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What model organisms and interactomics can reveal about the genetics of human obesity

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Abstract

Genome-wide association studies have identified a number of genes associated with human body weight. While some of these genes are large fields within obesity research, such as MC4R, POMC, FTO and BDNF, the majority do not have a clearly defined functional role explaining why they may affect body weight. Here, we searched biological databases and discovered 33 additional genes associated with human obesity (CADM2, GIPR, GPCR5B, LRP1B, NEGR1, NRXN3, SH2B1, FANCL, GNPDA2, HMGCR, MAP2K5, NUDT3, PRKD1, QPCTL, TNNI3K, MTCH2, DNAJC27, SLC39A8, MTIF3, RPL27A, SEC16B, ETV5, HMGA1, TFAP2B, TUB, ZNF608, FAIM2, KCTD15, LINGO2, POC5, PTBP2, TMEM18, TMEM160). We find that the majority have orthologues in distant species, such as D. melanogaster and C. elegans, suggesting that they are important for the biology of most bilateral species. Intriguingly, signalling cascade genes and transcription factors are enriched among these obesity genes, and several of the genes show properties that could be useful for potential drug discovery. In this review, we demonstrate how information from several distant model species, interactomics and signalling pathway analysis represents an important way to better understand the functional diversity of the surprisingly high number of molecules that seem to be important for human obesity.

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References

  1. Bouchard C (2008) How much progress have we made over the last few decades? Int J Obes 32(Suppl 7):S2–S7. doi:10.1038/ijo.2008.231

    Google Scholar 

  2. Maes HH, Neale MC, Eaves LJ (1997) Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27:325–351

    PubMed  CAS  Google Scholar 

  3. Wardle J, Carnell S, Haworth CM, Plomin R (2008) Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 87:398–404. pii:87/2/398

    Google Scholar 

  4. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Perusse L, Bouchard C (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14:529–644. doi:10.1038/oby.2006.71

    Google Scholar 

  5. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141. pii:S0092-8674(00)81865-6

    Google Scholar 

  6. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157. doi:10.1038/509

    PubMed  CAS  Google Scholar 

  7. Kask A, Rago L, Korrovits P, Wikberg JE, Schioth HB (1998) Evidence that orexigenic effects of melanocortin 4 receptor antagonist HS014 are mediated by neuropeptide Y. Biochem Biophys Res Commun 248:245–249. doi:10.1006/bbrc.1998.8961

    PubMed  CAS  Google Scholar 

  8. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578. doi:10.1038/nn1455

    PubMed  CAS  Google Scholar 

  9. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894. doi:10.1126/science.1141634

    PubMed  CAS  Google Scholar 

  10. Fredriksson R, Hagglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, Levine AS, Lindblom J, Schioth HB (2008) The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology 149:2062–2071. doi:10.1210/en.2007-1457

    PubMed  CAS  Google Scholar 

  11. Speakman JR, Rance KA, Johnstone AM (2008) Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity 16:1961–1965. doi:10.1038/oby.2008.318

    PubMed  CAS  Google Scholar 

  12. Tanofsky-Kraff M, Han JC, Anandalingam K, Shomaker LB, Columbo KM, Wolkoff LE, Kozlosky M, Elliott C, Ranzenhofer LM, Roza CA, Yanovski SZ, Yanovski JA (2009) The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr 90:1483–1488. doi:10.3945/ajcn.2009.28439

    PubMed  CAS  Google Scholar 

  13. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U (2009) Inactivation of the Fto gene protects from obesity. Nature 458:894–898. doi:10.1038/nature07848

    PubMed  CAS  Google Scholar 

  14. Church C, Lee S, Bagg EA, McTaggart JS, Deacon R, Gerken T, Lee A, Moir L, Mecinovic J, Quwailid MM, Schofield CJ, Ashcroft FM, Cox RD (2009) A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet 5:e1000599. doi:10.1371/journal.pgen.1000599

    PubMed  Google Scholar 

  15. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O’Rahilly S, Purmann C, Rees MG, Ridderstrale M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N, Wellcome Trust Case Control C, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, Hirschhorn JN, Genetic Investigation of ATC (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34

    PubMed  CAS  Google Scholar 

  16. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24. doi:10.1038/ng.274

    PubMed  CAS  Google Scholar 

  17. Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X (2007) Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 61:911–922. doi:10.1016/j.biopsych.2006.08.025

    PubMed  CAS  Google Scholar 

  18. Gunstad J, Schofield P, Paul RH, Spitznagel MB, Cohen RA, Williams LM, Kohn M, Gordon E (2006) BDNF Val66Met polymorphism is associated with body mass index in healthy adults. Neuropsychobiology 53:153–156. doi:10.1159/000093341

