Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Adipocyte and Cell Biology

What we know and what we need to know about adenovirus 36-induced obesity

International Journal of Obesity volume 44, pages 1197–1209 (2020)Cite this article

Subjects

Abstract

Background

Many internal and external factors are related to obesity. Pathogens that can induce obesity are the most interesting external factors. While the relationship between pathogenic human intestinal microbiota and obesity has been extensively studied, viruses have received relatively little attention. Among the human obesity-related viruses, adenovirus 36 (Ad36) is most commonly associated with obesity.

Methods

A literature search was conducted using the articles in the PubMed database published from April 1982 to April 2019. The following main keywords were used: (‘adenovirus 36’) and (‘obesity’) and (‘cellular mechanism’ or ‘genetic factor’ or ‘immune response’ or ‘inflammation’).

Results

In this review, we have discussed the known facts and what requires to be understood regarding Ad36-induced obesity. In particular, we have summarized the cellular mechanism of Ad36-induced obesity, as well as the genetic and immunological factors affected by Ad36 infection. Ad36 infection increases adipogenesis in animals and humans. Ad36-induced inflammation contributes to angiogenesis in adipose tissues, thereby maintaining proper glycemic control and metabolic robustness. The E4orf1 protein derived from Ad36 is responsible for increasing glucose uptake due to the translocation of GLUT4 via the Ras-PI3K pathway, which is involved in ‘distal’ insulin signaling.

Conclusions

We expect that this review will assist in guiding future investigations regarding Ad36-induced obesity. (1) Identification of the direct and indirect factors affecting Ad36-induced obesity and understanding their mechanism of action and (2) utilization of the Ad36-induced improvement in glycemic control for clinical applications, with efforts toward developing E4orf1-based drugs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Summary of the effects of adenovirus 36 and/or E4orf1 on preadipocytes and adipocytes.
Fig. 2: Effect of adenovirus 36 and/or E4orf1 on the insulin signaling pathway.
Fig. 3: Summary of the effects of adenovirus 36 on adipose tissue robustness (metabolic robustness).

Similar content being viewed by others

References

  1. Lyons MJ, Faust IM, Hemmes RB, Buskirk DR, Hirsch J, Zabriskie JB. A virally induced obesity syndrome in mice. Science. 1982;216:82–5.

    Article  CAS  PubMed  Google Scholar 

  2. Dhurandhar NV, Kulkarni P, Ajinkya SM, Sherikar A. Effect of adenovirus infection on adiposity in chicken. Vet Microbiol. 1992;31:101–7.

    Article  CAS  PubMed  Google Scholar 

  3. Whigham LD, Israel BA, Atkinson RL. Adipogenic potential of multiple human adenoviruses in vivo and in vitro in animals. Am J Physiol Regul Integr Comp Physiol. 2006;290:R190–4.

    Article  CAS  PubMed  Google Scholar 

  4. Akheruzzaman M, Hegde V, Dhurandhar NV. Twenty-five years of research about adipogenic adenoviruses: a systematic review. Obes Rev. 2019;20:499–509.

    Article  PubMed  Google Scholar 

  5. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew G, Cook ME, Atkinson RL. Transmissibility of adenovirus-induced adiposity in a chicken model. Int J Obes (Lond). 2001;25:990–6.

    Article  CAS  Google Scholar 

  6. Montes-Galindo DA, Espiritu-Mojarro AC, Melnikov V, Moy-López NA, Soriano-Hernandez AD, Galvan-Salazar HR, et al. Adenovirus 5 produces obesity and adverse metabolic, morphological, and functional changes in the long term in animals fed a balanced diet or a high-fat diet: a study on hamsters. Arch Virol. 2019;164:775–86.

    Article  CAS  PubMed  Google Scholar 

  7. Dhurandhar NV, Whigham LD, Abbott DH, Schultz-Darken NJ, Israel BA, Bradley SM, et al. Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys. J Nutr. 2002;132:3155–60.

