal S., Dev R., Nooruddin Z. I., Bruera E. (2011). Clinical outcomes and contributors to weight loss in a cancer Cachexia clinic. J. Palliat. Med. 14 1004–1008. 10.1089/jpm.2011.0098 PubMed DOI PMC

Demas G. E. (2004). The energetics of immunity: a neuroendocrine link between energy balance and immune function. Horm. Behav. 45 173–180. 10.1016/j.yhbeh.2003.11.002 PubMed DOI

Dengler V. L., Galbraith M. D., Espinosa J. M. (2014). Transcriptional regulation by hypoxia inducible factors. Crit. Rev. Biochem. Mol. Biol. 49 1–15. 10.3109/10409238.2013.838205 PubMed DOI PMC

Diaz-Ruiz R., Rigoulet M., Devin A. (2011). The Warburg and Crabtree effects: on the origin of cancer cell energy metabolism and of yeast glucose repression. Biochim. Biophys. Acta – Bioenerg. 1807 568–576. 10.1016/j.bbabio.2010.08.010 PubMed DOI

D’Ignazio L., Rocha S. (2016). Hypoxia induced NF-κB. Cells 5:10. 10.3390/cells5010010 PubMed DOI PMC

Dinarello C. A. (2006). The paradox of pro-inflammatory cytokines in cancer. Cancer Metast. Rev. 25 307–313. 10.1007/s10555-006-9000-8 PubMed DOI

Diskin C., Pålsson-McDermott E. M. (2018). Metabolic modulation in macrophage effector function. Front. Immunol. 9:270. 10.3389/fimmu.2018.00270 PubMed DOI PMC

Dodson M., Castro-Portuguez R., Zhang D. D. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 23 101107. 10.1016/j.redox.2019.101107 PubMed DOI PMC

Dolezal T. (2015). Adenosine: a selfish-immunity signal? Oncotarget 6 32307–32308. 10.18632/oncotarget.4685 PubMed DOI PMC

Dolezal T., Krejcova G., Bajgar A., Nedbalova P., Strasser P. (2019). Molecular regulations of metabolism during immune response in insects. Insect Biochem. Mol. Biol. 109 31–42. 10.1016/j.ibmb.2019.04.005 PubMed DOI

Duffy J. B. (2002). GAL4 system in drosophila: a fly geneticist’s swiss army knife. Genesis 34 1–15. 10.1002/gene.10150 PubMed DOI

Edholm E.-S., Rhoo K. H., Robert J. (2017). “Evolutionary aspects of macrophages polarization,” in Macrophages. Results and Problems in Cell Differentiation, Vol. 62 ed. Kloc M. (Cham: Springer; ), 3–22. 10.1007/978-3-319-54090-0_1 PubMed DOI PMC

Edwardson D. W., Boudreau J., Mapletoft J., Lanner C., Kovala A. T., Parissenti A. M. (2017). Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance. PLoS One 12:e0183662. 10.1371/journal.pone.0183662 PubMed DOI PMC

Eltzschig H. K. (2013). Extracellular adenosine signaling in molecular medicine. J. Mol. Med. 91 141–146. 10.1007/s00109-013-0999-z PubMed DOI PMC

Erridge C. (2010). Endogenous ligands of TLR2 and TLR4: agonists or assistants? J. Leukoc. Biol. 87 989–999. 10.1189/jlb.1209775 PubMed DOI

Escoll P., Buchrieser C. (2018). Metabolic reprogramming of host cells upon bacterial infection: why shift to a Warburg-like metabolism? FEBS J. 285 2146–2160. 10.1111/febs.14446 PubMed DOI

Felig P., Marliss E., Cahill G. F. (1969). Plasma amino acid levels and insulin secretion in obesity. N. Engl. J. Med. 281 811–816. 10.1056/NEJM196910092811503 PubMed DOI

Ferrandon D., Imler J. -L., Hetru C., Hoffmann J. A. (2007). The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections. Nat. Rev. Immunol. 7 862–874. 10.1038/nri2194 PubMed DOI

Figueroa-Clarevega A., Bilder D. (2015). Malignant Drosophila tumors interrupt insulin signaling to induce Cachexia-like wasting. Dev. Cell 33 47–55. 10.1016/j.devcel.2015.03.001 PubMed DOI PMC

Firth J. D., Ebert B. L., Ratcliffe P. J. (1995). Hypoxic regulation of lactate Dehydrogenase A. J. Biol. Chem. 270 21021–21027. 10.1074/jbc.270.36.21021 PubMed DOI

Fonseca G. W. P., da Farkas J., Dora E., von Haehling S., Lainscak M. (2020). Cancer cachexia and related metabolic dysfunction. Int. J. Mol. Sci. 21:2321. 10.3390/ijms21072321 PubMed DOI PMC

Forman H. J., Torres M. (2002). Reactive oxygen species and cell signaling. Am. J. Respir. Crit. Care Med. 166 S4–S8. 10.1164/rccm.2206007 PubMed DOI

Franken L., Schiwon M., Kurts C. (2016). Macrophages: sentinels and regulators of the immune system. Cell. Microbiol. 18 475–487. 10.1111/cmi.12580 PubMed DOI

Freire P. P., Fernandez G. J., Moraes D., Cury S. S., Dal Pai-Silva M., Reis P. P., et al. (2020). The expression landscape of cachexia-inducing factors in human cancers. J. Cachexia. Sarcopen. Muscle 11 947–961. 10.1002/jcsm.12565 PubMed DOI PMC

Galván-peña S., O’Neill L. A. J. (2014). Metabolic reprograming in macrophage polarization. Front. Immunol. 5:420. 10.3389/fimmu.2014.00420 PubMed DOI PMC

Gandhi C. R. (2020). Pro- and anti-fibrogenic functions of gram-negative bacterial Lipopolysaccharide in the liver. Front. Med. 7:130. 10.3389/fmed.2020.00130 PubMed DOI PMC

