Germline Signals Deploy NHR-49 to Modulate Fatty-Acid β-Oxidation and Desaturation in Somatic Tissues of

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Much is known about how increasing age impairs fertility but we know little about how reproduction influences rate of aging in animals. Studies in model organisms such as worms and flies have begun to shed light on this relationship. In worms, removing germ cells that give rise to sperm and oocytes extends lifespan, increases endurance and elevates fat. Fat metabolism and hormonal signals play major roles in this lifespan augmentation but the genetic mechanisms involved are poorly understood. We show that a gene, nhr-49, enhances worm lifespan following germ-cell removal. NHR-49 is increased in animals that lack germ cells by conserved longevity proteins, DAF-16 and TCER-1. NHR-49, in turn, increases levels of genes that help burn fat and convert saturated fats into unsaturated forms. Through synchronized enhancement of these processes, NHR-49 helps eliminate excess fat delegated for reproduction and converts lipids into forms that favor a long life. NHR-49 impacts these processes during aging in normal animals too, but using different regulatory mechanisms. Our data helps understand how normal lipid metabolic processes can be harnessed to adapt to physiological fluctuations brought on by changes in the reproductive status of animals.

Vyšlo v časopise: Germline Signals Deploy NHR-49 to Modulate Fatty-Acid β-Oxidation and Desaturation in Somatic Tissues of. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004829
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004829

Souhrn

Zdroje

1. KirkwoodT (1977) Evolution of ageing. Nature 270 : 301–304.

2. DroriD, FolmanY (1976) Environmental effects on longevity in the male rat: exercise, mating, castration and restricted feeding. Exp Gerontol 11 : 25–32 doi http://dx.doi.org/10.1016/0531-5565(76)90007-3.

3. RobertsonOH (1961) Relation of gonadal maturation to length of life in Pacific salmon. Fed Proc 20 : 29–30.

4. OssewaardeME, BotsML, VerbeekALM, PeetersPHM, van der GraafY, et al. (2005) Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 16 : 556–562 doi:10.1097/01.ede.0000165392.35273.d4

5. MessierV, Rabasa-LhoretR, Barbat-ArtigasS, ElishaB, KarelisAD, et al. (2011) Menopause and sarcopenia: A potential role for sex hormones. Maturitas 68 : 331–336 doi:10.1016/j.maturitas.2011.01.014

6. PartridgeL, GemsD, WithersDJ (2005) Sex and death: what is the connection? Cell 120 : 461–472 doi:10.1016/j.cell.2005.01.026

7. GhaziA (2013) Transcriptional networks that mediate signals from reproductive tissues to influence lifespan. Genesis 51 : 1–15 doi:10.1002/dvg.22345

8. HansenM, FlattT, AguilaniuH (2013) Reproduction, fat metabolism, and life span: what is the connection? Cell Metab 17 : 10–19 doi:10.1016/j.cmet.2012.12.003

9. AntebiA (2013) Regulation of longevity by the reproductive system. Exp Gerontol 48 : 596–602 doi:10.1016/j.exger.2012.09.009

10. GreenBB, WeissNS, DalingJR (1988) Risk of ovulatory infertility in relation to body weight. Fertil Steril 50 : 721–726.

11. Vom Saal FS, Finch CE, Nelson JF (1994) Natural History and Mechanisms of Reproductive Aging in Humans, Laboratory Rodents, and Other Selected Vertebrates. In: Knobil E, Neill JD, editors.The Physiology of Reproduction. Raven Press, Ltd, New York. pp. 1213–1314.

12. ValdesAM, AndrewT, GardnerJP, KimuraM, OelsnerE, et al. (2005) Obesity, cigarette smoking, and telomere length in women. Lancet 366 : 662–664 doi:10.1016/S0140-6736(05)66630-5

13. HsinH, KenyonC (1999) Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399 : 362–366 doi:10.1038/20694

14. AlperS, McElweeMK, ApfeldJ, LackfordB, FreedmanJH, et al. (2010) The Caenorhabditis elegans germ line regulates distinct signaling pathways to control lifespan and innate immunity. J Biol Chem 285 : 1822–1828 doi:10.1074/jbc.M109.057323

15. FlattT, MinK-J, D′AlterioC, Villa-CuestaE, CumbersJ, et al. (2008) Drosophila germ-line modulation of insulin signaling and lifespan. Proc Natl Acad Sci U S A 105 : 6368–6373 doi:10.1073/pnas.0709128105

16. RaeR, SinhaA, SommerRJ (2012) Genome-wide analysis of germline signaling genes regulating longevity and innate immunity in the nematode Pristionchus pacificus. PLoS Pathog 8: e1002864 doi:10.1371/journal.ppat.1002864

17. DrewryMD, WilliamsJM, HatleJD (2011) Life-extending dietary restriction and ovariectomy result in similar feeding rates but different physiologic responses in grasshoppers. Exp Gerontol 46 : 781–786 doi:10.1016/j.exger.2011.06.003