    Article  CAS  PubMed  Google Scholar 

  8. Pasarica M, Loiler S, Dhurandhar NV. Acute effect of infection by adipogenic human adenovirus Ad36. Arch Virol. 2008;153:2097–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Na HN, Hong YM, Michael BY, Park SH, Kim IB, Nam JH. Adenovirus 36 attenuates weight loss from exercise but improves glycemic control by increasing mitochondrial activity in the liver. PLoS One. 2014;9:e114534.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Shang Q, Wang H, Song Y, Wei L, Lavebratt C, Zhang F, et al. Serological data analyses show that adenovirus 36 infection is associated with obesity: a meta-analysis involving 5739 subjects. Obesity (Silver Spring). 2014;22:895–900.

    Article  Google Scholar 

  11. Xu MY, Cao B, Wang DF, Guo JH, Chen KL, Shi M, et al. Human adenovirus 36 infection increased the risk of obesity: a meta-analysis update. Medicine. 2015;94:e2357.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yamada T, Hara K, Kadowaki T. Association of adenovirus 36 infection with obesity and metabolic markers in humans: a meta-analysis of observational studies. PLoS One. 2012;7:e42031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB, et al. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (Lond). 2005;29:281–6.

    Article  CAS  Google Scholar 

  14. Atkinson RL, Lee I, Shin HJ, He J. Human adenovirus-36 antibody status is associated with obesity in children. Int J Pediatr Obes. 2010;5:157–60.

    Article  PubMed  Google Scholar 

  15. Broderick M, Hansen C, Irvine M, Metzgar D, Campbell K, Baker C, et al. Adenovirus 36 seropositivity is strongly associated with race and gender, but not obesity, among US military personnel. Int J Obes (Lond). 2010;34:302–8.

    Article  CAS  Google Scholar 

  16. Gabbert C, Donohue M, Arnold J, Schwimmer JB. Adenovirus 36 and obesity in children and adolescents. Pediatrics. 2010;126:721–6.

    Article  PubMed  Google Scholar 

  17. Goossens VJ, de Jager SA, Grauls GE, Gielen M, Vlietinck RF, Derom CA, et al. Lack of evidence for the role of human adenovirus‐36 in obesity in a European cohort. Obesity. 2011;19:220–1.

    Article  PubMed  Google Scholar 

  18. Na HN, Hong YM, Kim J, Kim HK, Jo I, Nam JH. Association between human adenovirus-36 and lipid disorders in Korean schoolchildren. Int J Obes (Lond). 2010;34:89–93.

    Article  Google Scholar 

  19. Na HN, Kim J, Lee HS, Shim KW, Kimm H, Jee SH, et al. Association of human adenovirus-36 in overweight Korean adults. Int J Obes (Lond). 2012;36:281–5.

    Article  CAS  Google Scholar 

  20. Trovato GM, Castro A, Tonzuso A, Garozzo A, Martines GF, Pirri C, et al. Human obesity relationship with Ad36 adenovirus and insulin resistance. Int J Obes (Lond). 2009;33:1402–9.

    Article  CAS  Google Scholar 

  21. Trovato GM, Martines GF, Garozzo A, Tonzuso A, Timpanaro R, Pirri C, et al. Ad36 adipogenic adenovirus in human non‐alcoholic fatty liver disease. Liver Int. 2010;30:184–90.

    Article  CAS  PubMed  Google Scholar 

  22. Trovato GM, Martines GF, Trovato FM, Pirri C, Pace P, Garozzo A, et al. Adenovirus-36 seropositivity enhances effects of nutritional intervention on obesity, bright liver, and insulin resistance. Dig Dis Sci. 2012;57:535–44.

    Article  CAS  PubMed  Google Scholar 

  23. Almgren M, Atkinson R, He J, Hilding A, Hagman E, Wolk A, et al. Adenovirus-36 is associated with obesity in children and adults in Sweden as determined by rapid ELISA. PLoS One. 2012;7:e41652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin WY, Dubuisson O, Rubicz R, Liu N, Allison DB, Curran JE, et al. Long-term changes in adiposity and glycemic control are associated with past adenovirus infection. Diabetes Care. 2013;36:701–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Tosh AK, Bray-Aschenbrenner A, El Khatib J, Ge B. Adenovirus-36 antibody status & BMI comparison among obese Missouri adolescents. Mo Med. 2012;109:402–3.