Ganeshan K., Nikkanen J., Man K., Leong Y. A., Sogawa Y., Maschek J. A., et al. (2019). Energetic trade-offs and hypometabolic states promote disease tolerance. Cell 177 399–413.e12. 10.1016/j.cell.2019.01.050 PubMed DOI PMC

Gao L., Mejıìas R., Echevarrıìa M., López-Barneo J. (2004). Induction of the glucose-6-phosphate dehydrogenase gene expression by chronic hypoxia in PC12 cells. FEBS Lett. 569 256–260. 10.1016/j.febslet.2004.06.004 PubMed DOI

Garedew A., Moncada S. (2008). Mitochondrial dysfunction and HIF1 stabilization in inflammation. J. Cell Sci. 121 3468–3475. 10.1242/jcs.034660 PubMed DOI

Gibson M. S., Domingues N., Vieira O. V. (2018). Lipid and non-lipid factors affecting macrophage dysfunction and inflammation in atherosclerosis. Front. Physiol. 9:654. 10.3389/fphys.2018.00654 PubMed DOI PMC

Gordon S., Martinez-Pomares L. (2017). Physiological roles of macrophages. Pflügers Arch. Eur. J. Physiol. 469 365–374. 10.1007/s00424-017-1945-7 PubMed DOI PMC

Grenz A., Homann D., Eltzschig H. K. (2011). Extracellular adenosine: a safety signal that dampens hypoxia-induced inflammation during ischemia. Antioxid. Redox Signal. 15 2221–2234. 10.1089/ars.2010.3665 PubMed DOI PMC

Gunnerson K. J., Shaw A. D., Chawla L. S., Bihorac A., Al-Khafaji A., Kashani K., et al. (2016). TIMP2•IGFBP7 biomarker panel accurately predicts acute kidney injury in high-risk surgical patients. J. Trauma Acute Care Surg. 80 243–249. 10.1097/TA.0000000000000912 PubMed DOI PMC

Ham J., Evans B. A. J. (2012). An emerging role for adenosine and its receptors in bone homeostasis. Front. Endocrinol. 3:113. 10.3389/fendo.2012.00113 PubMed DOI PMC

Haskó G., Cronstein B. (2013). Regulation of inflammation by adenosine. Front. Immunol. 4:85. 10.3389/fimmu.2013.00085 PubMed DOI PMC

He Q., Yang Q., Zhou Q., Zhu H., Niu W., Feng J., et al. (2014). Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes. PLoS One 9:e86326. 10.1371/journal.pone.0086326 PubMed DOI PMC

Heikkilä K., Ebrahim S., Lawlor D. A. (2008). Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur. J. Cancer 44 937–945. 10.1016/j.ejca.2008.02.047 PubMed DOI

Honegger B., Galic M., Köhler K., Wittwer F., Brogiolo W., Hafen E., et al. (2008). Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. J. Biol. 7:10. 10.1186/jbiol72 PubMed DOI PMC

Honors M. A., Kinzig K. P. (2012). The role of insulin resistance in the development of muscle wasting during cancer cachexia. J. Cachexia. Sarcopen. Muscle 3 5–11. 10.1007/s13539-011-0051-5 PubMed DOI PMC

Hsu C.-L., Lin W., Seshasayee D., Chen Y.-H., Ding X., Lin Z., et al. (2012). Equilibrative nucleoside transporter 3 deficiency perturbs lysosome function and macrophage homeostasis. Science 335 89–92. 10.1126/science.1213682 PubMed DOI

Hubler M. J., Kennedy A. J. (2016). Role of lipids in the metabolism and activation of immune cells. J. Nutr. Biochem. 34 1–7. 10.1016/j.jnutbio.2015.11.002 PubMed DOI PMC

Imran M., Smith H. L. (2007). The dynamics of bacterial infection, innate immune response, and antibiotic treatment. Discret. Contin. Dyn. Syst. B 8 127–143. 10.3934/dcdsb.2007.8.127 DOI

Iommarini L., Porcelli A. M., Gasparre G., Kurelac I. (2017). Non-canonical mechanisms regulating hypoxia-inducible factor 1 alpha in cancer. Front. Oncol. 7:286. 10.3389/fonc.2017.00286 PubMed DOI PMC

Irving P., Ubeda J.-M., Doucet D., Troxler L., Lagueux M., Zachary D., et al. (2005). New insights into Drosophila larval haemocyte functions through genome-wide analysis. Cell. Microbiol. 7 335–350. 10.1111/j.1462-5822.2004.00462.x PubMed DOI

Jiang H., Patel P. H., Kohlmaier A., Grenley M. O., McEwen D. G., Edgar B. A. (2009). Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila Midgut. Cell 137 1343–1355. 10.1016/j.cell.2009.05.014 PubMed DOI PMC

Jin N., Hatton N., Swartz D. R., Xia X., Harrington M. A., Larsen S. H., et al. (2000). Hypoxia Activates jun-n-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries. Am. J. Respir. Cell Mol. Biol. 23 593–601. 10.1165/ajrcmb.23.5.3921 PubMed DOI

Johansson K., Metzendorf C., Soderhall K. (2005). Microarray analysis of immune challenged hemocytes. Exp. Cell Res. 305 145–155. 10.1016/j.yexcr.2004.12.018 PubMed DOI

Jones W., Bianchi K. (2015). Aerobic glycolysis: beyond proliferation. Front. Immunol. 6:227. 10.3389/fimmu.2015.00227 PubMed DOI PMC

Kacsoh B. Z., Schlenke T. A. (2012). High hemocyte load is associated with increased resistance against parasitoids in Drosophila suzukii, a relative of D. melanogaster. PLoS One 7:e34721. 10.1371/journal.pone.0034721 PubMed DOI PMC

Kammerer T., Faihs V., Hulde N., Stangl M., Brettner F., Rehm M., et al. (2020). Hypoxic-inflammatory responses under acute hypoxia: in vitro experiments and prospective observational expedition trial. Int. J. Mol. Sci. 21:1034. 10.3390/ijms21031034 PubMed DOI PMC

