1932

Abstract

Over the past decade, studies conducted in have helped to uncover the ancient and complex origins of body fat regulation. This review highlights the powerful combination of genetics, pharmacology, and biochemistry used to study energy balance and the regulation of cellular fat metabolism in . The complete wiring diagram of the nervous system has been exploited to understand how the sensory nervous system regulates body fat and how food perception is coupled with the production of energy via fat metabolism. As a model organism, also offers a unique opportunity to discover neuroendocrine factors that mediate direct communication between the nervous system and the metabolic tissues. The coming years are expected to reveal a wealth of information on the neuroendocrine control of body fat in .

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-021014-071704
2015-02-10
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/physiol/77/1/annurev-physiol-021014-071704.html?itemId=/content/journals/10.1146/annurev-physiol-021014-071704&mimeType=html&fmt=ahah

Literature Cited

  1. Zhang Y, Lu H, Bargmann CI. 1.  2005. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438:179–84 [Google Scholar]
  2. Avery L, Shtonda BB. 2.  2003. Food transport in the C. elegans pharynx. J. Exp. Biol. 206:2441–57 [Google Scholar]
  3. Shtonda BB, Avery L. 3.  2006. Dietary choice behavior in Caenorhabditis elegans. J. Exp. Biol. 209:89–102 [Google Scholar]
  4. Avery L, Horvitz HR. 4.  1990. Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. J. Exp. Zool. 253:263–70 [Google Scholar]
  5. You YJ, Kim J, Raizen DM, Avery L. 5.  2008. Insulin, cGMP, and TGF-β signals regulate food intake and quiescence in C. elegans: a model for satiety. Cell Metab. 7:249–57 [Google Scholar]
  6. Schafer WR. 6.  2005. Deciphering the neural and molecular mechanisms of C. elegans behavior. Curr. Biol. 15:R723–29 [Google Scholar]
  7. Schafer WR, Sanchez BM, Kenyon CJ. 7.  1996. Genes affecting sensitivity to serotonin in Caenorhabditis elegans. Genetics 143:1219–30 [Google Scholar]
  8. Greer ER, Perez CL, Van Gilst MR, Lee BH, Ashrafi K. 8.  2008. Neural and molecular dissection of a C. elegans sensory circuit that regulates fat and feeding. Cell Metab. 8:118–31 [Google Scholar]
  9. Sze JY, Victor M, Loer C, Shi Y, Ruvkun G. 9.  2000. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403:560–64 [Google Scholar]
  10. Sawin ER, Ranganathan R, Horvitz HR. 10.  2000. C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26:619–31 [Google Scholar]
  11. Barros AG, Liu J, Lemieux GA, Mullaney BC, Ashrafi K. 11.  2012. Analyses of C. elegans fat metabolic pathways. Methods Cell Biol. 107:383–407 [Google Scholar]
  12. Yen K, Le TT, Bansal A, Narasimhan SD, Cheng JX, Tissenbaum HA. 12.  2010. A comparative study of fat storage quantitation in nematode Caenorhabditis elegans using label and label-free methods. PLOS ONE 5:9 [Google Scholar]
  13. Wählby C, Lee Conery A, Bray M-A, Kamentsky L, Larkins-Ford J. 13.  et al. 2014. High- and low-throughput scoring of fat mass and body fat distribution in C. elegans. Methods 68:3492–99 [Google Scholar]
  14. Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D. 14.  et al. 2013. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430–41 [Google Scholar]
  15. Srinivasan S, Sadegh L, Elle IC, Christensen AG, Faergeman NJ, Ashrafi K. 15.  2008. Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms. Cell Metab. 7:533–44 [Google Scholar]