    PubMed  PubMed Central  Google Scholar 

  26. Berger PK, Pollock NK, Laing EM, Warden SJ, Hill Gallant K, Hausman DB, et al. Association of adenovirus 36 infection with adiposity and inflammatory-related markers in children. J Clin Endocrinol Metab. 2014;99:3240–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Karamese M, Altoparlak U, Turgut A, Aydogdu S, Karamese SA. The relationship between adenovirus-36 seropositivity, obesity and metabolic profile in Turkish children and adults. Epidemiol Infect. 2015;143:3550–6.

    Article  CAS  PubMed  Google Scholar 

  28. Laing EM, Tripp RA, Pollock NK, Baile CA, Della‐Fera MA, Rayalam S, et al. Adenovirus 36, adiposity, and bone strength in late‐adolescent females. J Bone Miner Res. 2013;28:489–96.

    Article  PubMed  Google Scholar 

  29. Parra-Rojas I, Moral-Hernández D, Salgado-Bernabé AB, Guzmán-Guzmán IP, Salgado-Goytia L, Muñoz-Valle JF. Adenovirus-36 seropositivity and its relation with obesity and metabolic profile in children. Int J Endocrinol. 2013;2013:e463194.

    Article  Google Scholar 

  30. Sabin M, Burgner D, Atkinson R, Lee ZP-L, Magnussen C, Cheung M, et al. Longitudinal investigation of adenovirus 36 seropositivity and human obesity: the Cardiovascular Risk in Young Finns Study. Int J Obes (Lond). 2015;39:1644–50.

    Article  CAS  Google Scholar 

  31. Vander Wal JS, Huelsing J, Dubuisson O, Dhurandhar NV. An observational study of the association between adenovirus 36 antibody status and weight loss among youth. Obes Facts. 2013;6:269–78.

    Article  Google Scholar 

  32. Cakmakliogullari EK, Sanlidag T, Ersoy B, Akcali S, Var A, Cicek C. Are human adenovirus-5 and 36 associated with obesity in children? J Investig Med. 2014;62:821–4.

    Article  CAS  PubMed  Google Scholar 

  33. Chang X, Yi J, Jian-Fei L, Ya-qun G. The regulation of adenovirus type 36 infection and progranulin expression in Uygur obese patients. J Xi’an Jiaotong Univ. 2015;36:219.

    CAS  Google Scholar 

  34. Ergin S, Altan E, Pilanci O, Sirekbasan S, Cortuk O, Cizmecigil U, et al. The role of adenovirus 36 as a risk factor in obesity: the first clinical study made in the fatty tissues of adults in Turkey. Microb Pathog. 2015;80:57–62.

    Article  CAS  PubMed  Google Scholar 

  35. Wang I, Lin L, Li T. Role of adenovirus infection and obese gene mutation in obestiy. Occup Health. 2008;24:2087–9.

    CAS  Google Scholar 

  36. Aldhoon-Hainerová I, Zamrazilová H, Atkinson RL, Dušátková L, Sedláčková B, Hlavatý P, et al. Clinical and laboratory characteristics of 1179 Czech adolescents evaluated for antibodies to human adenovirus 36. Int J Obes (Lond). 2014;38:285–91.

    Article  CAS  Google Scholar 

  37. Voss JD, Burnett DG, Olsen CH, Haverkos HW, Atkinson RL. Adenovirus 36 antibodies associated with clinical diagnosis of overweight/obesity but not BMI gain: a military cohort study. J Clin Endocrinol Metab. 2014;99:E1708–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sapunar J, Fonseca L, Molina V, Ortiz E, Barra MI, Reimer C et al. Adenovirus 36 seropositivity is related to obesity risk, glycemic control, and leptin levels in Chilean subjects. Int J Obes (Lond). 2019; https://doi.org/10.1038/s41366-019-0321-4.

    Article  PubMed  Google Scholar 

  39. Kocazeybek B, Dinc HO, Ergin S, Saribas S, Ozcabi BT, Cizmecigil U, et al. Evaluation of adenovirus-36 (Ad-36) antibody seropositivity and adipokine levels in obese children. Microb Pathog. 2017;108:27–31.

    Article  CAS  PubMed  Google Scholar 

  40. LaVoy EC, Arlinghaus KR, Rooney BV, Gupta P, Atkinson R, Johnston CA. High adenovirus 36 seroprevalence among a population of Hispanic American youth. Int J Adolesc Med Health. 2018; https://doi.org/10.1515/ijamh-2018-0110.