    PubMed  CAS  Google Scholar 

  19. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Magi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segre AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpelainen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proenca C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grassler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jorgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, Konig IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaloy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimaki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B, Magic, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, Mulic R, Ngwa JS, Nelis M, Neville MJ, Nyholt DR, O’Donnell CJ, O’Rahilly S, Ong KK, Oostra B, Pare G, Parker AN, Perola M, Pichler I, Pietilainen KH, Platou CG, Polasek O, Pouta A, Rafelt S, Raitakari O, Rayner NW, Ridderstrale M, Rief W, Ruokonen A, Robertson NR, Rzehak P, Salomaa V, Sanders AR, Sandhu MS, Sanna S, Saramies J, Savolainen MJ, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick DS, Smit JH, Soranzo N, Sovio U, Stephens J, Surakka I, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tonjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, Waite LL, Wallaschofski H, Walters GB, Widen E, Wiegand S, Wild SH, Willemsen G, Witte DR, Witteman JC, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby JP, Farooqi IS, Hebebrand J, Huikuri HV, James AL, Kahonen M, Levinson DF, Macciardi F, Nieminen MS, Ohlsson C, Palmer LJ, Ridker PM, Stumvoll M, Beckmann JS, Boeing H, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Gronberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H, Procardis C, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, McCarroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O’Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, McCarthy MI, Hirschhorn JN, Ingelsson E, Loos RJ (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948

    PubMed  CAS  Google Scholar 

  20. Tseng CC, Zhang XY (2000) Role of G protein-coupled receptor kinases in glucose-dependent insulinotropic polypeptide receptor signaling. Endocrinology 141:947–952

    PubMed  CAS  Google Scholar 

  21. Kim SJ, Nian C, McIntosh CH (2011) Adipocyte expression of the glucose-dependent insulinotropic polypeptide receptor involves gene regulation by PPAR{gamma} and histone acetylation. J Lipid Res 52:759–770

    PubMed  CAS  Google Scholar 

  22. Song DH, Getty-Kaushik L, Tseng E, Simon J, Corkey BE, Wolfe MM (2007) Glucose-dependent insulinotropic polypeptide enhances adipocyte development and glucose uptake in part through Akt activation. Gastroenterology 133:1796–1805

    PubMed  CAS  Google Scholar 

  23. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J, Seino Y (1999) Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96:14843–14847

    PubMed  CAS  Google Scholar 

  24. Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovci A, Hansotia T, Drucker DJ, Wollheim C, Burcelin R, Thorens B (2004) Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clinical Invest 113:635–645

    CAS  Google Scholar 

  25. Hansotia T, Drucker DJ (2005) GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regul Pept 128(2):125–134

    PubMed  CAS  Google Scholar 

  26. Pederson RA, Satkunarajah M, McIntosh CH, Scrocchi LA, Flamez D, Schuit F, Drucker DJ, Wheeler MB (1998) Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor −/− mice. Diabetes 47:1046–1052

    PubMed  CAS  Google Scholar 

  27. Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738–742

    PubMed  CAS  Google Scholar 

  28. Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, Drucker DJ (2007) Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clinical Invest 117:143–152

    CAS  Google Scholar 

  29. Zaragosi LE, Wdziekonski B, Brigand KL, Villageois P, Mari B, Waldmann R, Dani C, Barbry P (2011) Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis. Genome Biol 12:R64. doi:10.1186/gb-2011-12-7-r64

    PubMed  CAS  Google Scholar 

  30. Martinelli R, Nardelli C, Pilone V, Buonomo T, Liguori R, Castano I, Buono P, Masone S, Persico G, Forestieri P, Pastore L, Sacchetti L (2010) miR-519d overexpression is associated with human obesity. Obesity 18:2170–2176. doi:10.1038/oby.2009.474

    PubMed  CAS  Google Scholar 

  31. Brauner-Osborne H, Wellendorph P, Jensen AA (2007) Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr Drug Targets 8:169–184

    PubMed  Google Scholar 

  32. Urwyler S (2011) Allosteric modulation of family C G-protein-coupled receptors: from molecular insights to therapeutic perspectives. Pharmacol Rev 63:59–126

    PubMed  CAS  Google Scholar 

  33. Pleines I, Elvers M, Strehl A, Pozgajova M, Varga-Szabo D, May F, Chrostek-Grashoff A, Brakebusch C, Nieswandt B (2009) Rac1 is essential for phospholipase C-gamma2 activation in platelets. Pflugers Archiv 457:1173–1185

    PubMed  CAS  Google Scholar 

  34. Rickhag M, Wieloch T, Gido G, Elmer E, Krogh M, Murray J, Lohr S, Bitter H, Chin DJ, von Schack D, Shamloo M, Nikolich K (2006) Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue. J Neurochem 96:14–29