18. MasonJB, CargillSL, AndersonGB, CareyJR (2009) Transplantation of young ovaries to old mice increased life span in transplant recipients. J Gerontol A Biol Sci Med Sci 64 : 1207–1211 doi:10.1093/gerona/glp134

19. MinK-J, LeeC-K, ParkH-N (2012) The lifespan of Korean eunuchs. Curr Biol 22: R792–3 doi:10.1016/j.cub.2012.06.036

20. LinK, HsinH, LibinaN, KenyonC (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28 : 139–145 doi:10.1038/88850

21. KenyonCJ (2010) The genetics of ageing. Nature 464 : 504–512 doi:10.1038/nature08980

22. MontesM, CloutierA, Sánchez-HernándezN, MichelleL, LemieuxB, et al. (2012) TCERG1 regulates alternative splicing of the Bcl-x gene by modulating the rate of RNA polymerase II transcription. Mol Cell Biol 32 : 751–762 doi:10.1128/MCB.06255-11

23. GhaziA, Henis-KorenblitS, KenyonC (2009) A transcription elongation factor that links signals from the reproductive system to lifespan extension in Caenorhabditis elegans. PLoS Genet 5: e1000639 doi:10.1371/journal.pgen.1000639

24. LapierreLR, GelinoS, MeléndezA, HansenM (2011) Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr Biol 21 : 1507–1514 doi:10.1016/j.cub.2011.07.042

25. LapierreLR, De Magalhaes FilhoCD, McQuaryPR, ChuC-C, VisvikisO, et al. (2013) The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun 4 : 2267 doi:10.1038/ncomms3267

26. HsuA-L, MurphyCT, KenyonC (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300 : 1142–1145 doi:10.1126/science.1083701

27. VilchezD, MorantteI, LiuZ, DouglasPM, MerkwirthC, et al. (2012) RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489 : 263–268 doi:10.1038/nature11315

28. WolffS, MaH, BurchD, MacielGA, HunterT, et al. (2006) SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 124 : 1039–1053 doi:10.1016/j.cell.2005.12.042

29. GerischB, RottiersV, LiD, MotolaDL, CumminsCL, et al. (2007) A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proc Natl Acad Sci U S A 104 : 5014–5019 doi:10.1073/pnas.0700847104

30. GoudeauJ, BelleminS, Toselli-MollereauE, ShamalnasabM, ChenY, et al. (2011) Fatty acid desaturation links germ cell loss to longevity through NHR-80/HNF4 in C. elegans. PLoS Biol 9: e1000599 doi:10.1371/journal.pbio.1000599

31. BermanJR, KenyonC (2006) Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell 124 : 1055–1068 doi:10.1016/j.cell.2006.01.039

32. WangMC, O′RourkeEJ, RuvkunG (2008) Fat metabolism links germline stem cells and longevity in C. elegans. Science 322 : 957–960 doi:10.1126/science.1162011

33. McCormickM, ChenK, RamaswamyP, KenyonC (2012) New genes that extend Caenorhabditis elegans′ lifespan in response to reproductive signals. Aging Cell 11 : 192–202 doi:10.1111/j.1474-9726.2011.00768.x

34. TaubertS, WardJD, YamamotoKR (2011) Nuclear hormone receptors in nematodes: evolution and function. Mol Cell Endocrinol 334 : 49–55 doi:10.1016/j.mce.2010.04.021

35. Contreras AV, TorresN, TovarAR (2013) PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 4 : 439–452 doi:10.3945/an.113.003798

36. Van GilstMR, HadjivassiliouH, JollyA, YamamotoKR (2005) Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3: e53 doi:10.1371/journal.pbio.0030053

37. Van GilstMR, HadjivassiliouH, YamamotoKR (2005) A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc Natl Acad Sci U S A 102 : 13496–13501 doi:10.1073/pnas.0506234102

38. AngeloG, Van GilstMR (2009) Starvation protects germline stem cells and extends reproductive longevity in C. elegans. Science 326 : 954–958 doi:10.1126/science.1178343

39. RualJ-F, CeronJ, KorethJ, HaoT, NicotA-S, et al. (2004) Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res 14 : 2162–2168 doi:10.1101/gr.2505604

40. KamathRS, FraserAG, DongY, PoulinG, DurbinR, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421 : 231–237 doi:10.1038/nature01278

41. Arantes-OliveiraN, ApfeldJ, DillinA, KenyonC (2002) Regulation of life-span by germ-line stem cells in Caenorhabditis elegans. Science 295 : 502–505 doi:10.1126/science.1065768

42. DillinA, HsuA-L, Arantes-OliveiraN, Lehrer-GraiwerJ, HsinH, et al. (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298 : 2398–2401 doi:10.1126/science.1077780

43. HoutenSM, WandersRJA (2010) A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. J Inherit Metab Dis 33 : 469–477 doi:10.1007/s10545-010-9061-2

44. O′RourkeEJ, SoukasAA, CarrCE, RuvkunG (2009) C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab 10 : 430–435 doi:10.1016/j.cmet.2009.10.002