  41. Tosh AK, Wasserman MG, McLeay II MT, Tepe SK. Human adenovirus-36 seropositivity and obesity among Midwestern US adolescents. Int J Adolesc Med Health. 2017; https://doi.org/10.1515/ijamh-2017-0126.

  42. Waye MMY, Chan JCN, Tong PCY, Ma R, Chan PKS. Association of human adenovirus-36 with diabetes, adiposity, and dyslipidaemia in Hong Kong Chinese. Hong Kong Med J. 2015;21:45–7.

    PubMed  Google Scholar 

  43. Zhou Y, Pan Q, Wang X, Zhang L, Xiao F, Guo L. The relationship between human adenovirus 36 and obesity in Chinese Han population. Biosci Rep. 2018;38:BSR20180553.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Pasarica M, Shin AC, Yu M, Yang HMO, Rathod M, Jen KLC, et al. Human adenovirus 36 induces adiposity, increases insulin sensitivity, and alters hypothalamic monoamines in rats. Obesity. 2006;14:1905–13.

    Article  CAS  PubMed  Google Scholar 

  45. Hwang KA, Park S, Ahn JH, Nam JH. Development of a standard protocol for quantitative polymerase chain reaction to detect adenovirus 36, which is associated with obesity. Acta Virol. 2018;62:350–9.

    Article  CAS  PubMed  Google Scholar 

  46. Krishnapuram R, Kirk-Ballard H, Zuberi A, Dhurandhar NV. Infectivity period of mice inoculated with human adenoviruses. Lab Anim. 2011;45:103–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jiao Y, Aisa Y, Liang X, Nuermaimaiti N. Regulation of PPAR c and CIDEC expression by adenovirus 36 in adipocyte differentiation. Mol Cell Biochem. 2017;428:1–8.

    Article  CAS  PubMed  Google Scholar 

  48. Rathod M, Vangipuram SD, Krishnan B, Heydari AR, Holland TC, Dhurandhar NV. Viral mRNA expression but not DNA replication is required for lipogenic effect of human adenovirus Ad-36 in preadipocytes. Int J Obes (Lond). 2006;31:78–86.

    Article  CAS  Google Scholar 

  49. Rogers PM, Fusinski KA, Rathod MA, Loiler SA, Pasarica M, Shaw MK, et al. Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene. Int J Obes (Lond). 2007;32:397–406.

    Article  CAS  Google Scholar 

  50. Vangipuram SD, Yu M, Tian J, Stanhope KL, Pasarica M, Havel PJ, et al. Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells. Int J Obes (Lond). 2006;31:87–96.

    Article  CAS  Google Scholar 

  51. Na HN, Kim H, Nam JH. Novel genes and cellular pathways related to infection with adenovirus-36 as an obesity agent in human mesenchymal stem cells. Int J Obes (Lond). 2012;36:195–200.

    Article  CAS  Google Scholar 

  52. Pasarica M, Mashtalir N, McAllister EJ, Kilroy GE, Koska J, Permana P, et al. Adipogenic human adenovirus Ad‐36 induces commitment, differentiation, and lipid accumulation in human adipose‐derived stem cells. Stem Cells. 2008;26:969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vangipuram SD, Sheele J, Atkinson RL, Holland TC, Dhurandhar NV. A human adenovirus enhances preadipocyte differentiation. Obes Res. 2004;12:770–7.

    Article  CAS  PubMed  Google Scholar 

  54. Wang ZQ, Yu Y, Zhang XH, Floyd EZ, Cefalu WT. Human adenovirus 36 decreases fatty acid oxidation and increases de novo lipogenesis in primary cultured human skeletal muscle cells by promoting Cidec/FSP27 expression. Int J Obes (Lond). 2010;34:1355–64.

    Article  CAS  Google Scholar 

  55. Rathod MA, Rogers PM, Vangipuram SD, McAllister EJ, Dhurandhar NV. Adipogenic cascade can be induced without adipogenic media by a human adenovirus. Obesity. 2009;17:657–64.