    PubMed  CAS  Google Scholar 

  35. Brauner-Osborne H, Krogsgaard-Larsen P (2000) Sequence and expression pattern of a novel human orphan G-protein-coupled receptor, GPRC5B, a family C receptor with a short amino-terminal domain. Genomics 65:121–128

    PubMed  CAS  Google Scholar 

  36. Sano T, Kim YJ, Oshima E, Shimizu C, Kiyonari H, Abe T, Higashi H, Yamada K, Hirabayashi Y (2011) Comparative characterization of GPRC5B and GPRC5CLacZ knockin mice; behavioral abnormalities in GPRC5B-deficient mice. Biochem Biophys Res Commun 412:460–465. doi:10.1016/j.bbrc.2011.07.118

    PubMed  CAS  Google Scholar 

  37. Simon MA (1994) Signal transduction during the development of the Drosophila R7 photoreceptor. Dev Biol 166(2):431–442

    PubMed  CAS  Google Scholar 

  38. Kohyama-Koganeya A, Kim Y-J, Miura M, Hirabayashi Y (2008) A Drosophila orphan G protein-coupled receptor BOSS functions as a glucose-responding receptor: loss of boss causes abnormal energy metabolism. Proc Natl Acad Sci USA 105:15328–15333

    PubMed  CAS  Google Scholar 

  39. Kohyama-Koganeya A, Hirabayashi Y (2010) The Drosophila 7-pass transmembrane glycoprotein BOSS and metabolic regulation: what Drosophila can teach us about human energy metabolism. In: Minoru F (ed) Methods in enzymology, vol 480, Glycobiology. Academic, New York, pp 525–538

  40. Morris DL, Cho KW, Zhou Y, Rui L (2009) SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes 58:2039–2047

    PubMed  CAS  Google Scholar 

  41. Donatello S, Fiorino A, Degl’Innocenti D, Alberti L, Miranda C, Gorla L, Bongarzone I, Rizzetti MG, Pierotti MA, Borrello MG (2007) SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling. Oncogene 26:6546–6559

    PubMed  CAS  Google Scholar 

  42. Li M, Li Z, Morris DL, Rui L (2007) Identification of SH2B2beta as an inhibitor for SH2B1- and SH2B2alpha-promoted Janus kinase-2 activation and insulin signaling. Endocrinol 148:1615–1621

    CAS  Google Scholar 

  43. Yoshiga D, Sato N, Torisu T, Mori H, Yoshida R, Nakamura S, Takaesu G, Kobayashi T, Yoshimura A (2007) Adaptor protein SH2-B linking receptor-tyrosine kinase and Akt promotes adipocyte differentiation by regulating peroxisome proliferator-activated receptor gamma messenger ribonucleic acid levels. Mol Endocrinol 21:1120–1131

    PubMed  CAS  Google Scholar 

  44. O’Brien KB, O’Shea JJ, Carter-Su C (2002) SH2-B family members differentially regulate JAK family tyrosine kinases. J Biol Chem 277:8673–8681

    PubMed  Google Scholar 

  45. Duan C, Tang C, Liao L, Li C, Su T, Chen Z (2010) Molecular mechanism of SH2B1 in regulating JAK2/IRS2 during obesity development. Zhong nan da xue xue baoYi xue ban 35:209–214

    CAS  Google Scholar 

  46. Song W, Ren D, Li W, Jiang L, Cho KW, Huang P, Fan C, Song Y, Liu Y, Rui L (2010) SH2B regulation of growth, metabolism, and longevity in both insects and mammals. Cell Metab 11:427–437

    PubMed  CAS  Google Scholar 

  47. Morris DL, Cho KW, Rui L (2010) Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice. Endocrinology 151:3643–3651

    PubMed  CAS  Google Scholar 

  48. Ren D, Zhou Y, Morris D, Li M, Li Z, Rui L (2007) Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest 117:397–406

    PubMed  CAS  Google Scholar 

  49. Kubo-Akashi C, Iseki M, Kwon SM, Takizawa H, Takatsu K, Takaki S (2004) Roles of a conserved family of adaptor proteins, Lnk, SH2-B, and APS, for mast cell development, growth, and functions: APS-deficiency causes augmented degranulation and reduced actin assembly. Biochem Biophys Res Commun 315:356–362

    PubMed  CAS  Google Scholar 

  50. Maures TJ, Kurzer JH, Carter-Su C (2007) SH2B1 (SH2-B) and JAK2: a multifunctional adaptor protein and kinase made for each other. Trends Endocrinol Metab 18:38–45

    PubMed  CAS  Google Scholar 

  51. Slack C, Werz C, Wieser D, Alic N, Foley A, Stocker H, Withers DJ, Thornton JM, Hafen E, Partridge L (2010) Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein. Lnk. PLoS Genet 6:e1000881

