Drosophila as a Model to Study Metabolic Disorders

  • Julia Hoffmann
  • Renja Romey
  • Christine Fink
  • Thomas RoederEmail author
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 135)


Metabolic disorders including obesity and diabetes are among the most relevant lifestyle diseases. They show a dramatically increasing incidence especially in industrialized countries. Although these diet-induced morbidities reached pandemic dimensions, our knowledge about the underlying mechanisms is surprisingly sparse. Simple model organisms including the fruit fly Drosophila melanogaster might fill this gap, inasmuch as they allow complementary scientific approaches enhancing our understanding regarding the pathomechanisms underlying these diseases. Based on the armamentarium of methods available to tailor disease models in the fly, very instructive information about diabetes or the effects of high-fat diets on heart ageing and dysfunction have been generated. In addition, genome wide approaches already have provided us with almost complete sets of genes relevant for fat storage defects or heart dysfunction.

Graphical Abstract


Ageing Diabetes Dietary restriction Heart dysfunction Longevity Metabolic disorder Obesity 



Adipokinetic hormone


Insulin like peptide


Insulin-producing cells


LexA operator


RNA interference


Target of rapamycin


Tuberous sclerosis complex


Upstream activating sequence


  1. 1.
    Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, Ruvkun G (2003) Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421:268–272CrossRefGoogle Scholar
  2. 2.
    Pospisilik JA, Schramek D, Schnidar H, Cronin SJ, Nehme NT, Zhang X, Knauf C, Cani PD, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely GG, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F, Hui CC, Esterbauer H, Penninger JM (2010) Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell 140:148–160CrossRefGoogle Scholar
  3. 3.
    Chien S, Reiter LT, Bier E, Gribskov M (2002) Homophila: human disease gene cognates in Drosophila. Nucleic Acids Res 30:149–151CrossRefGoogle Scholar
  4. 4.
    Reiter LT, Potocki L, Chien S, Gribskov M, Bier E (2001) A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res 11:1114–1125CrossRefGoogle Scholar
  5. 5.
    Drysdale R (2008) FlyBase : a database for the Drosophila research community. Methods Mol Biol 420:45–59Google Scholar
  6. 6.
    Wilson RJ, Goodman JL, Strelets VB (2008) FlyBase: integration and improvements to query tools. Nucleic Acids Res 36:D588–D593CrossRefGoogle Scholar
  7. 7.
    Crosby MA, Goodman JL, Strelets VB, Zhang P, Gelbart WM (2007) FlyBase: genomes by the dozen. Nucleic Acids Res 35:D486–D491CrossRefGoogle Scholar
  8. 8.
    Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson BJ (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448:151–156CrossRefGoogle Scholar
  9. 9.
    Cook KR, Parks AL, Jacobus LM, Kaufman TC, Matthews KA (2010) New research resources at the Bloomington Drosophila Stock Center. Fly (Austin) 4:88–91CrossRefGoogle Scholar
  10. 10.
    Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415Google Scholar
  11. 11.
    Duffy JB (2002) GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis 34:1–15CrossRefGoogle Scholar
  12. 12.
    McGuire SE, Le PT, Osborn AJ, Matsumoto K, Davis RL (2003) Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302:1765–1768CrossRefGoogle Scholar
  13. 13.
    Osterwalder T, Yoon KS, White BH, Keshishian H (2001) A conditional tissue-specific transgene expression system using inducible GAL4. Proc Natl Acad Sci U S A 98:12596–12601CrossRefGoogle Scholar
  14. 14.
    Yagi R, Mayer F, Basler K (2010) Refined LexA transactivators and their use in combination with the Drosophila Gal4 system. Proc Natl Acad Sci U S A 107:16166–16171CrossRefGoogle Scholar
  15. 15.
    Potter CJ, Luo L (2011) Using the Q system in Drosophila melanogaster. Nat Protoc 6:1105–1120CrossRefGoogle Scholar
  16. 16.
    Venken KJ, Carlson JW, Schulze KL, Pan H, He Y, Spokony R, Wan KH, Koriabine M, de Jong PJ, White KP, Bellen HJ, Hoskins RA (2009) Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster. Nat Methods 6:431–434CrossRefGoogle Scholar
  17. 17.
