Obesity is linked with a chronic low grade inflammation of non-infectious origin, typically marked by a preponderance of inflammatory cytokines, and a reduced presence of anti-inflammatory cytokines in adipose tissue or circulation. Inflammation in obesity is strongly linked with insulin resistance. However, approaches such as weight loss or anti-inflammatory therapy have not been adequate in countering insulin resistance linked with inflammation and obesity. Hence, a better understanding of the origins of obesity-associated inflammation is needed to design more effective approaches. Also, novel approaches that can improve insulin resistance independent of body weight or inflammation may be highly desirable. These two aspects are briefly described here. It is postulated that a preponderance of pro- and anti-inflammatory cytokines associated with body adiposity may in fact be a mechanism to maintain body fat stores within a desirable range. Excessive fat accumulation may derail this regulation, leading to a chronic state of inflammation associated with obesity and diabetes. Recognizing this underlying physiological basis for inflammation may help in understanding why anti-inflammatory therapy has not achieved significant improvement in insulin sensitivity. Finally, a novel strategy to potentially improve glycemic control is discussed. This strategy relates to a template offered by Ad36, -a human adenovirus, and its E4orf1 protein, which can enhance glucose disposal even in the presence of inflammation and obesity, and without weight loss. Overall, a different perspective about the origin of chronic inflammation, and a novel treatment strategy may help in countering the effects of chronic inflammation in obesity.

Keywords: Insulin resistance, Insulin sensitivity, Glycemic control, Metabolic syndrome, Adiposity, Adenovirus Ad36, E4orf1

1. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011;29:415-45.
   
2. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87-91.
   
3. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-808.
   
4. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-30.
   
5. Bougoulia M, Triantos A, Koliakos G. Effect of weight loss with or without orlistat treatment on adipocytokines, inflammation, oxidative markers in obese women. Hormones (Athens) 2006;5:259-69.
   
6. Rossi AP, Fantin F, Zamboni GA, Mazzali G, Zoico E, Bambace C, et al. Effect of moderate weight loss on hepatic, pancreatic and visceral lipids in obese subjects. Nutr Diabetes 2012;2:e32.
   
7. Dhurandhar NV. When commonsense does not make sense. Int J Obes (Lond) 2012;36:1332-3.
   
8. Gao Z, Yin J, Zhang J, He Q, McGuinness OP, Ye J. Inactivation of NF-kappaB p50 leads to insulin sensitization in liver through post-translational inhibition of p70S6K. J Biol Chem 2009;284:18368-76.
   
9. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, hepatic steatosis in obesity. J Clin Invest 2006;116:1494-505.
   
10. Ye J, McGuinness OP. Inflammation during obesity is not all bad:evidence from animal and human studies. Am J Physiol Endocrinol Metab 2013;304:E466-77.
    
11. Wang Y, Wang H, Hegde V, Dubuisson O, Gao Z, Dhurandhar NV, et al. Interplay of pro- and anti-inflammatory cytokines to determine lipid accretion in adipocytes. Int J Obes (Lond) 2013;37:1490-8.
    
12. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond) 2009;33:54-66.
    
13. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007;293:E1118-28.
    
14. Gao Z, Wang Z, Zhang X, Butler AA, Zuberi A, Gawronska-Kozak B, et al. Inactivation of PKCtheta leads to increased susceptibility to obesity and dietary insulin resistance in mice. Am J Physiol Endocrinol Metab 2007;292:E84-91.
    
15. Chavarro JE, Ehrlich S, Colaci DS, Wright DL, Toth TL, Petrozza JC, et al. Body mass index and short-term weight change in relation to treatment outcomes in women undergoing assisted reproduction. Fertil Steril 2012;98:109-16.
    
16. Frisch RE. Population, food intake, fertility. There is historical evidence for a direct effect of nutrition on reproductive ability. Science 1978;199:22-30.
    
17. Scott EC, Johnston FE. Critical fat, menarche, the maintenance of menstrual cycles: a critical review. J Adolesc Health Care 1982;2:249-60.
    