Karnovsky M. L. (1962). Metabolic basis of phagocytic activity. Physiol. Rev. 42 143–168. 10.1152/physrev.1962.42.1.143 PubMed DOI

Kazankov K., Jørgensen S. M. D., Thomsen K. L., Møller H. J., Vilstrup H., George J., et al. (2019). The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 16 145–159. 10.1038/s41575-018-0082-x PubMed DOI

Kedia-Mehta N., Finlay D. K. (2019). Competition for nutrients and its role in controlling immune responses. Nat. Commun. 10:2123. 10.1038/s41467-019-10015-4 PubMed DOI PMC

Khovidhunkit W., Kim M. S., Memon R. A., Shigenaga J. K., Moser A. H., Feingold K. R., et al. (2004). Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J. Lipid Res. 45 1169–1196. 10.1194/jlr.R300019-JLR200 PubMed DOI

Kierdorf K., Hersperger F., Sharrock J., Vincent C. M., Ustaoglu P., Dou J., et al. (2020). Muscle function and homeostasis require cytokine inhibition of AKT activity in Drosophila. eLife 9:e051595. 10.7554/eLife.51595 PubMed DOI PMC

Kim J., Tchernyshyov I., Semenza G. L., Dang C. V. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3 177–185. 10.1016/j.cmet.2006.02.002 PubMed DOI

Koehler F., Doehner W., Hoernig S., Witt C., Anker S. D., John M. (2007). Anorexia in chronic obstructive pulmonary disease — association to cachexia and hormonal derangement. Int. J. Cardiol. 119 83–89. 10.1016/j.ijcard.2006.07.088 PubMed DOI

Koelwyn G. J., Corr E. M., Erbay E., Moore K. J. (2018). Regulation of macrophage immunometabolism in atherosclerosis. Nat. Immunol. 19 526–537. 10.1038/s41590-018-0113-3 PubMed DOI PMC

Koivunen P., Hirsilä M., Remes A. M., Hassinen I. E., Kivirikko K. I., Myllyharju J. (2007). Inhibition of Hypoxia-Inducible Factor (HIF) hydroxylases by citric acid cycle intermediates. J. Biol. Chem. 282 4524–4532. 10.1074/jbc.M610415200 PubMed DOI

Koltai T. (2020). Cancer cachexia has many symptoms but only one cause: anoxia. F1000Res. 9:250. 10.12688/f1000research.22624.1 DOI

Korbecki J., Bajdak-Rusinek K. (2019). The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm. Res. 68 915–932. 10.1007/s00011-019-01273-5 PubMed DOI PMC

Kraakman M. J., Murphy A. J., Jandeleit-Dahm K., Kammoun H. L. (2014). Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? Front. Immunol. 5:470. 10.3389/fimmu.2014.00470 PubMed DOI PMC

Krejčová G., Bajgar A., Nedbalová P., Kovářová J., Kamps-Hughes N., Zemanová H., et al. (2020). Macrophage-derived insulin/IGF antagonist ImpL2 regulates systemic metabolism for mounting an effective acute immune response in Drosophila. bioRxiv [Preprint], 10.1101/2020.09.24.311670 DOI

Krejčová G., Danielová A., Nedbalová P., Kazek M., Strych L., Chawla G., et al. (2019). Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense. eLife 8:e050414. 10.7554/eLife.50414 PubMed DOI PMC

Krishnan J., Suter M., Windak R., Krebs T., Felley A., Montessuit C., et al. (2009). Activation of a HIF1α-PPARγ axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 9 512–524. 10.1016/j.cmet.2009.05.005 PubMed DOI

Kühnlein R. P. (2012). Lipid droplet-based storage fat metabolism in Drosophila. J. Lipid Res. 53 1430–1436. 10.1194/jlr.R024299 PubMed DOI PMC

Kullmann S., Valenta V., Wagner R., Tschritter O., Machann J., Häring H.-U., et al. (2020). Brain insulin sensitivity is linked to adiposity and body fat distribution. Nat. Commun. 11:1841. 10.1038/s41467-020-15686-y PubMed DOI PMC

Kwon D., Cha H.-J., Lee H., Hong S.-H., Park C., Park S.-H., et al. (2019). Protective effect of glutathione against oxidative stress-induced cytotoxicity in RAW 264.7 macrophages through activating the nuclear factor erythroid 2-Related Factor-2/Heme oxygenase-1 pathway. Antioxidants 8:82. 10.3390/antiox8040082 PubMed DOI PMC

Kwon Y., Song W., Droujinine I. A., Hu Y., Asara J. M., Perrimon N. (2015). systemic organ wasting induced by localized expression of the secreted insulin/igf antagonist ImpL2. Dev. Cell 33 36–46. 10.1016/j.devcel.2015.02.012 PubMed DOI PMC

Langin D. (2013). Adipose tissue lipolysis and insulin sensitivity. Endocr. Abstr. 32:S32.3. 10.1530/endoabs.32.S32.3 DOI

Lee G. J., Han G., Yun H. M., Lim J. J., Noh S., Lee J., et al. (2018). Steroid signaling mediates nutritional regulation of juvenile body growth via IGF-binding protein in Drosophila. Proc. Natl. Acad. Sci. U.S.A. 115 5992–5997. 10.1073/pnas.1718834115 PubMed DOI PMC

Lee S., Dong H. H. (2017). FoxO integration of insulin signaling with glucose and lipid metabolism. J. Endocrinol. 233 R67–R79. 10.1530/JOE-17-0002 PubMed DOI PMC

Leonard E. J., Skeel A., Chiang P. K., Cantoni G. L. (1978). The action of the adenosylhomocysteine hydrolase inhibitor, 3-deazaadenosine, on phagocytic function of mouse macrophages and human monocytes. Biochem. Biophys. Res. Commun. 84 102–109. 10.1016/0006-291X(78)90269-3 PubMed DOI