    Google Scholar 

  52. Werz C, Kohler K, Hafen E, Stocker H (2009) The Drosophila SH2B family adaptor Lnk acts in parallel to chico in the insulin signaling pathway. PLoS Genet 5:e1000596

    PubMed  Google Scholar 

  53. Zhang J, Yang XF, Liao DF, Wu Q, Liu ZX, He YD (2007) A study of the effects of quercetin on the expression of HMGCR and the cholesterol synthesis of HL-02 cells]. Zhonghua gan zang bing za zhi 15:143–145

    PubMed  CAS  Google Scholar 

  54. Dietschy JM, Turley SD, Spady DK (1993) Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 34:1637–1659

    PubMed  CAS  Google Scholar 

  55. Reed RM, Iacono A, Defilippis A, Eberlein M, Girgis RE, Jones S (2011) Advanced chronic obstructive pulmonary disease is associated with high levels of high-density lipoprotein cholesterol. J Heart Lung Transplant 30:674–678

    PubMed  Google Scholar 

  56. Ness GC, Chambers CM (2000) Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 224:8–19

    PubMed  CAS  Google Scholar 

  57. Easom RA, Zammit VA (1985) Effects of diabetes on the expressed and total activities of 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver in vivo. Reversal by insulin treatment. Biochem J 230:747–752

    PubMed  CAS  Google Scholar 

  58. Stange EF, Fleig WE, Schneider A, Nother-Fleig G, Alavi M, Preclik G, Ditschuneit H (1982) 3-Hydroxy-3-methylglutaryl CoA reductase in cultured hepatocytes. Regulation by heterologous lipoproteins and hormones. Atherosclerosis 41:67–80

    PubMed  CAS  Google Scholar 

  59. Belgacem YH, Martin JR (2007) Hmgcr in the corpus allatum controls sexual dimorphism of locomotor activity and body size via the insulin pathway in Drosophila. PLoS ONE 2:e187

    PubMed  Google Scholar 

  60. Jump DB (2010) Fatty acid regulation of hepatic lipid metabolism. Curr Opin Clin Nutr Metab Care 14:115–120

    Google Scholar 

  61. Wong RH, Sul HS (2010) Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr Opin Pharmacol 10:684–691

    PubMed  CAS  Google Scholar 

  62. Kunte AS, Matthews KA, Rawson RB (2006) Fatty acid auxotrophy in Drosophila larvae lacking SREBP. Cell Metab 3:439–448

    PubMed  CAS  Google Scholar 

  63. van der Meer DL, Degenhardt T, Vaisanen S, de Groot PJ, Heinaniemi M, de Vries SC, Muller M, Carlberg C, Kersten S (2010) Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis. Nucleic Acids Res 38(9):2839–2850

    PubMed  Google Scholar 

  64. Waterham HR (2002) Inherited disorders of cholesterol biosynthesis. Clin Genet 61:393–403

    PubMed  CAS  Google Scholar 

  65. Beg ZH, Brewer HB Jr (1981) Regulation of liver 3-hydroxy-3-methylglutaryl-CoA reductase. Curr Topics Cell Reg 20:139–184

    CAS  Google Scholar 

  66. Belles X, Martin D, Piulachs MD (2005) The mevalonate pathway and the synthesis of juvenile hormone in insects. Annu Rev Entomol 50:181–199

    PubMed  CAS  Google Scholar 

  67. Gruntenko NE, Wen D, Karpova EK, Adonyeva NV, Liu Y, He Q, Faddeeva NV, Fomin AS, Li S, Rauschenbach IY (2010) Altered juvenile hormone metabolism, reproduction and stress response in Drosophila adults with genetic ablation of the corpus allatum cells. Insect Biochem Mol Biol 40:891–897

    PubMed  CAS  Google Scholar 

  68. Haslam RJ, Koide HB, Hemmings BA (1993) Pleckstrin domain homology. Nature 363:309–310. doi:10.1038/363309b0

    PubMed  CAS  Google Scholar 

  69. Musacchio A, Gibson T, Rice P, Thompson J, Saraste M (1993) The PH domain: a common piece in the structural patchwork of signalling proteins. Trends Biochem Sci 18:343–348

    PubMed  CAS  Google Scholar 

  70. Ingley E, Hemmings BA (1994) Pleckstrin homology (PH) domains in signal transduction. J Cell Biochem 56:436–443. doi:10.1002/jcb.240560403

    PubMed  CAS  Google Scholar 

  71. Ono Y, Fujii T, Igarashi K, Kuno T, Tanaka C, Kikkawa U, Nishizuka Y (1989) Phorbol ester binding to protein kinase C requires a cysteine-rich zinc-finger-like sequence. Proc Natl Acad Sci USA 86:4868–4871

