Molecular Nexus between Insulin-like peptides and Downstream Kinases Regulate Glucose Homeostasis, Cell Survival and Growth in Drosophila

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Authors

  • Prem Rajak
     Department of Zoology, A. B. N. Seal College, Cooch Behar, West Bengal ,IN
  • Moutushi Mandi
     Toxicology Research Laboratory, Department of Zoology, The University of Burdwan, Purba Bardhaman, West Bengal ,IN
  • Anik Dutta
     Department of Zoology, Darjeeling Government College, Darjeeling, West Bengal ,IN
  • Sumedha Roy
     Toxicology Research Laboratory, Department of Zoology, The University of Burdwan, Purba Bardhaman, West Bengal ,IN

DOI:

https://doi.org/10.18311/jer/2018/23729

Keywords:

Akt, Drosophila, FOXO, Insulin-like Peptides, TOR

Abstract

Drosophila is a versatile model organism to study metabolic disorders, one such being diabetes mellitus. Eight insulin-like peptides (ILPs) have been identified in Drosophila. ILPs are produced from paired Insulin-producing cells present in brain ganglia. Another protein called adipokinetic hormone (AKH) is homologous to mammalian glucagon and is released from the corpora cardiaca. Synergistic action of ILP and AKH maintains sugar homeostasis in Drosophila. ILP binds with insulin receptors on the adipocytes and trigger autophosphorylation and dimerization. The activated receptors then initiate a downstream signaling by various modulators to phosphorylate Akt (protein kinase B, a serine-threonine-specific protein kinase). Akt, when activated, targets multiple signaling molecules including Target of Rapamycin (TOR) that participates in glucose metabolism, protein synthesis, cell proliferation, neuroendocrine signaling, and stress response. Akt also phosphorylates transcription factor FOXO that promotes cell survival by up-regulating TRAIL, a pro-apoptotic protein. High lipid accumulation in the fat body is linked with insulin resistance in Drosophila. Drosophila reared on high lipid diet shows up-regulation in protein kinase C (PKC). PKC is known to antagonize insulin signaling in fruit flies. A clear concept regarding the complex process of glucose homeostasis can be generated through further investigations. Since Drosophila has several advantages over vertebrate models, it can be used to identify additional modulators of insulin biology and metabolism.

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Published

2019-11-26

How to Cite

Rajak, P., Mandi, M., Dutta, A., & Roy, S. (2019). Molecular Nexus between Insulin-like peptides and Downstream Kinases Regulate Glucose Homeostasis, Cell Survival and Growth in <i>Drosophila</i>. Journal of Endocrinology and Reproduction, 22(1), 21–29. https://doi.org/10.18311/jer/2018/23729

Issue

Volume 22, Issue 1, June 2018

Section

Invited Review Article
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References

Templeman NM, Murphy, CT. Regulation of reproduction and longevity by nutrient-sensing pathways. J Cell Biol. 2018; 217(1):93-106. https://doi.org/10.1083/jcb.201707168 PMid:29074705 PMCid:PMC5748989.

Taguchi A, White MF. Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol. 2008; 70:191-212. https://doi.org/10.1146/annurev.physiol.70.113006.100533 PMid:17988211

Rhea JM, Wegener C, Bender M. The proprotein convertase encoded by amontillado (amon) is required in Drosophila corpora cardiaca endocrine cells producing the glucose regulatory hormone AKH. PLoS Genet. 2010; 6:e1000967. https://doi.org/10.1371/journal.pgen.1000967 PMid:20523747 PMCid:PMC2877730

Broughton SJ, Piper MD, Ikeya T, Bass, TM, Jacobson J, Driege Y, et al. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin like ligands. Proc Natl Acad Sci. USA. 2005; 102:3105-10. https://doi.org/10.1073/pnas.040577 5102 PMid:15708981 PMCid:PMC549445

Rajan A, Perrimon N. Of flies and men: insights on organismal metabolism from fruit flies. BMC Biol. 2013; 11:38. https://doi.org/10.1186/1741-7007-11-38 PMid:23587196 PMCid:PMC3626883

Baker KD, Thummel CS. Diabetic larvae and obese flies - emerging studies of metabolism in Drosophila. Cell Metab. 2007; 6:257-66. https://doi.org/10.1016/j.cmet.2007.09.002 PMid:17908555 PMCid:PMC2231808

Bai H, Kang P, Tatar M. Drosophila insulin-like peptide- 6 (dilp6) expression from fat body extends lifespan and represses secretion of Drosophila insulin-like peptide-2 from the brain. Aging Cell. 2012; 11:978-85. https:// doi.org/10.1111/acel.12000 PMid:22935001 PMCid:PMC 3500397

Ikeya T, Galic M, Belawat P, Nairz K, Hafen E. Nutrientdependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr Biol. 2002; 12:1293-300. https://doi.org/10.1016/S0960-9822(02)01043-6

Colombani J, Andersen DS, Leopold P. Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science, 2012; 336:582-85. https://doi. org/10.1126/science.1216689 PMid:22556251

Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol. 2001; 11:213-21. https://doi. org/10.1016/S0960-9822(01)00068-9

Slaidina M, Delanoue R, Gronke S, Partridge L, Leopold P. A Drosophila insulin-like peptide promotes growth during non-feeding states. Dev Cell. 2009; 17: 874-84. https://doi.org/10.1016/j.devcel.2009.10.009 PMid:20059956 PMCid:PMC2806523

Miguel-Aliaga I, Thor S, Gould AP. Post-mitotic specification of Drosophila insulinergic neurons from pioneer neurons. PLoS Biol. 2008; 6(3):e58. https://doi.org/10.1371/ journal.pbio.0060058 PMid:18336071 PMCid:PMC2265769

Iwami M, Furuya I, Kataoka H. Bombyx in related peptides: cDNA structure and expression in the brain of the hornworm Agrius convolvuli. Insect Biochem. Mol. Biol. 1996; 26:25-32. https://doi.org/10.1016/0965-1748(95)00057-7

Kimura-Kawakami M, Iwami M, Kawakami, A, Nagasawa, H, Suzuki, A, et al. Structure and expression of bombyxin- related peptide genes of the moth Samia cynthia ricini. Gen Comp Endocrinol. 1992; 86:257-68. https://doi. org/10.1016/0016-6480(92)90109-W

Riehle MA, Garczynski SF, Crim JW, Hill CA, Brown MR. Neuropeptides and peptide hormones in Anopheles gambiae. Science, 2002; 298:172-175. https://doi.org/10.1126/ science.1076827 PMid:12364794

Krieger MJ, Jahan N, Riehle MA, Cao C, Brown MR. Molecular characterization of insulin-like peptide genes and their expression in the African malaria mosquito, Anopheles gambiae. Insect Mol Biol. 2004; 13:305-15. https://doi.org/10.1111/j.0962-1075.2004.00489.x PMid:15157231

Wheeler DE, Buck N, Evans JD. Expression of insulin pathway genes during the period of caste determination in the honey bee, Apis mellifera. Insect Mol Biol. 2006; 15: 597-602. https://doi.org/10.1111/j.1365-2583.2006.00681.x PMid:17069635 PMCid:PMC1761130

Huybrechts J, Bonhomme J, Minoli S, Prunier-Leterme N, Dombrovsky A, et al. Neuropeptide and neurohormone precursors in the pea aphid, Acyrthosiphon pisum. Insect Mol Biol. 2010; 19:87-95. https://doi.org/10.1111/j.1365- 2583.2009.00951.x PMid:20482642

Van de Velde S, Badisco L, Claeys I, Verleyen P, Chen X, et al. Insulin-like peptides in Spodoptera littoralis (Lepidoptera): Detection, localization and identifcation. Gen Comp Endocrinol. 2007; 153:72-79. https://doi.org/10.1016/j. ygcen.2007.05.001 PMid:17559850

Lagueux M, Lwoff L, Meister M, Goltzene F, Hoffmann JA. cDNAs from neurosecretory cellsof brains of Locusta migratoria (Insecta, Orthoptera) encoding a novel member of the superfamily of insulins. Eur J Biochem. 1990; 187:249-54. https://doi.org/10.1111/j.1432-1033.1990. tb15302.x PMid:1688797

Badisco L, Claeys I, Van Hiel M, Clynen E, Huybrechts J, et al. Purifcation and characterization of an insulinrelated peptide in the desert locust, Schistocerca gregaria: Immunolocalization, cDNA cloning, transcript profiling and interaction with neuroparsin. J Mol Endocrinol. 2008; 40:137-150. https://doi.org/10.1677/JME-07-0161 PMid:18316472

Almudi I, Poernbacher I, Hafen E, Stocker H. The Lnk/ SH2B adaptor provides a fail-safe mechanism to establish the insulin receptor-Chico interaction. Cell Commun Signal. 2013; 11(1):26. https://doi.org/10.1186/1478- 811X-11-26 PMid:23590848 PMCid:PMC3637499

Slack C, Werz C, Wieser D Alic N, Foley A, Stocker H, Withers DJ, Thornton JM, Hafen E, Partridge L. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. PLoS Genet. 2010; 6(3):e1000881. https://doi.org/10.1371/journal. pgen.1000881 PMid:20333234 PMCid:PMC2841611

Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signaling pathways: Insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7:85-96. https://doi.org/10.1038/ nrm1837 PMid:16493415

Frame S, Cohen P, Biondi, RM. A common phosphate binding site explains the unique substrate specifcity of GSK3 and its inactivation by phosphorylation. Mol Cell 2001; 7:1321-7. https://doi.org/10.1016/S1097-2765(01)00253-2

Sano H, Kane S, Sano E, Miinea CP, Asara JM., et al. Insulinstimulated phosphorylation of a RabGTPase-activating protein regulates GLUT4 translocation. J Biol Chem. 2003; 278:14599-602. https://doi.org/10.1074/jbc.C300063200 PMid:12637568

Harris TE, Lawrence JC, Jr. TOR signaling. SciSTKE. 2003(212)re15. https://doi.org/10.1126/stke.2122003re15 PMid:14668532

