Loss of a Neural AMP-Activated Kinase Mimics the Effects of Elevated Serotonin on Fat, Movement, and Hormonal Secretions

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While it is well appreciated that food availability has profound effects on behavior, physiology, and metabolism, the molecular systems that link these complex processes together still remain poorly understood. An ancient cellular sensor of energy is AMP-activated protein kinase, AMPK. Here we show that in the genetically tractable C. elegans, loss of AMPK in the nervous system mimics many of the outcomes also seen upon elevated serotonin signaling, a neural indicator of food availability. We show that similar to elevated serotonin signaling, loss of neural AMPK causes reduced movement while enhancing fat metabolism and secretions of neuroendocrine hormones known to be systemic regulators of energy balance, development and aging. While AMPK is generally considered a mediator of hormonal signaling, our findings indicate that it also regulates their release. Our findings suggest that some previous results attributed to roles of AMPK in the regulation of peripheral metabolism may in fact be due to the roles of this kinase complex in the nervous system as a mediator of serotonin signaling.

Vyšlo v časopise: Loss of a Neural AMP-Activated Kinase Mimics the Effects of Elevated Serotonin on Fat, Movement, and Hormonal Secretions. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004394
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004394

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Zdroje

1. HardieDG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Publishing Group 8 : 774–785 doi:10.1038/nrm2249

2. LimCT, KolaB, KorbonitsM (2010) AMPK as a mediator of hormonal signalling. J Mol Endocrinol 44 : 87–97 doi:10.1677/JME-09-0063

3. MinokoshiY, AlquierT, FurukawaN, KimY-B, LeeA, et al. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428 : 569–574 doi:10.1038/nature02440

4. KahnBB, AlquierT, CarlingD, HardieDG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 1 : 15–25 doi:10.1016/j.cmet.2004.12.003

5. RattanR, GiriS, SinghAK, SinghI (2005) 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem 280 : 39582–39593 doi:10.1074/jbc.M507443200

6. ApfeldJ, O'ConnorG, McDonaghT, DiStefanoPS, CurtisR (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes & Development 18 : 3004–3009 doi:10.1101/gad.1255404

7. CunninghamKA, HuaZ, SrinivasanS, LiuJ, LeeBH, et al. (2012) AMP-Activated Kinase Links Serotonergic Signaling to Glutamate Release for Regulation of Feeding Behavior in C. elegans. Cell Metabolism 16 : 113–121 doi:10.1016/j.cmet.2012.05.014

8. SchulzTJ, ZarseK, VoigtA, UrbanN, BirringerM, et al. (2007) Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress. Cell Metabolism 6 : 280–293 doi:10.1016/j.cmet.2007.08.011

9. 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

10. FukuyamaM, SakumaK, ParkR, KasugaH, NagayaR, et al. (2012) C. elegans AMPKs promote survival and arrest germline development during nutrient stress. Biology Open 1 : 929–936.

11. XieM, RoyR (2012) Increased levels of hydrogen peroxide induce a HIF-1-dependent modification of lipid metabolism in AMPK compromised C. elegans dauer larvae. Cell Metabolism 16 : 322–335 doi:10.1016/j.cmet.2012.07.016

12. NarbonneP, RoyR (2006) Inhibition of germline proliferation during C. elegans dauer development requires PTEN, LKB1 and AMPK signalling. Development 13 : 611–619 doi:10.1242/dev.02232

13. GreerEL, DowlatshahiD, BankoMR, VillenJ, HoangK (2007) An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans. Current Biology 17 : 1646–1656 doi:10.1016/j.cub.2007.08.047

14. MairW, MorantteI, RodriguesAPC, ManningG, MontminyM, et al. (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470 : 404–408 doi:10.1038/nature09706

15. SzeJY, VictorM, LoerC, ShiY, RuvkunG (2000) Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403 : 560–564 doi:10.1038/35000609

16. LiangB, MoussaifM, KuanC-J, GargusJJ, SzeJY (2006) Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metabolism 4 : 429–440 doi:10.1016/j.cmet.2006.11.004

17. SawinER, RanganathanR, HorvitzHR (2000) C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26 : 619–631.

18. AveryL, HorvitzHR (1990) Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. J Exp Zool 253 : 263–270 doi:10.1002/jez.1402530305

19. SrinivasanS, SadeghL, ElleIC, ChristensenAGL, FaergemanNJ, et al. (2008) Serotonin Regulates C. elegans Fat and Feeding through Independent Molecular Mechanisms. Cell Metabolism 7 : 533–544 doi:10.1016/j.cmet.2008.04.012