Lewis A., Elks P. M. (2019). Hypoxia induces macrophage tnfa expression via cyclooxygenase and prostaglandin E2 in vivo. Front. Immunol. 10:2321. 10.3389/fimmu.2019.02321 PubMed DOI PMC

Lewis G. F., Carpentier A., Adeli K., Giacca A. (2002). Disordered fat storage and mobilization in the pathogenesis of insulin resistance and Type 2 diabetes. Endocr. Rev. 23 201–229. 10.1210/edrv.23.2.0461 PubMed DOI

Lim Y.-M., Lim H., Hur K. Y., Quan W., Lee H.-Y., Cheon H., et al. (2014). Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat. Commun. 5:4934. 10.1038/ncomms5934 PubMed DOI

Liou G.-Y. (2017). Inflammatory cytokine signaling during development of pancreatic and prostate cancers. J. Immunol. Res. 2017 1–10. 10.1155/2017/7979637 PubMed DOI PMC

Liu Y., Wu M., Ling J., Cai L., Zhang D., Gu H. F., et al. (2015). Serum IGFBP7 levels associate with insulin resistance and the risk of metabolic syndrome in a Chinese population. Sci. Rep. 5:10227. 10.1038/srep10227 PubMed DOI PMC

Loftus R. M., Finlay D. K. (2016). Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291 1–10. 10.1074/jbc.R115.693903 PubMed DOI PMC

Ma J., Wei K., Liu J., Tang K., Zhang H., Zhu L., et al. (2020). Glycogen metabolism regulates macrophage-mediated acute inflammatory responses. Nat. Commun. 11:1769. 10.1038/s41467-020-15636-8 PubMed DOI PMC

Maier A., Wu H., Cordasic N., Oefner P., Dietel B., Thiele C., et al. (2017). Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice. FASEB J. 31 4971–4984. 10.1096/fj.201700235R PubMed DOI

Mak R. H., Cheung W. (2006). Energy homeostasis and cachexia in chronic kidney disease. Pediatr. Nephrol. 21 1807–1814. 10.1007/s00467-006-0194-3 PubMed DOI

Makki K., Froguel P., Wolowczuk I. (2013). Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013 1–12. 10.1155/2013/139239 PubMed DOI PMC

Marette A. (2002). Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr. Opin. Clin. Nutr. Metab. Care 5 377–383. 10.1097/00075197-200207000-00005 PubMed DOI

Marik P. E., Bellomo R. (2013). Stress hyperglycemia: an essential survival response!. Crit. Care 17:305. 10.1186/cc12514 PubMed DOI PMC

Martínez-Castillo M., Rosique-Oramas D., Medina-Avila Z., Pérez-Hernández J. L., Higuera-De la Tijera F., Santana-Vargas D., et al. (2020). Differential production of insulin-like growth factor-binding proteins in liver fibrosis progression. Mol. Cell. Biochem. 469 65–75. 10.1007/s11010-020-03728-4 PubMed DOI

Marxsen J. H., Stengel P., Doege K., Heikkinen P., Jokilehto T., Wagner T., et al. (2004). Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4-hydroxylases. Biochem. J. 381 761–767. 10.1042/BJ20040620 PubMed DOI PMC

Matrone C., Pignataro G., Molinaro P., Irace C., Scorziello A., Di Renzo G. F., et al. (2004). HIF-1alpha reveals a binding activity to the promoter of iNOS gene after permanent middle cerebral artery occlusion. J. Neurochem. 90 368–378. 10.1111/j.1471-4159.2004.02483.x PubMed DOI

Melcarne C., Lemaitre B., Kurant E. (2019). Phagocytosis in Drosophila: from molecules and cellular machinery to physiology. Insect Biochem. Mol. Biol. 109 1–12. 10.1016/j.ibmb.2019.04.002 PubMed DOI

Mihajlovic Z., Tanasic D., Bajgar A., Perez-Gomez R., Steffal P., Krejci A. (2019). Lime is a new protein linking immunity and metabolism in Drosophila. Dev. Biol. 452 83–94. 10.1016/j.ydbio.2019.05.005 PubMed DOI

Mills C. D., Lenz L. L., Ley K. (2015). Macrophages at the fork in the road to health or disease. Front. Immunol. 6:59. 10.3389/fimmu.2015.00059 PubMed DOI PMC

Mills E. L., O’Neill L. A. (2016). Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur. J. Immunol. 46 13–21. 10.1002/eji.201445427 PubMed DOI

Miska J., Lee-Chang C., Rashidi A., Muroski M. E., Chang A. L., Lopez-Rosas A., et al. (2019). HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep. 27 226–237.e4. 10.1016/j.celrep.2019.03.029 PubMed DOI PMC

Molaei M., Vandehoef C., Karpac J. (2019). NF-κB shapes metabolic adaptation by attenuating foxo-mediated lipolysis in Drosophila. Dev. Cell 49 802–810.e6. 10.1016/j.devcel.2019.04.009 PubMed DOI PMC

Morgantini C., Jager J., Li X., Levi L., Azzimato V., Sulen A., et al. (2019). Liver macrophages regulate systemic metabolism through non-inflammatory factors. Nat. Metab. 1 445–459. 10.1038/s42255-019-0044-9 PubMed DOI

Mosser D. M., Edwards J. P. (2008). Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8 958–969. 10.1038/nri2448 PubMed DOI PMC

Mylonis I., Sembongi H., Befani C., Liakos P., Siniossoglou S., Simos G. (2012). Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J. Cell Sci. 125 3485–3493. 10.1242/jcs.106682 PubMed DOI PMC

Mylonis I., Simos G., Paraskeva E. (2019). Hypoxia-inducible factors and the regulation of lipid metabolism. Cells 8:214. 10.3390/cells8030214 PubMed DOI PMC

Nagao A., Kobayashi M., Koyasu S., Chow C. C. T., Harada H. (2019). HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int. J. Mol. Sci. 20:238. 10.3390/ijms20020238 PubMed DOI PMC