  16. Zhang P, Na H, Liu Z, Zhang S, Xue P. 16.  et al. 2012. Proteomic study and marker protein identification of Caenorhabditis elegans lipid droplets. Mol. Cell. Proteomics 11:317–28 [Google Scholar]
  17. Schroeder LK, Kremer S, Kramer MJ, Currie E, Kwan E. 17.  et al. 2007. Function of the Caenorhabditis elegans ABC transporter PGP-2 in the biogenesis of a lysosome-related fat storage organelle. Mol. Biol. Cell 18:995–1008 [Google Scholar]
  18. Xu N, Zhang SO, Cole RA, McKinney SA, Guo F. 18.  et al. 2012. The FATP1-DGAT2 complex facilitates lipid droplet expansion at the ER-lipid droplet interface. J. Cell Biol. 198:895–911 [Google Scholar]
  19. Inglis PN, Ou G, Leroux MR, Scholey JM. 19.  2007. The sensory cilia of Caenorhabditis elegans. WormBook, ed. C. elegans Res. Comm., doi:10.1895/wormbook.1.126.2, http://www.wormbook.org
  20. Beets I, Janssen T, Meelkop E, Temmerman L, Suetens N. 20.  et al. 2012. Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans. Science 338:543–45 [Google Scholar]
  21. Garrison JL, Macosko EZ, Bernstein S, Pokala N, Albrecht DR, Bargmann CI. 21.  2012. Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior. Science 338:540–43 [Google Scholar]
  22. Noble T, Stieglitz J, Srinivasan S. 22.  2013. An integrated serotonin and octopamine neuronal circuit directs the release of an endocrine signal to control C. elegans body fat. Cell Metab. 18:672–84 [Google Scholar]
  23. Watts JL. 23.  2009. Fat synthesis and adiposity regulation in Caenorhabditis elegans. Trends Endocrinol. Metab. 20:58–65 [Google Scholar]
  24. Watts JL, Browse J. 24.  2002. Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans. PNAS 99:95854–59 [Google Scholar]
  25. Perez CL, Van Gilst MR. 25.  2008. A 13C isotope labeling strategy reveals the influence of insulin signaling on lipogenesis in C. elegans. Cell Metab. 8:3266–74 [Google Scholar]
  26. Vrablik TL, Watts JL. 26.  2012. Emerging roles for specific fatty acids in developmental processes. Genes Dev. 26:631–37 [Google Scholar]
  27. Liu Y, Samuel BS, Breen PC, Ruvkun G. 27.  2014. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508:406–10 [Google Scholar]
  28. Kniazeva M, Sieber M, McCauley S, Zhang K, Watts JL, Han M. 28.  2003. Suppression of the ELO-2 FA elongation activity results in alterations of the fatty acid composition and multiple physiological defects, including abnormal ultradian rhythms, in Caenorhabditis elegans. Genetics 163:159–69 [Google Scholar]
  29. Ludewig AH, Schroeder FC. 29.  2013. Ascaroside signaling in C. elegans. WormBook C. elegans Res. Comm., doi:10.1895/wormbook.1.155.1, http://www.wormbook.org
  30. Zhang SO, Box AC, Xu N, Le Men J, Yu J. 30.  et al. 2010. Genetic and dietary regulation of lipid droplet expansion in Caenorhabditis elegans. PNAS 107:104640–45 [Google Scholar]
  31. Hermann GJ, Schroeder LK, Hieb CA, Kershner AM, Rabbitts BM. 31.  et al. 2005. Genetic analysis of lysosomal trafficking in Caenorhabditis elegans. Mol. Biol. Cell 16:3273–88 [Google Scholar]
  32. Mak HY. 32.  2012. Lipid droplets as fat storage organelles in Caenorhabditis elegans. Thematic review series: lipid droplet synthesis and metabolism: from yeast to man. J. Lipid Res. 53:28–33 [Google Scholar]
  33. O'Rourke EJ, Soukas AA, Carr CE, Ruvkun G. 33.  2009. C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab. 10:430–35 [Google Scholar]
  34. Marks MS, Heijnen HF, Raposo G. 34.  2013. Lysosome-related organelles: Unusual compartments become mainstream. Curr. Opin. Cell Biol. 25:495–505 [Google Scholar]
  35. Ding Y, Zhang S, Yang L, Na H, Zhang P. 35.  et al. 2013. Isolating lipid droplets from multiple species. Nat. Protoc. 8:43–51 [Google Scholar]
