Oxidative Stress Promotes Eating Behavior and Obesity in C. elegans via EGL-4 / DAF-16 Signaling
DOI:
https://doi.org/10.6000/1927-5951.2015.05.02.5Keywords:
Oxidative stress, Eating behavior, Obesity, EGL4/cGMP-dependent protein kinases, DAF-16/FOXO, C. elegans, HEK293 cells.Abstract
Oxidative stress is associated with pathophysiological progress of many diseases. The objective of study was to investigate whether increased environmental oxidative stress stimulation can promote excessive eating behavior, a common cause of obesity, and to identify the molecular mechanism.The cGMP-dependent kinase (PKG) activator 8-pCPT-cGMP was applied in worm swimming assay to study behavior shifting between quiescence and foraging in C. elegans. Genetically modified C. elegans (egl-4 loss or gain of function, and daf-16 mutant) were treated with paraquat, an oxidative stress inducer. Worm’s foraging behavior, body fat accumulation and body length were determined. The foxo1::gfp-transfectedHEK293 cells and C. elegans (daf-16::gfpTJ356) were further used to examine the effect of paraquat on PKG expression and FOXO nuclear translocation.A novel swimming assay using PKGactivator stimulation was developed, which allows the rapid and effective study of foraging behavior in C. elegans. Paraquat treatment significantly inhibited quiescence, promoted foraging behavior, increased body fat accumulation and body growth. These responses were associated with diminished PKG expression/activation and increased FOXO (DAF-16) nuclear translocation in both transfected C. elegans and HEK293 cells.Our data suggest that PKG/FOXO signaling may plays an important role in mediating oxidative stress-induced excessive eating behavior and obesity development.
References
Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood) 2009; 28(5): w822-31. http://dx.doi.org/10.1377/hlthaff.28.5.w822
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311(8): 806-14. http://dx.doi.org/10.1001/jama.2014.732
Lev-Ran A. Human obesity: an evolutionary approach to understanding our bulging waistline. Diabetes Metab Res Rev 2001; 17(5): 347-62. http://dx.doi.org/10.1002/dmrr.230
Osborne KA, Robichon A, Burgess E, Butland S, Shaw RA, Coulthard A, et al. Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 1997; 277(5327): 834-6. http://dx.doi.org/10.1126/science.277.5327.834
Fitzpatrick MJ, Sokolowski MB. In Search of Food: Exploring the Evolutionary Link Between cGMP-Dependent Protein Kinase (PKG) and Behaviour. Integr Comp Biol 2004; 44(1): 28-36. http://dx.doi.org/10.1093/icb/44.1.28
You YJ, Kim J, Raizen DM, Avery L. Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety. Cell Metab 2008; 7(3): 249-57. http://dx.doi.org/10.1016/j.cmet.2008.01.005
Moon TM, Osborne BW, Dostmann WR. The switch helix: a putative combinatorial relay for interprotomer communication in cGMP-dependent protein kinase. Biochim Biophys Acta 2013; 1834(7): 1346-51. http://dx.doi.org/10.1016/j.bbapap.2013.02.009
Kaun KR, Sokolowski MB. cGMP-dependent protein kinase: linking foraging to energy homeostasis. Genome 2009; 52(1): 1-7. http://dx.doi.org/10.1139/G08-090
Raizen DM, Zimmerman JE, Maycock MH, Ta UD, You YJ, Sundaram MV, et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature 2008; 451(7178): 569-72. http://dx.doi.org/10.1038/nature06535
Ghosh R, Emmons SW. Calcineurin and protein kinase G regulate C. elegans behavioral quiescence during locomotion in liquid. BMC Genetics 2010; 11: 7. http://dx.doi.org/10.1186/1471-2156-11-7
Inserte J, Hernando V, Vilardosa U, Abad E, Poncelas-Nozal M, Garcia-Dorado D. Activation of cGMP/protein kinase G pathway in postconditioned myocardium depends on reduced oxidative stress and preserved endothelial nitric oxide synthase coupling. J Am Heart Assoc 2013; 2(1): e005975. http://dx.doi.org/10.1161/JAHA.112.005975
Hui L, Hong Y, Jingjing Z, Yuan H, Qi C, Nong Z. HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA. Free Radic Biol Med 2010; 49(3): 467-73. http://dx.doi.org/10.1016/j.freeradbiomed.2010.05.002