Nagy C., Haschemi A. (2015). Time and demand are two critical dimensions of immunometabolism: the process of macrophage activation and the pentose phosphate pathway. Front. Immunol. 6:164. 10.3389/fimmu.2015.00164 PubMed DOI PMC

Narsale A. A., Carson J. A. (2014). Role of interleukin-6 in cachexia. Curr. Opin. Support. Palliat. Care 8 321–327. 10.1097/SPC.0000000000000091 PubMed DOI PMC

Nässel D. R., Broeck J. V. (2016). Insulin/IGF signaling in Drosophila and other insects: factors that regulate production, release and post-release action of the insulin-like peptides. Cell. Mol. Life Sci. 73 271–290. 10.1007/s00018-015-2063-3 PubMed DOI PMC

Nässel D. R., Liu Y., Luo J. (2015). Insulin/IGF signaling and its regulation in Drosophila. Gen. Comp. Endocrinol. 221 255–266. 10.1016/j.ygcen.2014.11.021 PubMed DOI

Newsholme P., Curi R., Gordon S., Newsholme E. A. (1986). Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages. Biochem. J. 239 121–125. 10.1042/bj2390121 PubMed DOI PMC

Nonnenmacher Y., Hiller K. (2018). Biochemistry of proinflammatory macrophage activation. Cell. Mol. Life Sci. 75 2093–2109. 10.1007/s00018-018-2784-1 PubMed DOI PMC

Obach M., Navarro-Sabaté À, Caro J., Kong X., Duran J., Gómez M. (2004). 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible Factor-1 binding sites necessary for transactivation in response to hypoxia. J. Biol. Chem. 279 53562–53570. 10.1074/jbc.M406096200 PubMed DOI

Oldefest M., Nowinski J., Hung C.-W., Neelsen D., Trad A., Tholey A., et al. (2013). Upd3 - an ancestor of the four-helix bundle cytokines. Biochem. Biophys. Res. Commun. 436 66–72. 10.1016/j.bbrc.2013.04.107 PubMed DOI

Olefsky J. M., Glass C. K. (2010). Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72 219–246. 10.1146/annurev-physiol-021909-135846 PubMed DOI

Olson J. M., Jinka T. R., Larson L. K., Danielson J. J., Moore J. T., Carpluck J., et al. (2013). Circannual rhythm in body temperature, torpor, and sensitivity to A 1 adenosine receptor agonist in arctic ground squirrels. J. Biol. Rhythms 28 201–207. 10.1177/0748730413490667 PubMed DOI PMC

O’Neill L. A. J. (2015). A broken krebs cycle in macrophages. Immunity 42 393–394. 10.1016/j.immuni.2015.02.017 PubMed DOI

Owusu-Ansah E., Song W., Perrimon N. (2013). Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155 699–712. 10.1016/j.cell.2013.09.021 PubMed DOI PMC

Palazon A., Goldrath A. W., Nizet V., Johnson R. S. (2014). HIF transcription factors, inflammation, and immunity. Immunity 41 518–528. 10.1016/j.immuni.2014.09.008 PubMed DOI PMC

Panday A., Sahoo M. K., Osorio D., Batra S. (2015). NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell. Mol. Immunol. 12 5–23. 10.1038/cmi.2014.89 PubMed DOI PMC

Patel H. J., Patel B. M. (2017). TNF-α and cancer cachexia: molecular insights and clinical implications. Life Sci. 170 56–63. 10.1016/j.lfs.2016.11.033 PubMed DOI

Pavlou S., Wang L., Xu H., Chen M. (2017). Higher phagocytic activity of thioglycollate-elicited peritoneal macrophages is related to metabolic status of the cells. J. Inflamm. 14:4. 10.1186/s12950-017-0151-x PubMed DOI PMC

Péan C. B., Schiebler M., Tan S. W. S., Sharrock J. A., Kierdorf K., Brown K. P., et al. (2017). Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection. Nat. Commun. 8:14642. 10.1038/ncomms14642 PubMed DOI PMC

Perry R. J., Samuel V. T., Petersen K. F., Shulman G. I. (2014). The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510 84–91. 10.1038/nature13478 PubMed DOI PMC

Peyssonnaux C., Cejudo-Martin P., Doedens A., Zinkernagel A. S., Johnson R. S., Nizet V. (2007). Cutting edge: essential role of hypoxia inducible Factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178 7516–7519. 10.4049/jimmunol.178.12.7516 PubMed DOI

Pizarro T. T., Cominelli F. (2007). Cloning IL-1 and the birth of a new era in cytokine biology. J. Immunol. 178 5411–5412. 10.4049/jimmunol.178.9.5411 PubMed DOI

Popa C., Netea M. G., van Riel P. L. C. M., van der Meer J. W. M., Stalenhoef A. F. H. (2007). The role of TNF-α in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J. Lipid Res. 48 751–762. 10.1194/jlr.R600021-JLR200 PubMed DOI

Porporato P. E. (2016). Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 5:e200. 10.1038/oncsis.2016.3 PubMed DOI PMC

Prabakaran S. (2015). Mitochondria to nucleus: activate HIF1α. Sci. Signal. 8:ec330. 10.1126/scisignal.aad8189 DOI

Puigserver P., Rhee J., Donovan J., Walkey C. J., Yoon J. C., Oriente F., et al. (2003). Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature 423 550–555. 10.1038/nature01667 PubMed DOI

Rajan A., Perrimon N. (2011). Drosophila as a model for interorgan communication: lessons from studies on energy homeostasis. Dev. Cell 21 29–31. 10.1016/j.devcel.2011.06.034 PubMed DOI PMC

Ramond E., Dudzic J. P., Lemaitre B. (2020). Comparative RNA-Seq analyses of Drosophila plasmatocytes reveal gene specific signatures in response to clean injury and septic injury. PLoS One 15:e0235294. 10.1371/journal.pone.0235294 PubMed DOI PMC