  36. O'Rourke EJ, Ruvkun G. 36.  2013. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15:668–76 [Google Scholar]
  37. Salway JG. 37.  1999. Metabolism at a Glance Malden, MA: Blackwell Sci.
  38. Lee KZ, Kniazeva M, Han M, Pujol N, Ewbank JJ. 38.  2010. The fatty acid synthase fasn-1 acts upstream of WNK and Ste20/GCK-VI kinases to modulate antimicrobial peptide expression in C. elegans epidermis. Virulence 1:113–22 [Google Scholar]
  39. Li Y, Paik YK. 39.  2011. A potential role for fatty acid biosynthesis genes during molting and cuticle formation in Caenorhabditis elegans. BMB Rep. 44:285–90 [Google Scholar]
  40. Van Gilst MR, Hadjivassiliou H, Yamamoto KR. 40.  2005. A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. PNAS 102:13496–501 [Google Scholar]
  41. Jo H, Shim J, Lee JH, Lee J, Kim JB. 41.  2009. IRE-1 and HSP-4 contribute to energy homeostasis via fasting-induced lipases in C. elegans. Cell Metab. 9:440–48 [Google Scholar]
  42. Grove CA, De Masi F, Barrasa MI, Newburger DE, Alkema MJ. 42.  et al. 2009. A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 138:314–27 [Google Scholar]
  43. Jia K, Chen D, Riddle DL. 43.  2004. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131:3897–906 [Google Scholar]
  44. Jones KT, Greer ER, Pearce D, Ashrafi K. 44.  2009. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLOS Biol. 7:e60 [Google Scholar]
  45. Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G. 45.  2009. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23:496–511 [Google Scholar]
  46. Beaven SW, Tontonoz P. 46.  2006. Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu. Rev. Med. 57:313–29 [Google Scholar]
  47. Taubert S, Ward JD, Yamamoto KR. 47.  2011. Nuclear hormone receptors in nematodes: evolution and function. Mol. Cell. Endocrinol. 334:49–55 [Google Scholar]
  48. Larsen PL, Albert PS, Riddle DL. 48.  1995. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139:1567–83 [Google Scholar]
  49. Antebi A, Culotti JG, Hedgecock EM. 49.  1998. daf-12 regulates developmental age and the dauer alternative in Caenorhabditis elegans. Development 125:1191–205 [Google Scholar]
  50. Ludewig AH, Kober-Eisermann C, Weitzel C, Bethke A, Neubert K. 50.  et al. 2004. A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging. Genes Dev. 18:2120–33 [Google Scholar]
  51. Jeong PY, Jung M, Yim YH, Kim H, Park M. 51.  et al. 2005. Chemical structure and biological activity of the Caenorhabditis elegans dauer-inducing pheromone. Nature 433:541–45 [Google Scholar]
  52. Mahanti P, Bose N, Bethke A, Judkins JC, Wollam J. 52.  et al. 2014. Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan. Cell Metab. 19:73–83 [Google Scholar]
  53. Motola DL, Cummins CL, Rottiers V, Sharma KK, Li T. 53.  et al. 2006. Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124:1209–23 [Google Scholar]
  54. Pathare PP, Lin A, Bornfeldt KE, Taubert S, Van Gilst MR. 54.  2012. Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLOS Genet. 8:e1002645 [Google Scholar]
  55. Van Gilst MR, Hadjivassiliou H, Jolly A, Yamamoto KR. 55.  2005. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLOS Biol. 3:e53 [Google Scholar]
  56. McKay RM, McKay JP, Avery L, Graff JM. 56.  2003. C. elegans: a model for exploring the genetics of fat storage. Dev. Cell 4:131–42 [Google Scholar]