Rudyk O, Phinikaridou A, Prysyazhna O, Burgoyne JR, Botnar RM, Eaton P. Protein kinase G oxidation is a major cause of injury during sepsis. Proc Natl Acad Sci USA 2013; 110(24): 9909-13. http://dx.doi.org/10.1073/pnas.1301026110
Liu S, Ma X, Gong M, Shi L, Lincoln T, Wang S. Glucose down-regulation of cGMP-dependent protein kinase I expression in vascular smooth muscle cells involves NAD(P)H oxidase-derived reactive oxygen species. Free Radic Biol Med 2007; 42(6): 852-63. http://dx.doi.org/10.1016/j.freeradbiomed.2006.12.025
Ghosh R, Emmons SW. Episodic swimming behavior in the nematode C. elegans. J Exp Biol 2008; 211(Pt 23): 3703-11. http://dx.doi.org/10.1242/jeb.023606
Wang C, Blough ER, Arvapalli R, Dai X, Paturi S, Manne N, et al. Metabolic syndrome-induced tubulointerstitial injury: role of oxidative stress and preventive effects of acetaminophen. Free Radic Biol Med 2013; 65: 1417-26. http://dx.doi.org/10.1016/j.freeradbiomed.2013.10.005
Keaney JF, Jr., Larson MG, Vasan RS, Wilson PW, Lipinska I, Corey D, et al. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol 2003; 23(3): 434-9. http://dx.doi.org/10.1161/01.ATV.0000058402.34138.11
Ali S, Jain SK, Abdulla M, Athar M. Paraquat induced DNA damage by reactive oxygen species. Biochem Mol Biol Int 1996; 39(1): 63-7. http://dx.doi.org/10.1080/15216549600201061
Kanao T, Sawada T, Davies SA, Ichinose H, Hasegawa K, Takahashi R, et al. The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in Drosophila. PLoS One 2012; 7(2): e30958. http://dx.doi.org/10.1371/journal.pone.0030958
Borniquel S, Garcia-Quintans N, Valle I, Olmos Y, Wild B, Martinez-Granero F, et al. Inactivation of Foxo3a and subsequent downregulation of PGC-1 alpha mediate nitric oxide-induced endothelial cell migration. Mol Cell Biol 2010; 30(16): 4035-44. http://dx.doi.org/10.1128/MCB.00175-10
Kwon IK, Wang R, Thangaraju M, Shuang H, Liu K, Dashwood R, et al. PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. Oncogene 2010; 29(23): 3423-34. http://dx.doi.org/10.1038/onc.2010.91
Kitamura T, Feng Y, Kitamura YI, Chua SC, Jr., Xu AW, Barsh GS, et al. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med 2006; 12(5): 534-40. http://dx.doi.org/10.1038/nm1392
Hong SH, Lee KS, Kwak SJ, Kim AK, Bai H, Jung MS, et al. Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals. PLoS Genet 2012; 8(8): e1002857. http://dx.doi.org/10.1371/journal.pgen.1002857
Ren H, Plum-Morschel L, Gutierrez-Juarez R, Lu TY, Kim-Muller JY, Heinrich G, et al. Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons. Diabetes 2013; 62(10): 3373-83. http://dx.doi.org/10.2337/db13-0597
Wu M, Katta A, Gadde MK, Liu H, Kakarla SK, Fannin J, et al. Aging-associated dysfunction of akt/protein kinase B: s-nitrosylation and acetaminophen intervention. PLoS One 2009; 4(7): e6430. http://dx.doi.org/10.1371/journal.pone.0006430
Wang Y, Wu M, Al-Rousan R, Liu H, Fannin J, Paturi S, et al. Iron-induced cardiac damage: role of apoptosis and deferasirox intervention. J Pharmacol Exp Ther 2011; 336(1): 1-8. http://dx.doi.org/10.1124/jpet.110.172668
Laufs U, Wassmann S, Czech T, Munzel T, Eisenhauer M, Bohm M, et al. Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25(4): 809-14. http://dx.doi.org/10.1161/01.ATV.0000158311.24443.af
Kelishadi R, Mirghaffari N, Poursafa P, Gidding SS. Lifestyle and environmental factors associated with inflammation, oxidative stress and insulin resistance in children. Atherosclerosis 2009; 203(1): 311-9. http://dx.doi.org/10.1016/j.atherosclerosis.2008.06.022
Srimahachota S, Wunsuwan R, Siritantikorn A, Boonla C, Chaiwongkarjohn S, Tosukhowong P. Effects of lifestyle modification on oxidized LDL, reactive oxygen species production and endothelial cell viability in patients with coronary artery disease. Clin Biochem 2010; 43(10-11): 858-62. http://dx.doi.org/10.1016/j.clinbiochem.2010.04.056
Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H, et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 2008; 57(8): 1071-7. http://dx.doi.org/10.1016/j.metabol.2008.03.010
Galili O, Versari D, Sattler KJ, Olson ML, Mannheim D, McConnell JP, et al. Early experimental obesity is associated with coronary endothelial dysfunction and oxidative stress. Am J Physiol Heart Circ Physiol 2007; 292(2): H904-11. http://dx.doi.org/10.1152/ajpheart.00628.2006
Kang KS, Yahashi S, Azuma M, Sakashita A, Shioda S, Matsuda K. Effect of Intraperitoneal Injection of Curcumin on Food Intake in a Goldfish Model. J Mol Neurosci 2011; 45(2): 172-6. http://dx.doi.org/10.1007/s12031-010-9390-5
Navarro A, Sanchez-Pino MJ, Gomez C, Bandez MJ, Cadenas E, Boveris A. Dietary thioproline decreases spontaneous food intake and increases survival and neurological function in mice. Antioxid Redox Signal 2007; 9(1): 131-41. http://dx.doi.org/10.1089/ars.2007.9.131
Downloads
Published
Issue
Section
License
Copyright (c) 2015 Wensheng Li, Eric Blough, Cuifen Wang, Larry Dial, Omolola Olajide, Randa Al-Jayoussi, Nesreen BenHamed , Miaozong Wu

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Similar Articles
- Jamaluddin, Nur Atina , Yonelian Yuyun, The Analysis of Protein Level and Amino Acid Profile in Eels (Anguilla marmorata (Q.) Gaimard and Anguilla bicolor) of Lake Poso , Journal of Pharmacy and Nutrition Sciences : Vol. 9 No. 1 (2019)
- Kenichiro Yasutake, Motoyuki Kohjima, Yusuke Murata, Manabu Nakashima, Makoto Nakamuta , Munechika Enjoji, Association between Visceral Fat and Body Mass Index in Patients with Cirrhosis , Journal of Pharmacy and Nutrition Sciences : Vol. 4 No. 1 (2014)
- Isabel Veloso Alves Pereira, Claudia Pinto Marques Souza de Oliveira, José Tadeu Stefano, Nathalia Cavalheiro Halla, João Avancini Ferreira Alves, Francisco Rafael Martins Laurindo, Flair José Carrilho, Yo Jyo Hen Shi Ko (YHK) Modulates the Expression of Proteins Involved in de novo Lipogenesis and Lipid Exportation in Experimental Nonalcoholic Steatohepatitis (NASH) , Journal of Pharmacy and Nutrition Sciences : Vol. 3 No. 1 (2013)
- Rashidi Othman , Norazian Mohd. Hassan , Ainaa Eliah Abu Bakar , Nur Hidayah Noh , Nurrulhidayah Ahmad Fadzillah , Noraini Mahmad, Manipulation of Environmental Stress Towards Lutein Production in Chlorella fusca Cell Culture , Journal of Pharmacy and Nutrition Sciences : Vol. 9 No. 5 (2019)
- Abhita Malaviya, Parash Parajuli , Paul W. Sylvester, Anticancer Effects of Combined γ-Tocotrienol and PPARγ-Antagonist Treatment are Associated with a Suppression in Adipogenic Factor Expression , Journal of Pharmacy and Nutrition Sciences : Vol. 4 No. 1 (2014)
- Mina Seifzadeh, Prevention of Lipid Oxidation in Kilka Fillet (Clupeonella Cultriventris) using Biodegradable Packaging in the Refrigerator (3°C) , Journal of Pharmacy and Nutrition Sciences : Vol. 14 (2024)
- Di Viesti, G. Carnevale, M.M. Carrozzo, M. Zavatti , M. Baraldi, Influence of Parmigiano Reggiano Diet on Male Sexual Behavior in Rats: Behavioral and Neurochemical Study , Journal of Pharmacy and Nutrition Sciences : Vol. 2 No. 1 (2012)
- Sovan Pattanaik, Sudam Chandra Si, Sudhanshu Sekhar Rout, Anindya Bose , Siva Shankar Nayak, In Silico Design & Development of Some Selected Flavonols Against Beta–Glucuronidase Inhibitory Activity , Journal of Pharmacy and Nutrition Sciences : Vol. 5 No. 1 (2015)
- Syed Muhammad Ghufran Saeed, Syed Asad Sayeed, Seema Ashraf, Nassimunnisa Nassimunnisa, Fizza Batool, Rashida Ali, Shahina Naz, Rahmanullah Siddiqi, Investigations of In vitro Digestibility of Proteins Bound to Food Colors , Journal of Pharmacy and Nutrition Sciences : Vol. 1 No. 1 (2011)
- Mumtaz Hussain , Shariza Sahudin, Obesity, Type-II Diabetes and the Use of Food Labels: A Malaysian Perspective , Journal of Pharmacy and Nutrition Sciences : Vol. 9 No. 3 (2019)
You may also start an advanced similarity search for this article.