    PubMed  CAS  Google Scholar 

  72. Ha CH, Jin ZG (2009) Protein kinase D1, a new molecular player in VEGF signaling and angiogenesis. Mol Cells 28:1–5. doi:10.1007/s10059-009-0109-9

    PubMed  CAS  Google Scholar 

  73. Park JE, Kim YI, Yi AK (2009) Protein kinase D1 is essential for MyD88-dependent TLR signaling pathway. J Immunol 182:6316–6327. doi:10.4049/jimmunol.0804239

    PubMed  CAS  Google Scholar 

  74. Gilon P, Henquin JC (2001) Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr Rev 22:565–604

    PubMed  CAS  Google Scholar 

  75. Mitrani P, Srinivasan M, Dodds C, Patel MS (2007) Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats. Am J Physiol Endocrinol Metab 292:E1069–E1078. doi:10.1152/ajpendo.00477.2006

    PubMed  CAS  Google Scholar 

  76. Anichini E, Zamperini A, Chevanne M, Caldini R, Pucci M, Fibbi G, Del Rosso M (1997) Interaction of urokinase-type plasminogen activator with its receptor rapidly induces activation of glucose transporters. Biochemistry 36:3076–3083. doi:10.1021/bi9619379

    PubMed  CAS  Google Scholar 

  77. Fibbi G, Caldini R, Chevanne M, Pucci M, Schiavone N, Morbidelli L, Parenti A, Granger HJ, Del Rosso M, Ziche M (1998) Urokinase-dependent angiogenesis in vitro and diacylglycerol production are blocked by antisense oligonucleotides against the urokinase receptor. Lab Invest 78:1109–1119

    PubMed  CAS  Google Scholar 

  78. Sumara G, Formentini I, Collins S, Sumara I, Windak R, Bodenmiller B, Ramracheya R, Caille D, Jiang H, Platt KA, Meda P, Aebersold R, Rorsman P, Ricci R (2009) Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell 136:235–248. doi:10.1016/j.cell.2008.11.018

    PubMed  CAS  Google Scholar 

  79. Feng H, Ren M, Chen L, Rubin CS (2007) Properties, regulation, and in vivo functions of a novel protein kinase D: Caenorhabditis elegans DKF-2 links diacylglycerol second messenger to the regulation of stress responses and life span. J Biol Chem 282:31273–31288. doi:10.1074/jbc.M701532200

    PubMed  CAS  Google Scholar 

  80. Kleyn PW, Fan W, Kovats SG, Lee JJ, Pulido JC, Wu Y, Berkemeier LR, Misumi DJ, Holmgren L, Charlat O, Woolf EA, Tayber O, Brody T, Shu P, Hawkins F, Kennedy B, Baldini L, Ebeling C, Alperin GD, Deeds J, Lakey ND, Culpepper J, Chen H, Glucksmann-Kuis MA, Carlson GA, Duyk GM, Moore KJ (1996) Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85:281–290. pii:S0092-8674(00)81104-6

    Google Scholar 

  81. Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L (1999) Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286(5447):2119–2125. pii:8081

    Google Scholar 

  82. Chintapalli VR, Wang J, Dow JA (2007) Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat Genet 39:715–720. doi:10.1038/ng2049

    PubMed  CAS  Google Scholar 

  83. Mukhopadhyay A, Deplancke B, Walhout AJ, Tissenbaum HA (2005) C. elegans tubby regulates life span and fat storage by two independent mechanisms. Cell Metab 2:35–42. doi:10.1016/j.cmet.2005.06.004

    PubMed  CAS  Google Scholar 

  84. Mukhopadhyay A, Pan X, Lambright DG, Tissenbaum HA (2007) An endocytic pathway as a target of tubby for regulation of fat storage. EMBO Rep 8:931–938. doi:10.1038/sj.embor.7401055

    PubMed  CAS  Google Scholar 

  85. Popovic D, Akutsu M, Novak I, Harper JW, Behrends C, Dikic I (2012) Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol Cell Biol 32:1733–1744. doi:10.1128/MCB.06717-11

    PubMed  CAS  Google Scholar 

  86. Bains M, Zaegel V, Mize-Berge J, Heidenreich KA (2011) IGF-I stimulates Rab7-RILP interaction during neuronal autophagy. Neurosci Lett 488:112–117. doi:10.1016/j.neulet.2010.09.018

    PubMed  CAS  Google Scholar 

  87. Harbison ST, Yamamoto AH, Fanara JJ, Norga KK, Mackay TF (2004) Quantitative trait loci affecting starvation resistance in Drosophila melanogaster. Genetics 166(4):1807–1823

    PubMed  CAS  Google Scholar 

  88. Haecker A, Qi D, Lilja T, Moussian B, Andrioli LP, Luschnig S, Mannervik M (2007) Drosophila brakeless interacts with atrophin and is required for tailless-mediated transcriptional repression in early embryos. PLoS Biol 5:e145. doi:10.1371/journal.pbio.0050145