Ramond E., Jamet A., Coureuil M., Charbit A. (2019). Pivotal role of mitochondria in macrophage response to bacterial pathogens. Front. Immunol. 10:2461. 10.3389/fimmu.2019.02461 PubMed DOI PMC

Ratcliffe N. A., Rowley A. F. (1975). Cellular defense reactions of insect hemocytes in vitro: phagocytosis in a new suspension culture system. J. Invertebr. Pathol. 26 225–233. 10.1016/0022-2011(75)90053-1 PubMed DOI

Park Y. M. (2014). CD36, a scavenger receptor implicated in atherosclerosis. Exp. Mol. Med. 46:e99. 10.1038/emm.2014.38 PubMed DOI PMC

Remmerie A., Scott C. L. (2018). Macrophages and lipid metabolism. Cell. Immunol. 330 27–42. 10.1016/j.cellimm.2018.01.020 PubMed DOI PMC

Riddle S. R., Ahmad A., Ahmad S., Deeb S. S., Malkki M., Schneider B. K., et al. (2000). Hypoxia induces hexokinase II gene expression in human lung cell line A549. Am. J. Physiol. Cell. Mol. Physiol. 278 L407–L416. 10.1152/ajplung.2000.278.2.L407 PubMed DOI

Riganti C., Gazzano E., Polimeni M., Aldieri E., Ghigo D. (2012). The pentose phosphate pathway: an antioxidant defense and a crossroad in tumor cell fate. Free Radic. Biol. Med. 53 421–436. 10.1016/j.freeradbiomed.2012.05.006 PubMed DOI

Ristow M., Schmeisser K. (2014). Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response 12 288–341. 10.2203/dose-response.13-035.Ristow PubMed DOI PMC

Rossol M., Heine H., Meusch U., Quandt D., Klein C., Sweet M. J., et al. (2011). LPS-induced cytokine production in human monocytes and macrophages. Crit. Rev. Immunol. 31 379–446. 10.1615/CritRevImmunol.v31.i5.20 PubMed DOI

Roth K. J., Copple B. L. (2015). Role of hypoxia-inducible factors in the development of liver fibrosis. Cell. Mol. Gastroenterol. Hepatol. 1 589–597. 10.1016/j.jcmgh.2015.09.005 PubMed DOI PMC

Rouzer C. A., Scott W. A., Griffith O. W., Hamill A. L., Cohn Z. A. (1982). Glutathione metabolism in resting and phagocytizing peritoneal macrophages. J. Biol. Chem. 257 2002–2008. 10.1016/s0021-9258(19)68139-1 PubMed DOI

Ruan W., Wu M., Shi L., Li F., Dong L., Qiu Y., et al. (2017). Serum levels of IGFBP7 are elevated during acute exacerbation in COPD patients. Int. J. Chron. Obstruct. Pulmon. Dis. Volume 12 1775–1780. 10.2147/COPD.S132652 PubMed DOI PMC

Ryter S. W., Koo J. K., Choi A. M. K. (2014). Molecular regulation of autophagy and its implications for metabolic diseases. Curr. Opin. Clin. Nutr. Metab. Care 17 329–337. 10.1097/MCO.0000000000000068 PubMed DOI PMC

Sag D., Carling D., Stout R. D., Suttles J. (2008). Adenosine 5′-monophosphate-activated protein Kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181 8633–8641. 10.4049/jimmunol.181.12.8633 PubMed DOI PMC

Salazar J., Bermúdez V., Olivar L. C., Torres W., Palmar J., Añez R., et al. (2018). Insulin resistance indices and coronary risk in adults from Maracaibo city, Venezuela: a cross sectional study. F1000Research 7:44. 10.12688/f1000research.13610.2 PubMed DOI PMC

Sancho D., Enamorado M., Garaude J. (2017). Innate immune function of mitochondrial metabolism. Front. Immunol. 8:527. 10.3389/fimmu.2017.00527 PubMed DOI PMC

Santoleri D., Titchenell P. M. (2019). Resolving the paradox of hepatic insulin resistance. Cell. Mol. Gastroenterol. Hepatol. 7 447–456. 10.1016/j.jcmgh.2018.10.016 PubMed DOI PMC

Sarkar P., Stefi R. V., Pasupuleti M., Paray B. A., Al-Sadoon M. K., Arockiaraj J. (2020). Antioxidant molecular mechanism of adenosyl homocysteinase from cyanobacteria and its wound healing process in fibroblast cells. Mol. Biol. Rep. 47 1821–1834. 10.1007/s11033-020-05276-y PubMed DOI PMC

Schrader J., Haddy F. J., Gerlach E. (1977). Release of adenosine, inosine and hypoxanthine from the isolated guinea pig heart during hypoxia, flow-autoregulation and reactive hyperemia. Pflügers Arch. Eur. J. Physiol. 369 1–6. 10.1007/BF00580802 PubMed DOI

Schwartsburd P. M. (2017). Catabolic and anabolic faces of insulin resistance and their disorders: a new insight into circadian control of metabolic disorders leading to diabetes. Futur. Sci. OA 3:FSO201. 10.4155/fsoa-2017-0015 PubMed DOI PMC

Scialò F., Fernández-Ayala D. J., Sanz A. (2017). Role of mitochondrial reverse electron transport in ROS signaling: potential roles in health and disease. Front. Physiol. 8:428. 10.3389/fphys.2017.00428 PubMed DOI PMC

Scott B. N. V., Sarkar T., Kratofil R. M., Kubes P., Thanabalasuriar A. (2019). Unraveling the host’s immune response to infection: seeing is believing. J. Leukoc. Biol. 106 323–335. 10.1002/JLB.4RI1218-503R PubMed DOI PMC

Shen G., Li X. (2017). “The multifaceted role of hypoxia-inducible Factor 1 (HIF1) in lipid metabolism,” in Hypoxia and Human Diseases, eds Zheng J., Zhou C. (London: InTechopen; ), 10.5772/65340 DOI