    Article  CAS  PubMed  Google Scholar 

  56. Almgren M, Atkinson RL, Hilding A, He J, Brismar K, Schalling M, et al. Human adenovirus-36 is uncommon in type 2 diabetes and is associated with increased insulin sensitivity in adults in Sweden. Ann Med. 2014;46:539–46.

    Article  CAS  PubMed  Google Scholar 

  57. Dhurandhar NV, Dhurandhar EJ, Ingram DK, Vaughan K, Mattison JA. Natural infection of human adenovirus 36 in rhesus monkeys is associated with a reduction in fasting glucose. J Diabetes. 2014;6:614–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rogers PM, Mashtalir N, Rathod MA, Dubuisson O, Wang Z, Dasuri K, et al. Metabolically favorable remodeling of human adipose tissue by human adenovirus type 36. Diabetes. 2008;57:2321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang ZQ, Cefalu WT, Zhang XH, Yu Y, Qin J, Son L, et al. Human adenovirus type 36 enhances glucose uptake in diabetic and nondiabetic human skeletal muscle cells independent of insulin signaling. Diabetes. 2008;57:1805–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Krishnapuram R, Dhurandhar EJ, Dubuisson O, Kirk-Ballard H, Bajpeyi S, Butte N, et al. Template to improve glycemic control without reducing adiposity or dietary fat. Am J Physiol Endocrinol Metab. 2011;300:E779–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Blümer RME, van Roomen CP, Meijer AJ, Houben-Weerts JHPM, Sauerwein HP, Dubbelhuis PF. Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes. Metabolism. 2008;57:1655–62.

    Article  PubMed  CAS  Google Scholar 

  62. Pereira RI, Leitner JW, Erickson C, Draznin B. Pioglitazone acutely stimulates adiponectin secretion from mouse and human adipocytes via activation of the phosphatidylinositol 3′-kinase. Life Sci. 2008;83:638–43.

    Article  CAS  PubMed  Google Scholar 

  63. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–95.

    Article  CAS  PubMed  Google Scholar 

  64. Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21:1443–55.

    Article  CAS  PubMed  Google Scholar 

  65. Na HN, Nam JH. Adenovirus 36 as an obesity agent maintains the obesity state by increasing MCP-1 and inducing inflammation. J Infect Dis. 2012;205:914–22.

    Article  CAS  PubMed  Google Scholar 

  66. Marseglia L, Manti S, D’Angelo G, Nicotera A, Parisi E, Di Rosa G, et al. Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci. 2014;16:378–400.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Moseti D, Regassa A, Kim WK. Molecular regulation of adipogenesis and potential anti-adipogenic bioactive molecules. Int J Mol Sci. 2016;17:E124.

    Article  PubMed  CAS  Google Scholar 

  68. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev. 2000;14:1293–307.

    CAS  PubMed  Google Scholar 

  69. Furuhashi M, Saitoh S, Shimamoto K, Miura T. Fatty acid-binding protein 4 (FABP4): pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. Clin Med Insights Cardiol. 2015;8:23–33.

    PubMed  PubMed Central  Google Scholar 

  70. Wu LE, Samocha-Bonet D, Whitworth PT, Fazakerley DJ, Turner N, Biden TJ, et al. Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity. Mol Metab. 2014;3:465–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Xu H, Hertzel AV, Steen KA, Bernlohr DA. Loss of fatty acid binding protein 4/aP2 reduces macrophage inflammation through activation of SIRT3. Mol Endocrinol. 2016;30:325–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lee YS, Kim J-w, Osborne O, Oh DY, Sasik R, Schenk S, et al. Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity. Cell. 2014;157:1339–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013;93:1–21.

    Article  CAS  PubMed  Google Scholar 

  74. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond). 2009;33:54–66.

    Article  CAS  Google Scholar 

  75. Jang MK, Son YH, Jung MH. ATF3 plays a role in adipocyte hypoxia-mediated mitochondria dysfunction in obesity. Biochem Biophys Res Commun. 2013;431:421–7.

    Article  CAS  PubMed  Google Scholar 

  76. Koh EH, Park JY, Park HS, Jeon MJ, Ryu JW, Kim M, et al. Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes. 2007;56:2973–81.

    Article  CAS  PubMed  Google Scholar 

  77. Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12:537–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718–23.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Castaner O, Goday A, Park Y-M, Lee S-H, Magkos F, Shiow S-ATE, et al. The gut microbiome profile in obesity: a systematic review. Int J Endocrinol. 2018;2018:4095789.