    PubMed  Google Scholar 

  89. Wang L, Charroux B, Kerridge S, Tsai CC (2008) Atrophin recruits HDAC1/2 and G9a to modify histone H3K9 and to determine cell fates. EMBO Rep 9:555–562. doi:10.1038/embor.2008.67

    PubMed  CAS  Google Scholar 

  90. Martin-Blanco E, Roch F, Noll E, Baonza A, Duffy JB, Perrimon N (1999) A temporal switch in DER signaling controls the specification and differentiation of veins and interveins in the Drosophila wing. Development 126:5739–5747

    PubMed  CAS  Google Scholar 

  91. Charroux B, Freeman M, Kerridge S, Baonza A (2006) Atrophin contributes to the negative regulation of epidermal growth factor receptor signaling in Drosophila. Dev Biol 291:278–290. doi:10.1016/j.ydbio.2005.12.012

    PubMed  CAS  Google Scholar 

  92. Kankel MW, Duncan DM, Duncan I (2004) A screen for genes that interact with the Drosophila pair-rule segmentation gene fushi tarazu. Genetics 168:161–180. doi:10.1534/genetics.104.027250

    PubMed  CAS  Google Scholar 

  93. Meng X, Kondo M, Morino K, Fuke T, Obata T, Yoshizaki T, Ugi S, Nishio Y, Maeda S, Araki E, Kashiwagi A, Maegawa H (2010) Transcription factor AP-2β: a negative regulator of IRS-1 gene expression. Biochem Biophys Res Commun 392:526–532

    PubMed  CAS  Google Scholar 

  94. Wenke AK, Bosserhoff AK (2010) Roles of AP-2 transcription factors in the regulation of cartilage and skeletal development. FEBS J 277:894–902

    PubMed  CAS  Google Scholar 

  95. Eckert D, Buhl S, Weber S, Jager R, Schorle H (2005) The AP-2 family of transcription factors. Genome Biol 6:246

    PubMed  Google Scholar 

  96. Dutta S, Dawid IB (2010) Kctd15 inhibits neural crest formation by attenuating Wnt/β-catenin signaling output. Development 137:3013–3018

    PubMed  CAS  Google Scholar 

  97. 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(1):148–160

    PubMed  CAS  Google Scholar 

  98. Giot L, Bader JS, Brouwer C, Chaudhuri A, Kuang B, Li Y, Hao YL, Ooi CE, Godwin B, Vitols E, Vijayadamodar G, Pochart P, Machineni H, Welsh M, Kong Y, Zerhusen B, Malcolm R, Varrone Z, Collis A, Minto M, Burgess S, McDaniel L, Stimpson E, Spriggs F, Williams J, Neurath K, Ioime N, Agee M, Voss E, Furtak K, Renzulli R, Aanensen N, Carrolla S, Bickelhaupt E, Lazovatsky Y, DaSilva A, Zhong J, Stanyon CA, Finley RL Jr, White KP, Braverman M, Jarvie T, Gold S, Leach M, Knight J, Shimkets RA, McKenna MP, Chant J, Rothberg JM (2003) A protein interaction map of Drosophila melanogaster. Science 302:1727–1736

    PubMed  CAS  Google Scholar 

  99. Tomancak P, Berman BP, Beaton A, Weiszmann R, Kwan E, Hartenstein V, Celniker SE, Rubin GM (2007) Global analysis of patterns of gene expression during Drosophila embryogenesis. Genome Biol 8:R145

    PubMed  Google Scholar 

  100. Tomancak P, Beaton A, Weiszmann R, Kwan E, Shu S, Lewis SE, Richards S, Ashburner M, Hartenstein V, Celniker SE, Rubin GM (2002) Systematic determination of patterns of gene expression during Drosophila embryogenesis. Genome Biol 3:R88

    Google Scholar 

  101. Ueki K, Yamauchi T, Tamemoto H, Tobe K, Yamamoto-Honda R, Kaburagi Y, Akanuma Y, Yazaki Y, Aizawa S, Nagai R, Kadowaki T (2000) Restored insulin-sensitivity in IRS-1-deficient mice treated by adenovirus-mediated gene therapy. J Clin Invest 105:1437–1445

    PubMed  CAS  Google Scholar 

  102. Eloranta JJ, Hurst HC (2002) Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo. J Biol Chem 277:30798–30804

    PubMed  CAS  Google Scholar 

  103. Bayon Y, Trinidad AG, de la Puerta ML, Del Carmen Rodriguez M, Bogetz J, Rojas A, De Pereda JM, Rahmouni S, Williams S, Matsuzawa S, Reed JC, Crespo MS, Mustelin T, Alonso A (2008) KCTD5, a putative substrate adaptor for cullin3 ubiquitin ligases. FEBS J 275:3900–3910