45. PerezCL, Van GilstMR (2008) A 13C isotope labeling strategy reveals the influence of insulin signaling on lipogenesis in C. elegans. Cell Metab 8 : 266–274 doi:10.1016/j.cmet.2008.08.007

46. PatharePP, LinA, BornfeldtKE, TaubertS, van GilstMR (2012) Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genet 8: e1002645 doi:10.1371/journal.pgen.1002645

47. ChamoliM, SinghA, MalikY, MukhopadhyayA (2014) A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans. Aging Cell 13 : 641–655 doi:10.1111/acel.12218

48. XuM, JooHJ, PaikYK (2011) Novel functions of lipid-binding protein 5 in Caenorhabditis elegans fat metabolism. J Biol Chem 286 : 28111–28118 doi:10.1074/jbc.M111.227165

49. Artal-SanzM, TavernarakisN (2009) Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 461 : 793–797 doi:10.1038/nature08466

50. HuangW, LiZ, XuY, WangW, ZhouM, et al. (2014) PKG and NHR-49 signalling co-ordinately regulate short-term fasting-induced lysosomal lipid accumulation in C. elegans. Biochem J 461 : 509–520 doi:10.1042/BJ20140191

51. BrockTJ, BrowseJ, WattsJL (2007) Fatty acid desaturation and the regulation of adiposity in Caenorhabditis elegans. Genetics 176 : 865–875 doi:10.1534/genetics.107.071860

52. WattsJL (2009) Fat synthesis and adiposity regulation in Caenorhabditis elegans. Trends Endocrinol Metab 20 : 58–65 doi:10.1016/j.tem.2008.11.002

53. Gonzalez-CovarrubiasV, BeekmanM, UhH-W, DaneA, TroostJ, et al. (2013) Lipidomics of familial longevity. Aging Cell 12 : 426–434 doi:10.1111/acel.12064

54. GillinghamLG, Harris-JanzS, JonesPJH (2011) Dietary monounsaturated fatty acids are protective against metabolic syndrome and cardiovascular disease risk factors. Lipids 46 : 209–228 doi:10.1007/s11745-010-3524-y

55. MorganNG, DhayalS, DiakogiannakiE, WeltersHJ (2008) The cytoprotective actions of long-chain mono-unsaturated fatty acids in pancreatic beta-cells. Biochem Soc Trans 36 : 905–908 doi:10.1042/BST0360905

56. CalderPC, YaqoobP (2009) Omega-3 polyunsaturated fatty acids and human health outcomes. Biofactors 35 : 266–272 doi:10.1002/biof.42

57. GuarenteL (2008) Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132 : 171–176 doi:10.1016/j.cell.2008.01.007

58. NarbonneP, RoyR (2009) Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457 : 210–214 doi:10.1038/nature07536

59. DobrzynP, SampathH, DobrzynA, MiyazakiM, NtambiJM (2008) Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart. Am J Physiol Endocrinol Metab 294: E357–64 doi:10.1152/ajpendo.00471.2007

60. VercesiAE, CastilhoRF, KowaltowskiAJ, OliveiraHCF (2007) Mitochondrial energy metabolism and redox state in dyslipidemias. IUBMB Life 59 : 263–268 doi:10.1080/15216540601178091

61. SavaryS, TrompierD, AndréolettiP, Le BorgneF, DemarquoyJ, et al. (2012) Fatty acids -⁠ induced lipotoxicity and inflammation. Curr Drug Metab 13 : 1358–1370.

62. ZhouYP, GrillVJ (1995) Long term exposure to fatty acids and ketones inhibits β-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab 80 : 1584–1590.

63. KraegenEW, CooneyGJ (2008) Free fatty acids and skeletal muscle insulin resistance. Curr Opin Lipidol 19 : 235–241 doi:10.1097/01.mol.0000319118.44995.9a

64. BuschAK, GurisikE, Cordery DV, SudlowM, DenyerGS, et al. (2005) Increased fatty acid desaturation and enhanced expression of stearoyl coenzyme A desaturase protects pancreatic beta-cells from lipoapoptosis. Diabetes 54 : 2917–2924.

65. MurphyCT, McCarrollSA, BargmannCI, FraserA, KamathRS, et al. (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424 : 277–283 doi:10.1038/nature01789

66. Tullet JMa, HertweckM, AnJH, BakerJ, HwangJY, et al. (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132 : 1025–1038 doi:10.1016/j.cell.2008.01.030

67. KenyonC, ChangJ, GenschE, RudnerA, TabtiangR (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366 : 461–4.

68. AmritFRG, MayRC (2010) Younger for longer: insulin signalling, immunity and ageing. Curr Aging Sci 3 : 166–176 doi:10.2174/1874609811003030166

69. AmritFRG, RatnappanR, KeithSA, GhaziA (2014) The C. elegans lifespan assay toolkit. Methods 68 : 465–475 doi:10.1016/j.ymeth.2014.04.002

70. KeithSA, AmritFRG, RatnappanR, GhaziA (2014) The C. elegans healthspan and stress-resistance assay toolkit. Methods 68 : 476–486 doi:10.1016/j.ymeth.2014.04.003