20. HorvitzHR, ChalfieM, TrentC, SulstonJE, EvansPD (1982) Serotonin and octopamine in the nematode Caenorhabditis elegans. Science 216 : 1012–1014 doi:10.1126/science.6805073

21. ShtondaBB, AveryL (2006) Dietary choice behavior in Caenorhabditis elegans. Journal of Experimental Biology 209 : 89–102 doi:10.1242/jeb.01955

22. ZhangY, LuH, BargmannCI (2005) Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438 : 179–184 doi:10.1038/nature04216

23. MeloJA, RuvkunG (2012) Inactivation of conserved C. elegans genes engages pathogen -⁠ and xenobiotic-associated defenses. Cell 149 : 452–466 doi:10.1016/j.cell.2012.02.050

24. YouY-J, KimJ, CobbM, AveryL (2006) Starvation activates MAP kinase through the muscarinic acetylcholine pathway in Caenorhabditis elegans pharynx. Cell Metabolism 3 : 237–245 doi:10.1016/j.cmet.2006.02.012

25. RBM, LP, LAF, LDL (1975) Analgesic effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake. Psychopharmacol Commun 1 : 511–521.

26. RanganathanR, SawinER, TrentC, HorvitzHR (2001) Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine. Journal of Neuroscience 21 : 5871–5884.

27. BargmannCI, HorvitzHR (1991) Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans.. Neuron 7 : 729–742.

28. LeeH, ChoJS, LambacherN, LeeJ, LeeSJ, et al. (2008) The Caenorhabditis elegans AMP-activated Protein Kinase AAK-2 Is Phosphorylated by LKB1 and Is Required for Resistance to Oxidative Stress and for Normal Motility and Foraging Behavior. Journal of Biological Chemistry 283 : 14988–14993 doi:10.1074/jbc.M709115200

29. DempseyCM, MackenzieSM, GargusA, BlancoG (2005) Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior. Genetics 169 : 1425–1436 doi:10.1534/genetics.104.032540

30. HobsonRJ, HapiakVM, XiaoH, BuehrerKL (2006) SER-7, a Caenorhabditis elegans 5-HT7-like receptor, is essential for the 5-HT stimulation of pharyngeal pumping and egg laying. Genetics 172 : 159–169 doi:10.1534/genetics.105.044495

31. NobleT, StieglitzJ, SrinivasanS (2013) An integrated serotonin and octopamine neuronal circuit directs the release of an endocrine signal to control C. elegans body fat. Cell Metabolism 18 : 672–684 doi:10.1016/j.cmet.2013.09.007

32. Biological Engineering Division Massachusetts Institute of Technology Barry R. Masters Visiting Scientist, Peter So Professor of Mechanical and Biological Engineering Massachusetts Institute of Technology (2008) Handbook of Biomedical Nonlinear Optical Microscopy. Oxford University Press. .1 pp

33. WangMC, MinW, FreudigerCW, RuvkunG, XieXS (2011) RNAi screening for fat regulatory genes with SRS microscopy. Nat Methods 8 : 135–U152 doi:10.1038/NMETH.1556

34. HellererT, AxaengC, BrackmannC, HillertzP, PilonM, et al. (2007) Monitoring of lipid storage in Caenorhabditis elegans using coherent anti-Stokes Raman scattering (CARS) microscopy. Proc Natl Acad Sci USA 104 : 14658–14663 doi:10.1073/pnas.0703594104

35. 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

36. TaubertS, Van GilstMR, HansenM, YamamotoKR (2006) A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans. Genes & Development 20 : 1137–1149 doi:10.1101/gad.1395406

37. Hu PJ (2007) Dauer. WormBook : the online review of C elegans biology: 1–19. doi:10.1895/wormbook.1.144.1.

38. KimuraKD, TissenbaumHA, LiuY, RuvkunG (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277 : 942–946.

39. Gumienny TL, Savage-Dunn C (2005) TGF-β signaling in C. elegans. WormBook : the online review of C elegans biology: 1–34.

40. CassadaRC, RussellRL (1975) The dauerlarva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev Biol 46 : 326–342 doi:10.1016/0012-1606(75)90109-8

41. LeeBH, LiuJ, WongD, SrinivasanS, AshrafiK (2011) Hyperactive Neuroendocrine Secretion Causes Size, Feeding, and Metabolic Defects of C. elegans Bardet-Biedl Syndrome Mutants. PLoS Biol 9: e1001219 doi:10.1371/journal.pbio.1001219.g007

42. HussonSJ, MertensI, JanssenT, LindemansM, SchoofsL (2007) Neuropeptidergic signaling in the nematode Caenorhabditis elegans. Progress in Neurobiology 82 : 33–55 doi:10.1016/j.pneurobio.2007.01.006

43. RenP, LimCS, JohnsenR, AlbertPS, PilgrimD, et al. (1996) Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274 : 1389–1391.