    PubMed  CAS  Google Scholar 

  104. Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, Pelloni M, De Simone G, Pedone EM, Gallinari P, Giorgi A, Steinkuhler C, Vitagliano L, Pedone C, Schinin ME, Screpanti I, Gulino A (2010) Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol 12:132–142

    PubMed  CAS  Google Scholar 

  105. Correale S, Pirone L, Di Marcotullio L, De Smaele E, Greco A, Mazza D, Moretti M, Alterio V, Vitagliano L, Di Gaetano S, Gulino A, Pedone EM (2011) Molecular organization of the cullin E3 ligase adaptor KCTD11. Biochimie 93:715–724

    PubMed  CAS  Google Scholar 

  106. Ren J, Gao X, Jin C, Zhu M, Wang X, Shaw A, Wen L, Yao X, Xue Y (2009) Systematic study of protein sumoylation: development of a site-specific predictor of SUMOsp 2.0. Proteomics 9:3409–3412

    PubMed  CAS  Google Scholar 

  107. Xue Y, Zhou F, Fu C, Xu Y, Yao X (2006) SUMOsp: a web server for sumoylation site prediction. Nucleic Acids Res 34:W254–W257

    PubMed  CAS  Google Scholar 

  108. Ding X, Luo C, Zhou J, Zhong Y, Hu X, Zhou F, Ren K, Gan L, He A, Zhu J, Gao X, Zhang J (2009) The interaction of KCTD1 with transcription factor AP-2alpha inhibits its transactivation. J Cell Biochem 106:285–295

    PubMed  CAS  Google Scholar 

  109. Kuba M, Higure Y, Susaki H, Hayato R, Kuba K (2007) Bidirectional Ca2+ coupling of mitochondria with the endoplasmic reticulum and regulation of multimodal Ca2+ entries in rat brown adipocytes. Am J Physiol Cell Physiol 292:C896–C908

    PubMed  CAS  Google Scholar 

  110. Decuypere J-P, Monaco G, Bultynck G, Missiaen L, De Smedt H, Parys JB (2011) The IP3 receptor–mitochondria connection in apoptosis and autophagy. Biochim Biophys Acta 1813:1003–1013

    PubMed  CAS  Google Scholar 

  111. Wadhwa R, Taira K, Kaul SC (2002) An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where? Cell Stress Chaperones 7:309–316

    PubMed  CAS  Google Scholar 

  112. Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911

    PubMed  CAS  Google Scholar 

  113. Espenshade P, Gimeno RE, Holzmacher E, Teung P, Kaiser CA (1995) Yeast SEC16 gene encodes a multidomain vesicle coat protein that interacts with Sec23p. J Cell Biol 131:311–324

    PubMed  CAS  Google Scholar 

  114. Miller EA, Barlowe C (2010) Regulation of coat assembly—sorting things out at the ER. Curr Opin Cell Biol 22:447–453

    PubMed  CAS  Google Scholar 

  115. Ivan V, de Voer G, Xanthakis D, Spoorendonk KM, Kondylis V, Rabouille C (2008) Drosophila Sec16 mediates the biogenesis of tER sites upstream of Sar1 through an arginine-rich motif. Mol Biol Cell 19:4352–4365

    PubMed  CAS  Google Scholar 

  116. Supek F, Madden DT, Hamamoto S, Orci L, Schekman R (2002) Sec16p potentiates the action of COPII proteins to bud transport vesicles. J Cell Biol 158:1029–1038

    PubMed  CAS  Google Scholar 

  117. Gimeno RE, Espenshade P, Kaiser CA (1996) COPII coat subunit interactions: Sec24p and Sec23p bind to adjacent regions of Sec16p. Mol Biol Cell 7:1815–1823

    PubMed  CAS  Google Scholar 

  118. Gimeno RE, Espenshade P, Kaiser CA (1995) SED4 encodes a yeast endoplasmic reticulum protein that binds Sec16p and participates in vesicle formation. J Cell Biol 131:325–338

    PubMed  CAS  Google Scholar 

  119. Shaywitz DA, Espenshade PJ, Gimeno RE, Kaiser CA (1997) COPII subunit interactions in the assembly of the vesicle coat. J Biol Chem 272:25413–25416

    PubMed  CAS  Google Scholar 

  120. Zaltsman Y, Shachnai L, Yivgi-Ohana N, Schwarz M, Maryanovich M, Houtkooper RH, Vaz FM, De Leonardis F, Fiermonte G, Palmieri F, Gillissen B, Daniel PT, Jimenez E, Walsh S, Koehler CM, Roy SS, Walter L, Hajnoczky G, Gross A (2010) MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat Cell Biol 12:553–562