    PubMed  PubMed Central  Google Scholar 

  80. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

    Article  PubMed  Google Scholar 

  81. Koliada A, Syzenko G, Moseiko V, Budovska L, Puchkov K, Perederiy V, et al. Association between body mass index and Firmicutes/Bacteroidetes ratio in an adult Ukrainian population. BMC Microbiol. 2017;17:120.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Wasimuddin, Corman VM, Ganzhorn JU, Rakotondranary J, Ratovonamana YR, Drosten C, et al. Adenovirus infection is associated with altered gut microbial communities in a non-human primate. Sci Rep. 2019;9:13410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sang Y, Shields LE, Sang ER, Si H, Pigg A, Blecha F. Ileal transcriptome analysis in obese rats induced by high-fat diets and an adenoviral infection. Int J Obes (Lond). 2019; https://doi.org/10.1038/s41366-019-0323-2.

    Article  PubMed  Google Scholar 

  84. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170:605–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. McMurphy TB, Huang W, Xiao R, Liu X, Dhurandhar NV, Cao L. Hepatic expression of adenovirus 36 E4ORF1 improves glycemic control and promotes glucose metabolism through AKT activation. Diabetes. 2017;66:358–71.

    Article  CAS  PubMed  Google Scholar 

  86. Na HN, Dubuisson O, Hegde V, Nam JH, Dhurandhar NV. Human adenovirus Ad36 and its E4orf1 gene enhance cellular glucose uptake even in the presence of inflammatory cytokines. Biochimie. 2016;124:3–10.

    Article  CAS  PubMed  Google Scholar 

  87. Frese KK, Lee SS, Thomas DL, Latorre IJ, Weiss RS, Glaunsinger BA, et al. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene. 2003;22:710–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dhurandhar EJ, Dubuisson O, Mashtalir N, Krishnapuram R, Hegde V, Dhurandhar NV. E4orf1: a novel ligand that improves glucose disposal in cell culture. PLoS One. 2011;6:e23394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yoon I, Park S, Kim R, Ko H, Nam J. Insulin-sparing and fungible effects of E4orf1 combined with an adipocyte-targeting sequence in mouse models of type 1 and type 2 diabetes. Int J Obes (Lond). 2017;41:1601–5.

    Article  CAS  Google Scholar 

  90. Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2004;10:65–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Metz HE, Houghton AM. Insulin receptor substrate regulation of phosphoinositide 3-kinase. Clin Cancer Res. 2011;17:206–11.

    Article  CAS  PubMed  Google Scholar 

  92. Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest. 2000;106:165–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kusminski CM, Gallardo-Montejano VI, Wang ZV, Hegde V, Bickel PE, Dhurandhar NV, et al. E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte. Mol Metab. 2015;4:653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shastri AA, Hegde V, Peddibhotla S, Feizy Z, Dhurandhar NV. E4orf1: a protein for enhancing glucose uptake despite impaired proximal insulin signaling. PLoS One. 2018;13:e0208427.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Krishnapuram R, Kirk-Ballard H, Dhurandhar EJ, Dubuisson O, Messier V, Rabasa-Lhoret R, et al. Insulin receptor-independent upregulation of cellular glucose uptake. Int J Obes (Lond). 2013;37:146–53.

    Article  CAS  Google Scholar 

  96. Na HN, Hegde V, Dubuisson O, Dhurandhar NV. E4orf1 enhances glucose uptake independent of proximal insulin signaling. PLoS One. 2016;11:e0161275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Jinesh G, Sambandam V, Vijayaraghavan S, Balaji K, Mukherjee S. Molecular genetics and cellular events of K-Ras-driven tumorigenesis. Oncogene. 2018;37:839–46.

    Article  CAS  PubMed  Google Scholar 

  98. Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, et al. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 2008;22:2941–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19:557–66.

    Article  CAS  PubMed  Google Scholar 

  100. Zuo Y, Qiang L, Farmer SR. Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma-associated repression of HDAC1 at the C/ebp alpha gene promoter. J Biol Chem. 2006;281:7960–7.