Shen G.-M., Zhao Y.-Z., Chen M.-T., Zhang F.-L., Liu X.-L., Wang Y., et al. (2012). Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia. Biochem. J. 441 675–683. 10.1042/BJ20111377 PubMed DOI

Shi J., Fan J., Su Q., Yang Z. (2019). Cytokines and abnormal glucose and lipid metabolism. Front. Endocrinol. 10:703. 10.3389/fendo.2019.00703 PubMed DOI PMC

Shin M., Cha N., Koranteng F., Cho B., Shim J. (2020). Subpopulation of macrophage-like plasmatocytes attenuates systemic growth via JAK/STAT in the Drosophila fat body. Front. Immunol. 11:63. 10.3389/fimmu.2020.00063 PubMed DOI PMC

Shin K. C., Hwang I., Choe S. S., Park J., Ji Y., Kim J. I., et al. (2017). Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation. Nat. Commun. 8:1087. 10.1038/s41467-017-01232-w PubMed DOI PMC

Siegert I., Schödel J., Nairz M., Schatz V., Dettmer K., Dick C., et al. (2015). Ferritin-mediated iron sequestration stabilizes hypoxia-inducible Factor-1α upon LPS activation in the presence of ample oxygen. Cell Rep. 13 2048–2055. 10.1016/j.celrep.2015.11.005 PubMed DOI

Silva D., Moreira D., Cordeiro-da-Silva A., Quintas C., Gonçalves J., Fresco P. (2020). Intracellular adenosine released from THP-1 differentiated human macrophages is involved in an autocrine control of Leishmania parasitic burden, mediated by adenosine A2A and A2B receptors. Eur. J. Pharmacol. 885:173504. 10.1016/j.ejphar.2020.173504 PubMed DOI

Silva-Vilches C., Ring S., Mahnke K. (2018). ATP and its metabolite adenosine as regulators of dendritic cell activity. Front. Immunol. 9:2581. 10.3389/fimmu.2018.02581 PubMed DOI PMC

Soeters M. R., Soeters P. B. (2012). The evolutionary benefit of insulin resistance. Clin. Nutr. 31 1002–1007. 10.1016/j.clnu.2012.05.011 PubMed DOI

Srikanthan P., Hevener A. L., Karlamangla A. S. (2010). Sarcopenia exacerbates obesity-associated insulin resistance and Dysglycemia: findings from the national health and nutrition examination survey III. PLoS One 5:e10805. 10.1371/journal.pone.0010805 PubMed DOI PMC

Stenholm S., Harris T. B., Rantanen T., Visser M., Kritchevsky S. B., Ferrucci L. (2008). Sarcopenic obesity: definition, cause and consequences. Curr. Opin. Clin. Nutr. Metab. Care 11 693–700. 10.1097/MCO.0b013e328312c37d PubMed DOI PMC

Straub R. H. (2014). Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res. Ther. 16:S4. 10.1186/ar4688 PubMed DOI PMC

Stuart L. M., Ezekowitz R. A. (2008). Phagocytosis and comparative innate immunity: learning on the fly. Nat. Rev. Immunol. 8 131–141. 10.1038/nri2240 PubMed DOI

Stunault M. I., Bories G., Guinamard R. R., Ivanov S. (2018). Metabolism plays a key role during macrophage activation. Med. Inflamm. 2018:2426138. 10.1155/2018/2426138 PubMed DOI PMC

Tadaishi M., Toriba Y., Shimizu M., Kobayashi-Hattori K. (2018). Adenosine stimulates hepatic glycogenolysis via adrenal glands-liver crosstalk in mice. PLoS One 13:e0209647. 10.1371/journal.pone.0209647 PubMed DOI PMC

Tattikota S. G., Cho B., Liu Y., Hu Y., Barrera V., Steinbaugh M. J., et al. (2020). A single-cell survey of Drosophila blood. eLife 9:e54818. 10.7554/eLife.54818 PubMed DOI PMC

Tehlivets O., Malanovic N., Visram M., Pavkov-Keller T., Keller W. (2013). S-adenosyl-L-homocysteine hydrolase and methylation disorders: yeast as a model system. Biochim. Biophys. Acta Mol. Basis Dis. 1832 204–215. 10.1016/j.bbadis.2012.09.007 PubMed DOI PMC

Teng O., Ang C. K. E., Guan X. L. (2017). Macrophage-bacteria interactions—a lipid-centric relationship. Front. Immunol. 8:1836. 10.3389/fimmu.2017.01836 PubMed DOI PMC

Texada M. J., Jørgensen A. F., Christensen C. F., Koyama T., Malita A., Smith D. K., et al. (2019). A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion. Nat. Commun. 10:1955. 10.1038/s41467-019-09943-y PubMed DOI PMC

Theret M., Mounier R., Rossi F. (2019). The origins and non-canonical functions of macrophages in development and regeneration. Development 146:dev156000. 10.1242/dev.156000 PubMed DOI

Thomas A. P., Halestrap A. P. (1981). The rôle of mitochondrial pyruvate transport in the stimulation by glucagon and phenylephrine of gluconeogenesis from l-lactate in isolated rat hepatocytes. Biochem. J. 198 551–560. 10.1042/bj1980551 PubMed DOI PMC

Tilg H., Hotamisligil G. S. (2006). Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterol. 131 934–945. 10.1053/j.gastro.2006.05.054 PubMed DOI

Tonelli C., Chio I. I. C., Tuveson D. A. (2018). Transcriptional regulation by Nrf2. Antioxid. Redox Signal. 29 1727–1745. 10.1089/ars.2017.7342 PubMed DOI PMC

Van den Berghe G. (2002). Beyond diabetes: saving lives with insulin in the ICU. Int. J. Obes. 26 S3–S8. 10.1038/sj.ijo.0802171 PubMed DOI