    PubMed  CAS  Google Scholar 

  121. Grinberg M, Schwarz M, Zaltsman Y, Eini T, Niv H, Pietrokovski S, Gross A (2005) Mitochondrial carrier homolog 2 is a target of tBID in cells signaled to die by tumor necrosis factor alpha. Mol Cell Biol 25:4579–4590

    PubMed  CAS  Google Scholar 

  122. Endo T, Yamano K (2010) Transport of proteins across or into the mitochondrial outer membrane. Biochim Biophys Acta 1803:706–714

    PubMed  CAS  Google Scholar 

  123. Ryan MT, Wagner R, Pfanner N (2000) The transport machinery for the import of preproteins across the outer mitochondrial membrane. Int J Biochem Cell Biol 32:13–21

    PubMed  CAS  Google Scholar 

  124. Pusnik M, Charriere F, Maser P, Waller RF, Dagley MJ, Lithgow T, Schneider A (2009) The single mitochondrial porin of Trypanosoma brucei is the main metabolite transporter in the outer mitochondrial membrane. Mol Biol Evol 26:671–680

    PubMed  CAS  Google Scholar 

  125. Salinas T, Duchene AM, Delage L, Nilsson S, Glaser E, Zaepfel M, Marechal-Drouard L (2006) The voltage-dependent anion channel, a major component of the tRNA import machinery in plant mitochondria. Proc Natl Acad Sci USA 103:18362–18367

    PubMed  CAS  Google Scholar 

  126. Schleiff E, Silvius JR, Shore GC (1999) Direct membrane insertion of voltage-dependent anion-selective channel protein catalyzed by mitochondrial Tom20. J Cell Biol 145:973–978

    PubMed  CAS  Google Scholar 

  127. Kmita H, Antos N, Wojtkowska M, Hryniewiecka L (2004) Processes underlying the upregulation of Tom proteins in S. cerevisiae mitochondria depleted of the VDAC channel. J Bioenerg Biomembr 36:187–193

    PubMed  CAS  Google Scholar 

  128. Cogliati S, Scorrano L (2010) A BID on mitochondria with MTCH2. Cell Res 20:863–865

    PubMed  Google Scholar 

  129. Cho SY, Lee JH, Bae HD, Jeong EM, Jang GY, Kim CW, Shin DM, Jeon JH, Kim IG (2010) Transglutaminase 2 inhibits apoptosis induced by calcium-overload through down-regulation of Bax. Expl Mol Med 42:639–650

    CAS  Google Scholar 

  130. Kaddour-Djebbar I, Choudhary V, Brooks C, Ghazaly T, Lakshmikanthan V, Dong Z, Kumar MV (2010) Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells. Int J Oncol 36:1437–1444

    PubMed  CAS  Google Scholar 

  131. Billing O, Kao G, Naredi P (2011) Mitochondrial function is required for secretion of DAF-28/insulin in C. elegans. PLoS ONE 6:e14507. doi:10.1371/journal.pone.0014507

    PubMed  CAS  Google Scholar 

  132. Ravasi T, Suzuki H, Cannistraci CV, Katayama S, Bajic VB, Tan K, Akalin A, Schmeier S, Kanamori-Katayama M, Bertin N, Carninci P, Daub CO, Forrest AR, Gough J, Grimmond S, Han JH, Hashimoto T, Hide W, Hofmann O, Kamburov A, Kaur M, Kawaji H, Kubosaki A, Lassmann T, van Nimwegen E, MacPherson CR, Ogawa C, Radovanovic A, Schwartz A, Teasdale RD, Tegnér J, Lenhard B, Teichmann SA, Arakawa T, Ninomiya N, Murakami K, Tagami M, Fukuda S, Imamura K, Kai C, Ishihara R, Kitazume Y, Kawai J, Hume DA, Ideker T, Hayashizaki Y (2010) An atlas of combinatorial transcriptional regulation in mouse and man. Cell 140:744–752

    PubMed  CAS  Google Scholar 

  133. Rask-Andersen M, Almen MS, Schioth HB (2011) Trends in the exploitation of novel drug targets. Nat Rev Drug Discov 10:579–590. doi:10.1038/nrd3478

    PubMed  CAS  Google Scholar 

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  1. Department of Neuroscience, Functional Pharmacology, Biomedical Center, Uppsala University, Box 593, 75 124, Uppsala, Sweden

    Michael J. Williams, Markus S. Almén, Robert Fredriksson & Helgi B. Schiöth

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Williams, M.J., Almén, M.S., Fredriksson, R. et al. What model organisms and interactomics can reveal about the genetics of human obesity. Cell. Mol. Life Sci. 69, 3819–3834 (2012). https://doi.org/10.1007/s00018-012-1022-5

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