    Venken KJ, Schulze KL, Haelterman NA, Pan H, He Y, Evans-Holm M, Carlson JW, Levis RW, Spradling AC, Hoskins RA, Bellen HJ (2011) MiMIC: a highly versatile transposon insertion resource for engineering Drosophila melanogaster genes. Nat Methods 8:737–743CrossRefGoogle Scholar
  18. 18.
    Venken KJ, Bellen HJ (2007) Transgenesis upgrades for Drosophila melanogaster. Development 134:3571–3584CrossRefGoogle Scholar
  19. 19.
    Venken KJ, Bellen HJ (2012) Genome-wide manipulations of Drosophila melanogaster with transposons, Flp recombinase, and PhiC31 integrase. Methods Mol Biol 859:203–228Google Scholar
  20. 20.
    Ruden DM, De Luca M, Garfinkel MD, Bynum KL, Lu X (2005) Drosophila nutrigenomics can provide clues to human gene-nutrient interactions. Annu Rev Nutr 25:499–522CrossRefGoogle Scholar
  21. 21.
    Ruden DM, Lu X (2006) Evolutionary conservation of metabolism explains how Drosophila nutrigenomics can help us understand human nutrigenomics. Genes Nutr 1:75–83CrossRefGoogle Scholar
  22. 22.
    Murphy KG, Bloom SR (2006) Gut hormones and the regulation of energy homeostasis. Nature 444:854–859CrossRefGoogle Scholar
  23. 23.
    Arrese EL, Soulages JL (2010) Insect fat body: energy, metabolism, and regulation. Annu Rev Entomol 55:207–225CrossRefGoogle Scholar
  24. 24.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefGoogle Scholar
  25. 25.
    Lemaitre B, Hoffmann J (2007) The host defense of Drosophila melanogaster. Annu Rev Immunol 25:697–743CrossRefGoogle Scholar
  26. 26.
    Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8:49–62CrossRefGoogle Scholar
  27. 27.
    Billeter JC, Atallah J, Krupp JJ, Millar JG, Levine JD (2009) Specialized cells tag sexual and species identity in Drosophila melanogaster. Nature 461:987–991CrossRefGoogle Scholar
  28. 28.
    Gutierrez E, Wiggins D, Fielding B, Gould AP (2007) Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature 445:275–280CrossRefGoogle Scholar
  29. 29.
    de Velasco B, Erclik T, Shy D, Sclafani J, Lipshitz H, McInnes R, Hartenstein V (2007) Specification and development of the pars intercerebralis and pars lateralis, neuroendocrine command centers in the Drosophila brain. Dev Biol 302:309–323CrossRefGoogle Scholar
  30. 30.
    Rulifson EJ, Kim SK, Nusse R (2002) Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296:1118–1120CrossRefGoogle Scholar
  31. 31.
    Teleman AA (2010) Molecular mechanisms of metabolic regulation by insulin in Drosophila. Biochem J 425:13–26CrossRefGoogle Scholar
  32. 32.
    Broughton S, Alic N, Slack C, Bass T, Ikeya T, Vinti G, Tommasi AM, Driege Y, Hafen E, Partridge L (2008) Reduction of DILP2 in Drosophila triages a metabolic phenotype from lifespan revealing redundancy and compensation among DILPs. PLoS One 3:e3721CrossRefGoogle Scholar
  33. 33.
    Rajan A, Perrimon N (2012) Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell 151:123–137CrossRefGoogle Scholar
  34. 34.
    Geminard C, Rulifson EJ, Leopold P (2009) Remote control of insulin secretion by fat cells in Drosophila. Cell Metab 10:199–207CrossRefGoogle Scholar
  35. 35.
    Slaidina M, Delanoue R, Gronke S, Partridge L, Leopold P (2009) A Drosophila insulin-like peptide promotes growth during nonfeeding states. Dev Cell 17:874–884CrossRefGoogle Scholar
  36. 36.
    Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP (2008) A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size. Genes Dev 22:1877–1893CrossRefGoogle Scholar
  37. 37.
    DiAngelo JR, Birnbaum MJ (2009) Regulation of fat cell mass by insulin in Drosophila melanogaster. Mol Cell Biol 29:6341–6352CrossRefGoogle Scholar
  38. 38.
    Demontis F, Perrimon N (2009) Integration of Insulin receptor/Foxo signaling and dMyc activity during muscle growth regulates body size in Drosophila. Development 136:983–993CrossRefGoogle Scholar
  39. 39.
    DiAngelo JR, Bland ML, Bambina S, Cherry S, Birnbaum MJ (2009) The immune response attenuates growth and nutrient storage in Drosophila by reducing insulin signaling. Proc Natl Acad Sci U S A 106:20853–20858CrossRefGoogle Scholar
  40. 40.
    Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A 106:2700–2705CrossRefGoogle Scholar
  41. 41.
    Hedrick SM (2009) The cunning little vixen: Foxo and the cycle of life and death. Nat Immunol 10:1057–1063CrossRefGoogle Scholar
  42. 42.
    Kim SK, Rulifson EJ (2004) Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells. Nature 431:316–320CrossRefGoogle Scholar