  57. Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K. 57.  et al. 2011. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147:840–52 [Google Scholar]
  58. Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY. 58.  et al. 2006. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 442:700–4 [Google Scholar]
  59. Magner DB, Wollam J, Shen Y, Hoppe C, Li D. 59.  et al. 2013. The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans. Cell Metab. 18:212–24 [Google Scholar]
  60. MacNeil LT, Watson E, Arda HE, Zhu LJ, Walhout AJ. 60.  2013. Diet-induced developmental acceleration independent of TOR and insulin in C. elegans. Cell 153:240–52 [Google Scholar]
  61. Watson E, MacNeil LT, Ritter AD, Yilmaz LS, Rosebrock AP. 61.  et al. 2014. Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits. Cell 156:759–70 [Google Scholar]
  62. Watson E, MacNeil LT, Arda HE, Zhu LJ, Walhout AJ. 62.  2013. Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell 153:253–66 [Google Scholar]
  63. Mullaney BC, Blind RD, Lemieux GA, Perez CL, Elle IC. 63.  et al. 2010. Regulation of C. elegans fat uptake and storage by acyl-CoA synthase-3 is dependent on NR5A family nuclear hormone receptor nhr-25. Cell Metab 12:398–410 [Google Scholar]
  64. Arda HE, Taubert S, MacNeil LT, Conine CC, Tsuda B. 64.  et al. 2010. Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network. Mol. Syst. Biol. 6:367 [Google Scholar]
  65. Taubert S, Van Gilst MR, Hansen M, Yamamoto KR. 65.  2006. A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans. Genes Dev. 20:1137–49 [Google Scholar]
  66. Kong D, Tong Q, Ye C, Koda S, Fuller PM. 66.  et al. 2012. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151:645–57 [Google Scholar]
  67. Liu J, Li T, Yang D, Ma R, Moran TH, Smith WW. 67.  2012. Synphilin-1 alters metabolic homeostasis in a novel Drosophila obesity model. Int. J. Obes. 36:1529–36 [Google Scholar]
  68. Lu M, Sarruf DA, Talukdar S, Sharma S, Li P. 68.  et al. 2011. Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat. Med. 17:618–22 [Google Scholar]
  69. Nonogaki K, Abdallah L, Goulding EH, Bonasera SJ, Tecott LH. 69.  2003. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT2C receptor mutant mice. Diabetes 52:315–20 [Google Scholar]
  70. Chan EW, He Y, Chui CS, Wong AY, Lau WC, Wong IC. 70.  2013. Efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled trials (RCTs) and narrative review on short-term RCTs. Obes. Rev. 14:383–92 [Google Scholar]
  71. Wise SD. 71.  1992. Clinical studies with fluoxetine in obesity. Am. J. Clin. Nutr. 55:S181–84 [Google Scholar]
  72. Gershon MD. 72.  2013. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20:14–21 [Google Scholar]
  73. Cunningham KA, Hua Z, Srinivasan S, Liu J, Lee BH. 73.  et al. 2012. AMP-activated kinase links serotonergic signaling to glutamate release for regulation of feeding behavior in C. elegans. Cell Metab. 16:113–21 [Google Scholar]
  74. Chase DL, Koelle MR. 74.  2007. Biogenic amine neurotransmitters in C. elegans. WormBook C. elegans Res. Comm., doi:10.1895/wormbook.1.132.1, http://www.wormbook.org
  75. Song BM, Avery L. 75.  2012. Serotonin activates overall feeding by activating two separate neural pathways in Caenorhabditis elegans. J. Neurosci. 32:1920–31 [Google Scholar]