Van den Bossche J., Baardman J., de Winther M. P. J. (2015). Metabolic characterization of polarized M1 and M2 bone marrow-derived macrophages using real-time extracellular flux analysis. J. Vis. Exp. 2015:53424. 10.3791/53424 PubMed DOI PMC

van Niekerk G., Davis T., Engelbrecht A.-M. (2017). Hyperglycaemia in critically ill patients: the immune system’s sweet tooth. Crit. Care 21:202. 10.1186/s13054-017-1775-1 PubMed DOI PMC

Vijayan V., Pradhan P., Braud L., Fuchs H. R., Gueler F., Motterlini R., et al. (2019). Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis. Redox Biol. 22:101147. 10.1016/j.redox.2019.101147 PubMed DOI PMC

Wang A., Luan H. H., Medzhitov R. (2019). An evolutionary perspective on immunometabolism. Science 363:eaar3932. 10.1126/science.aar3932 PubMed DOI PMC

Wang C.-W., Purkayastha A., Jones K. T., Thaker S. K., Banerjee U. (2016). In vivo genetic dissection of tumor growth and the Warburg effect. eLife 5:e018126. 10.7554/eLife.18126 PubMed DOI PMC

Wang L., Sexton T. R., Venard C., Giedt M., Guo Q., Chen Q., et al. (2014). Pleiotropy of the Drosophila JAK pathway cytokine Unpaired 3 in development and aging. Dev. Biol. 395 218–231. 10.1016/j.ydbio.2014.09.015 PubMed DOI

Wang T., Liu H., Lian G., Zhang S.-Y., Wang X., Jiang C. (2017). HIF1 α -induced glycolysis metabolism is essential to the activation of inflammatory macrophages. Med. Inflamm. 2017 1–10. 10.1155/2017/9029327 PubMed DOI PMC

Warburg O. (1956). On the origin of cancer cells. Science 123 309–314. 10.1126/science.123.3191.309 PubMed DOI

Warburg O., Wind F., Negelein E. (1927). The metabolism of tumors in the body. J. Gen. Physiol. 8 519–530. 10.1085/jgp.8.6.519 PubMed DOI PMC

Watts E. R., Walmsley S. R. (2019). Inflammation and hypoxia: HIF and PHD isoform selectivity. Trends Mol. Med. 25 33–46. PubMed

Werb Z., Cohn Z. A. (1972). Plasma membrane synthesis in the macrophage following phagocytosis of polystyrene latex particles. J. Biol. Chem. 247 2439–2446. 10.1016/s0021-9258(19)45448-3 PubMed DOI

Wolowczuk I., Verwaerde C., Viltart O., Delanoye A., Delacre M., Pot B., et al. (2008). Feeding our immune system: impact on metabolism. Clin. Dev. Immunol. 2008:639803. 10.1155/2008/639803 PubMed DOI PMC

Woodcock K. J., Kierdorf K., Pouchelon C. A., Vivancos V., Dionne M. S., Geissmann F. (2015). Macrophage-derived upd3 cytokine causes impaired glucose homeostasis and reduced lifespan in Drosophila fed a lipid-rich diet. Immunity 42 133–144. 10.1016/j.immuni.2014.12.023 PubMed DOI PMC

Wynn T. A., Chawla A., Pollard J. W. (2013). Macrophage biology in development, homeostasis and disease. Nature 496 445–455. 10.1038/nature12034 PubMed DOI PMC

Xing J., Lu J. (2016). HIF-1α activation attenuates IL-6 and TNF-α pathways in hippocampus of rats following transient global ischemia. Cell. Physiol. Biochem. 39 511–520. 10.1159/000445643 PubMed DOI

Xu Q., Choksi S., Qu J., Jang J., Choe M., Banfi B., et al. (2016). NADPH oxidases are essential for macrophage differentiation. J. Biol. Chem. 291 20030–20041. 10.1074/jbc.M116.731216 PubMed DOI PMC

Yamashita A., Zhao Y., Matsuura Y., Yamasaki K., Moriguchi-Goto S., Sugita C., et al. (2014). Increased metabolite levels of glycolysis and pentose phosphate pathway in rabbit atherosclerotic arteries and hypoxic macrophage. PLoS One 9:e86426. 10.1371/journal.pone.0086426 PubMed DOI PMC

Yang H., Hultmark D. (2017). Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism. Sci. Rep. 7:15713. 10.1038/s41598-017-15940-2 PubMed DOI PMC

Yang H., Kronhamn J., Ekström J., Korkut G. G., Hultmark D. (2015). JAK/STAT signaling in Drosophila muscles controls the cellular immune response against parasitoid infection. EMBO Rep. 16 1664–1672. 10.15252/embr.201540277 PubMed DOI PMC

Yang W., Huang J., Wu H., Wang Y., Du Z., Ling Y., et al. (2020). Molecular mechanisms of cancer cachexia-induced muscle atrophy (Review). Mol. Med. Rep. 22 4967–4980. 10.3892/mmr.2020.11608 PubMed DOI PMC

Zanin R. F., Braganhol E., Bergamin L. S., Campesato L. F. I., Filho A. Z., Moreira J. C. F., et al. (2012). differential macrophage activation alters the expression profile of NTPDase and Ecto-5′-nucleotidase. PLoS One 7:e31205. 10.1371/journal.pone.0031205 PubMed DOI PMC

Zeng T., Zhang C.-L., Xiao M., Yang R., Xie K.-Q. (2016). Critical roles of kupffer cells in the pathogenesis of alcoholic liver disease: from basic science to clinical trials. Front. Immunol. 7:538. 10.3389/fimmu.2016.00538 PubMed DOI PMC

Zhang D., Zheng H., Zhou Y., Tang X., Yu B., Li J. (2007). Association of IL-1beta gene polymorphism with cachexia from locally advanced gastric cancer. BMC Cancer 7:45. 10.1186/1471-2407-7-45 PubMed DOI PMC

Current insights into insect immune memory

JAK/STAT mediated insulin resistance in muscles is essential for effective immune response