    Article  CAS  PubMed  Google Scholar 

  101. Madsen MS, Siersbaek R, Boergesen M, Nielsen R, Mandrup S. Peroxisome proliferator-activated receptor gamma and C/EBPalpha synergistically activate key metabolic adipocyte genes by assisted loading. Mol Cell Biol. 2014;34:939–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Armoni M, Harel C, Karnieli E. Transcriptional regulation of the GLUT4 gene: from PPAR-gamma and FOXO1 to FFA and inflammation. Trends Endocrinol Metab. 2007;18:100–7.

    Article  CAS  PubMed  Google Scholar 

  103. Puri V, Ranjit S, Konda S, Nicoloro SM, Straubhaar J, Chawla A, et al. Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc Natl Acad Sci USA. 2008;105:7833–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Huh JY, Park YJ, Ham M, Kim JB. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells. 2014;37:365–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep. 2005;5:70–5.

    Article  CAS  PubMed  Google Scholar 

  106. Park S, Park HL, Lee SY, Nam JH. Characteristics of adipose tissue macrophages and macrophage-derived insulin-like growth factor-1 in virus-induced obesity. Int J Obes (Lond). 2015;40:460–70.

    Article  CAS  Google Scholar 

  107. Rull A, Camps J, Alonso-Villaverde C, Joven J. Insulin resistance, inflammation, and obesity: role of monocyte chemoattractant protein-1 (or CCL2) in the regulation of metabolism. Mediat Inflamm. 2010;2010:326580.

    Article  CAS  Google Scholar 

  108. Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA. 2003;100:7265–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Na HN, Nam JH. Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36. Int J Obes (Lond). 2014;38:1470–4.

    Article  CAS  Google Scholar 

  110. Na HN, Park S, Jeon HJ, Kim HB, Nam JH. Reduction of adenovirus 36-induced obesity and inflammation by mulberry extract. Microbiol Immunol. 2014;58:303–6.

    Article  CAS  PubMed  Google Scholar 

  111. Dhurandhar NV. A framework for identification of infections that contribute to human obesity. Lancet Infect Dis. 2011;11:963–9.

    Article  PubMed  Google Scholar 

  112. Kraakman MJ, Murphy AJ, Jandeleit-Dahm K, Kammoun HL. Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? Front Immunol. 2014;5:470.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Castoldi A, Naffah de Souza C, Camara NO, Moraes-Vieira PM. The macrophage switch in obesity development. Front Immunol. 2015;6:637.

    PubMed  Google Scholar 

  114. Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes. 2009;58:2574–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cao Y. Angiogenesis as a therapeutic target for obesity and metabolic diseases. Chem Immunol Allergy. 2014;99:170–9.

    Article  CAS  PubMed  Google Scholar 

  116. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121:2094–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lin D, Chun TH, Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem Pharmacol. 2016;119:8–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Blüher M. Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance? Clin Sci (Lond). 2016;130:1603–14.

    Article  Google Scholar 

  119. Gallagher KA, Joshi A, Carson WF, Schaller M, Allen R, Mukerjee S, et al. Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes. 2015;64:1420–30.

    Article  CAS  PubMed  Google Scholar 

  120. Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009;114:3244–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Catholic University of Korea Research Fund 2019 to JHN; Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science and ICT (NRF-2015M3A9B5030157 to JHN and NRF-2019R1A2C1086151 to JAK); and the KRIBB Research Initiative Program (to JAK). We thank Hae Li Ko for figure drawing.

Author information

Author notes

  1. These authors contributed equally: Jihye Kim, Hana Na, Jung-Ae Kim

Authors and Affiliations

  1. Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, 17104, Republic of Korea

    Jihye Kim

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, 02118, MA, USA

    Hana Na

  3. Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea

    Jung-Ae Kim

  4. Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, 34113, Republic of Korea

    Jung-Ae Kim

  5. Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, Republic of Korea

    Jae-Hwan Nam

Authors
  1. Jihye Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hana Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jung-Ae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae-Hwan Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae-Hwan Nam.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J., Na, H., Kim, JA. et al. What we know and what we need to know about adenovirus 36-induced obesity. Int J Obes 44, 1197–1209 (2020). https://doi.org/10.1038/s41366-020-0536-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-0536-4

This article is cited by

Search

Advanced search

Quick links