  76. Brock TJ, Browse J, Watts JL. 76.  2006. Genetic regulation of unsaturated fatty acid composition in C. elegans. PLOS Genet. 2:e108 [Google Scholar]
  77. Flavell SW, Pokala N, Macosko EZ, Albrecht DR, Larsch J, Bargmann CI. 77.  2013. Serotonin and the neuropeptide PDF initiate and extend opposing behavioral states in C. elegans. Cell 154:1023–35 [Google Scholar]
  78. Cuellar GE, Ruiz AM, Monsalve MC, Berber A. 78.  2000. Six-month treatment of obesity with sibutramine 15 mg; a double-blind, placebo-controlled monocenter clinical trial in a Hispanic population. Obes. Res. 8:71–82 [Google Scholar]
  79. Fanghanel G, Cortinas L, Sanchez-Reyes L, Berber A. 79.  2000. A clinical trial of the use of sibutramine for the treatment of patients suffering essential obesity. Int. J. Obes. Relat. Metab. Disord. 24:144–50 [Google Scholar]
  80. Talbot PS, Bradley S, Clarke CP, Babalola KO, Philipp AW. 80.  et al. 2010. Brain serotonin transporter occupancy by oral sibutramine dosed to steady state: a PET study using (11)C-DASB in healthy humans. Neuropsychopharmacology 35:741–51 [Google Scholar]
  81. Wong D, Sullivan K, Heap G. 81.  2012. The pharmaceutical market for obesity therapies. Nat. Rev. Drug Discov. 11:669–70 [Google Scholar]
  82. Hu PJ. 82.  2007. Dauer. WormBook C. elegans Res. Comm., doi:10.1895/wormbook.1.144.1, http://www.wormbook.org
  83. Kimura KD, Riddle DL, Ruvkun G. 83.  2011. The C. elegans DAF-2 insulin-like receptor is abundantly expressed in the nervous system and regulated by nutritional status. Cold Spring Harb. Symp. Quant. Biol. 76:113–20 [Google Scholar]
  84. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. 84.  1997. daf-2, an insulin receptor–like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–46 [Google Scholar]
  85. Narasimhan SD, Yen K, Bansal A, Kwon ES, Padmanabhan S, Tissenbaum HA. 85.  2011. PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism. PLOS Genet. 7:e1001377 [Google Scholar]
  86. Ren P, Lim CS, Johnsen R, Albert PS, Pilgrim D, Riddle DL. 86.  1996. Control of C. elegans larval development by neuronal expression of a TGF-β homolog. Science 274:1389–91 [Google Scholar]
  87. Guillemin R. 87.  1977. Endorphins, brain peptides that act like opiates. N. Engl. J. Med. 296:226–28 [Google Scholar]
  88. Guillemin R, Lemke G. 88.  2013. A conversation with Roger Guillemin. Annu. Rev. Physiol. 75:1–22 [Google Scholar]
  89. Yalow RS, Berson SA. 89.  1960. Immunoassay of endogenous plasma insulin in man. 1960. Obes. Res. 4:583–600 [Google Scholar]
  90. Kao G, Nordenson C, Still M, Ronnlund A, Tuck S, Naredi P. 90.  2007. ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells. Cell 128:577–87 [Google Scholar]
  91. Lee BH, Ashrafi K. 91.  2008. A TRPV channel modulates C. elegans neurosecretion, larval starvation survival, and adult lifespan. PLOS Genet. 4:e1000213 [Google Scholar]
  92. Li C, Kim K. 92.  2008. Neuropeptides. WormBook C. elegans Res. Comm., doi:10.1895/wormbook.1.142.1, http://www.wormbook.org
  93. Pokala N, Liu Q, Gordus A, Bargmann CI. 93.  2014. Inducible and titratable silencing of Caenorhabditis elegans neurons in vivo with histamine-gated chloride channels. PNAS 111:2770–75 [Google Scholar]
/content/journals/10.1146/annurev-physiol-021014-071704
Loading
/content/journals/10.1146/annurev-physiol-021014-071704
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error