44. SchackwitzWS, InoueT, ThomasJH (1996) Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans.. Neuron 17 : 719–728.

45. KaoG, NordensonC, StillM, RönnlundA, TuckS, et al. (2007) ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells. Cell 128 : 577–587 doi:10.1016/j.cell.2006.12.031

46. SieburthD, MadisonJM, KaplanJM (2006) PKC-1 regulates secretion of neuropeptides. Nat Neurosci 10 : 49–57 doi:10.1038/nn1810

47. LeeBH, AshrafiK (2008) A TRPV Channel Modulates C. elegans Neurosecretion, Larval Starvation Survival, and Adult Lifespan. PLoS Genet 4: e1000213 doi:10.1371/journal.pgen.1000213

48. AnnK (1997) Novel Ca2+-binding Protein (CAPS) Related to UNC-31 Required for Ca2+-activated Exocytosis. Journal of Biological Chemistry 272 : 19637–19640 doi:10.1074/jbc.272.32.19637

49. SchadeMA, ReynoldsNK, DollinsCM, MillerKG (2005) Mutations that rescue the paralysis of Caenorhabditis elegans ric-8 (synembryn) mutants activate the G alpha(s) pathway and define a third major branch of the synaptic signaling network. Genetics 169 : 631–649 doi:10.1534/genetics.104.032334

50. HarrisGP, HapiakVM, WraggRT, MillerSB, HughesLJ, et al. (2009) Three distinct amine receptors operating at different levels within the locomotory circuit are each essential for the serotonergic modulation of chemosensation in Caenorhabditis elegans. Journal of Neuroscience 29 : 1446–1456 doi:10.1523/JNEUROSCI.4585-08.2009

51. ZimmermannR, StraussJG, HaemmerleG, SchoiswohlG, Birner-GruenbergerR, et al. (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306 : 1383–1386 doi:10.1126/science.1100747

52. GreerER, PerezCL, Van GilstMR, LeeBH, AshrafiK (2008) Neural and molecular dissection of a C. elegans sensory circuit that regulates fat and feeding. Cell Metabolism 8 : 118–131 doi:10.1016/j.cmet.2008.06.005

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

54. BrooksKK, LiangB, WattsJL (2009) The Influence of Bacterial Diet on Fat Storage in C. elegans. PLoS ONE 4: e7545 doi:10.1371/journal.pone.0007545

55. LemieuxGA, LiuJ, MayerN, BaintonRJ, AshrafiK, et al. (2011) A whole-organism screen identifies new regulators of fat storage. Nat Chem Biol 7 : 206–213 doi:10.1038/nchembio.534

56. HardieDG, AshfordMLJ (2014) AMPK: Regulating Energy Balance at the Cellular and Whole Body Levels. Physiology (Bethesda) 29 : 99–107 doi:10.1152/physiol.00050.2013

57. XueB, KahnBB (2006) AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. J Physiol (Lond) 574 : 73–83 doi:10.1113/jphysiol.2006.113217

58. LópezM, VarelaL, VázquezMJ, Rodríguez-CuencaS, GonzálezCR, et al. (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16 : 1001–1008 doi:10.1038/nm.2207

59. MinokoshiY, KimY-B, PeroniOD, FryerLGD, MüllerC, et al. (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415 : 339–343 doi:10.1038/415339a

60. Daniel D LamLKH (2007) Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes. Expert Rev Mol Med 9 : 1–24 doi:10.1017/S1462399407000245

61. EvenP, NicolaidisS (1986) Metabolic mechanism of the anorectic and leptogenic effects of the serotonin agonist fenfluramine. Appetite 7 Suppl: 141–163

62. RothwellNJ, StockMJ (1987) Effect of diet and fenfluramine on thermogenesis in the rat: possible involvement of serotonergic mechanisms. Int J Obes 11 : 319–324.

63. Le Feuvre RA, Aisenthal L, Rothwell NJ (1991) Involvement of corticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) and related compounds. Brain Res: 245–250. doi:10.1016/0006-8993(91)90348-Y.

64. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77 : 71–94.

65. Barros AG deA, LiuJ, LemieuxGA, MullaneyBC, AshrafiK (2012) Analyses of C. elegans fat metabolic pathways. Methods Cell Biol 107 : 383–407 doi:10.1016/B978-0-12-394620-1.00013-8