  43. 43.
    Braco JT, Gillespie EL, Alberto GE, Brenman JE, Johnson EC (2012) Energy-dependent modulation of glucagon-like signaling in Drosophila via the AMP-activated protein kinase. Genetics 192:457–466CrossRefGoogle Scholar
  44. 44.
    Gronke S, Muller G, Hirsch J, Fellert S, Andreou A, Haase T, Jackle H, Kuhnlein RP (2007) Dual lipolytic control of body fat storage and mobilization in Drosophila. PLoS Biol 5:e137CrossRefGoogle Scholar
  45. 45.
    Corl AB, Rodan AR, Heberlein U (2005) Insulin signaling in the nervous system regulates ethanol intoxication in Drosophila melanogaster. Nat Neurosci 8:18–19CrossRefGoogle Scholar
  46. 46.
    Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R (2004) Insulin regulation of heart function in aging fruit flies. Nat Genet 36:1275–1281CrossRefGoogle Scholar
  47. 47.
    Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20:267–275CrossRefGoogle Scholar
  48. 48.
    Oldham S (2011) Obesity and nutrient sensing TOR pathway in flies and vertebrates: functional conservation of genetic mechanisms. Trends Endocrinol Metab 22:45–52CrossRefGoogle Scholar
  49. 49.
    McDaniel ML, Marshall CA, Pappan KL, Kwon G (2002) Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. Diabetes 51:2877–2885CrossRefGoogle Scholar
  50. 50.
    Beller M, Riedel D, Jansch L, Dieterich G, Wehland J, Jackle H, Kuhnlein RP (2006) Characterization of the Drosophila lipid droplet subproteome. Mol Cell Proteomics 5:1082–1094CrossRefGoogle Scholar
  51. 51.
    Miura S, Gan JW, Brzostowski J, Parisi MJ, Schultz CJ, Londos C, Oliver B, Kimmel AR (2002) Functional conservation for lipid storage droplet association among Perilipin, ADRP, and TIP47 (PAT)-related proteins in mammals, Drosophila, and Dictyostelium. J Biol Chem 277:32253–32257CrossRefGoogle Scholar
  52. 52.
    Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R (2006) Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312:734–737CrossRefGoogle Scholar
  53. 53.
    Gronke S, Beller M, Fellert S, Ramakrishnan H, Jackle H, Kuhnlein RP (2003) Control of fat storage by a Drosophila PAT domain protein. Curr Biol 13:603–606CrossRefGoogle Scholar
  54. 54.
    Gronke S, Mildner A, Fellert S, Tennagels N, Petry S, Muller G, Jackle H, Kuhnlein RP (2005) Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab 1:323–330CrossRefGoogle Scholar
  55. 55.
    Birse RT, Choi J, Reardon K, Rodriguez J, Graham S, Diop S, Ocorr K, Bodmer R, Oldham S (2010) High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metab 12:533–544CrossRefGoogle Scholar
  56. 56.
    Lim HY, Bodmer R (2011) Phospholipid homeostasis and lipotoxic cardiomyopathy: a matter of balance. Fly (Austin) 5:234–236CrossRefGoogle Scholar
  57. 57.
    Lim HY, Wang W, Wessells RJ, Ocorr K, Bodmer R (2011) Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila. Genes Dev 25:189–200CrossRefGoogle Scholar
  58. 58.
    Pasco MY, Leopold P (2012) High sugar-induced insulin resistance in Drosophila relies on the lipocalin Neural Lazarillo. PLoS One 7:e36583CrossRefGoogle Scholar
  59. 59.
    Musselman LP, Fink JL, Narzinski K, Ramachandran PV, Hathiramani SS, Cagan RL, Baranski TJ (2011) A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis Model Mech 4:842–849CrossRefGoogle Scholar
  60. 60.
    Hull-Thompson J, Muffat J, Sanchez D, Walker DW, Benzer S, Ganfornina MD, Jasper H (2009) Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet 5:e1000460CrossRefGoogle Scholar
  61. 61.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867CrossRefGoogle Scholar
  62. 62.
    Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Carrera P, Inhester T, Schultze JL, Hoch M (2010) FOXO-dependent regulation of innate immune homeostasis. Nature 463:369–373CrossRefGoogle Scholar
  63. 63.
    Chiang J, Shen YC, Wang YH, Hou YC, Chen CC, Liao JF, Yu MC, Juan CW, Liou KT (2009) Honokiol protects rats against eccentric exercise-induced skeletal muscle damage by inhibiting NF-kappaB induced oxidative stress and inflammation. Eur J Pharmacol 610:119–127CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Julia Hoffmann
    • 1
  • Renja Romey
    • 1
  • Christine Fink
    • 1
  • Thomas Roeder
    • 1
    Email author
  1. 1.Christian-Albrechts University KielKielGermany

Personalised recommendations