Zhang H, Stallock JP, Ng JC, Reinhard C, Neufeld TP. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 2000; 14:2712-24. https://doi.org/10.1101/gad.835000 PMid:11069888 PMCid:PMC317034

Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 2000; 14:2689-94. https://doi.org/10.1101/gad.845700 PMid:11069885 PMCid:PMC317036

Katoh M, Katoh M. Human FOX gene family (Review). Int. J. Oncol. 2004; 25:1495-00. https://doi.org/10.3892/ ijo.25.5.1495

Lam EWF, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans. 2006; 34:722-26. https://doi.org/10.1042/BST0340722 PMid:17052182

Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP. A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size. Genes Dev. 2008; 22:1877-93. https://doi.org/10.1101/ gad.1670508 PMid:18628395 PMCid:PMC2492735

Luo J, Lushchak OV, Goergen P, Williams MJ, Nässel DR. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior. PLoS ONE, 2014; 9:e99732. eCollection 2014. https://doi.org/10.1371/journal.pone.0099732 PMid:24923784 PMCid:PMC4055686

Enell LE, Kapan N, Söderberg JAE, Kahsai L, Nässel DR. Insulin signaling, lifespan and stress resistance are modulated by metabotropic GABA receptors on insulin producing cells in the brain of Drosophila. PLoS ONE. 2010; 5:e15780. https://doi.org/10.1371/journal.pone.0015780 PMid:21209905 PMCid:PMC3012717

Rajan A, Perrimon N. Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell, 2012; 151:123-37. https:// doi.org/10.1016/j.cell.2012.08.019 PMid:23021220 PMCid:PMC3475207

Kapan N, Lushchak OV, Luo J, Nässel DR. Identified peptidergic neurons in the Drosophila brain regulate insulin- producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin. Cell Mol Life Sci. 2012; 69:4051-66. https://doi.org/10.1007/s00018- 012-1097-z PMid:22828865

Kwak SJ, Hong SH, Bajracharya R, Yang SY, Lee KS, Yu K. Drosophila adiponectin receptor in insulin producing cells regulates glucose and lipid metabolism by controlling insulin secretion. PLoS ONE. 2013; 8:e68641. https:// doi.org/10.1371/journal.pone.0068641 PMid:23874700 PMCid:PMC3709998

Unger RH, Eisentraut AM, Madison LL. The effects of total starvation upon the levels of circulating glucagon and insulin in man. J Clin Invest. 1963; 42: 1031-39. https://doi.org/10.1172/JCI104788 PMid:13995385 PMCid:PMC289371

Alfa RW, Park S, Skelly KR, Poffenberger G, Jain N, Gu X, Kockel L, Wang J, Liu Y, Powers AC et al. Suppression of insulin production and secretion by a decretin hormone. Cell Metab. 2015; 21:323-33. https://doi.org/10.1016/j. cmet.2015.01.006 PMid:25651184 PMCid:PMC4349554

Morris SNS, Coogan C, Chamseddin K, Fernandez- Kim SO, Kolli S, Keller JN, Bauer JH. Development of diet-induced insulin resistance in adult Drosophila melanogaster. Biochim Biophys Acta. 2012; 1822:1230-37. https:// doi.org/10.1016/j.bbadis.2012.04.012 PMid:22542511 PMCid:PMC3601833

Musselman LP, Fink JL, Narzinski K, Ramachandran PV, Hathiramani SS, Cagan RL, Baranski TJ. A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis Model Mech. 2011; 4:842-49.

Skorupa DA, Dervisefendic A, Zwiener J, Pletcher SD. Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster. Aging Cell. 2008; 7:478-90. https://doi.org/10.1111/j.1474-9726.2008.00400.x PMid:18485125 PMCid:PMC2574586

Mattila J, Kallijärvi J, Puig O. RNAi screening for kinases and phosphatases identifies FoxO regulators. Proc Natl Acad Sci. USA. 2008; 105:14873-78. https://doi.org/10.1073/ pnas.0803022105 PMid:18815370 PMCid:PMC2567460

Hwangbo DS, Gershman B, Tu MP, Palmer M,Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signaling in brain and fat body. Nature, 2004; 429:562-66. https://doi.org/10.1038/nature02549 PMid:15175753

Evans DS, Kapahi P, Hsueh WC, Kockel L. TOR signaling never gets old: aging, longevity and TORC1 activity. Ageing Res Rev. 2011; 10:225-37. https://doi.org/10.1016/j. arr.2010.04.001 PMid:20385253 PMCid:PMC2943975

Puig O, Tjian R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev. 2005; 19:2435- 46. https://doi.org/10.1101/gad.1340505 PMid:16230533 PMCid:PMC1257398

Matsumoto M, Han S, Kitamura T, Accili D. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest. 2006; 116:2464-72.

Marr MT, D'Alessio JA, Puig O, Tjian R. IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback. Genes Dev. 2007; 21:175- 83. https://doi.org/10.1101/gad.1506407 PMid:17234883 PMCid:PMC1770900