18. Jensen TK, Andersson AM, Jørgensen N, Andersen AG, Carlsen E, Petersen JH, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril 2004;82:863-70.
    
19. Shayeb AG, Harrild K, Mathers E, Bhattacharya S. An exploration of the association between male body mass index and semen quality. Reprod Biomed Online 2011;23:717-23.
    
20. Veleva Z, Tiitinen A, Vilska S, Hyd?n-Granskog C, Tom?s C, Martikainen H, et al. High and low BMI increase the risk of miscarriage after IVF/ICSI and FET. Hum Reprod 2008;23:878-84.
    
21. Wigand R, Gelderblom H, Wadell G. New human adenovirus (candidate adenovirus 36), a novel member of subgroup D. Arch Virol 1980;64:225-33.
    
22. Dhurandhar NV. Is obesity caused by an adenovirus? Expert Rev Anti Infect Ther 2012;10:521-4.
    
23. Dhurandhar NV. A framework for identification of infections that contribute to human obesity. Lancet Infect Dis 2011;11:963-9.
    
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.
    
25. 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:E779-89.
    
26. Parra-Rojas I, Del Moral-Hern?ndez O, Salgado-Bernab? AB, Guzm?n-Guzm?n IP, Salgado-Goytia L, Mu?oz-Valle JF. Adenovirus-36 seropositivity and its relation with obesity and metabolic profile in children. Int J Endocrinol 2013;2013:463194.
    
27. 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.
    
28. Aldhoon-Hainerov? I, Zamrazilov? H, Atkinson RL, Du??tkov? L, Sedl??kov? B, Hlavat? 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.
    
29. Dhurandhar NV, Geurts L, Atkinson RL, Casteilla L, Clement K, Gerard P, et al. Harnessing the beneficial properties of adipogenic microbes for improving human health. Obes Rev 2013 [Epub ahead of print].
    
30. 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.
    
31. 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.
    
32. 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, insulin resistance. Dig Dis Sci 2012;57:535-44.
    
33. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew GF, Cook ME, Atkinson RL. Increased adiposity in animals due to a human vi rus. Int J Obes Relat Metab Disord 2000;24:989-96.
    
34. Vangipuram SD, Sheele J, Atkinson RL, Holland TC, Dhurandhar NV. A human adenovirus enhances preadipocyte differentiation. Obes Res 2004;12:770-7.
    
35. 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) 2007;31:78-86.
    
36. Rathod M, Rogers PM, Vangipuram SD, McAllister EJ, Dhurandhar NV. Adipogenic cascade can be induced without adipogenic media by a human adenovirus. Obesity (Silver Spring) 2009;17:657-64.
    
37. Pasarica M, Mashtalir N, McAllister EJ, Kilroy GE, Koska J, Permana P, et al. Adipogenic human adenovirus Ad-36 induces commitment, differentiation, lipid accumulation in human adipose-derived stem cells. Stem Cells 2008;26:969-78.
    
38. Dhurandhar NV. Insulin sparing action of Adenovirus 36 and its E4orf1 protein. J Diabetes Complications 2013;27:191-9.
    
39. 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) 2007;31:87-96.
    
40. Pasarica M, Shin AC, Yu M, Ou Yang HM, Rathod M, Jen KL, et al. Human adenovirus 36 induces adiposity, increases insulin sensitivity, alters hypothalamic monoamines in rats. Obesity (Silver Spring) 2006;14:1905-13.
    
41. 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.
    
42. 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.
    
43. Dubuisson O, Dhurandhar EJ, Krishnapuram R, Kirk-Ballard H, Gupta AK, Hegde V, et al. PPARgamma-independent increase in glucose uptake and adiponectin abundance in fat cells. Endocrinology 2011;152:3648-60.
    
44. Dhurandhar EJ, Krishnapuram R, Hegde V, Dubuisson O, Tao R, Dong XC, et al. E4orf1 improves lipid and glucose metabolism in hepatocytes: a template to improve steatosis & hyperglycemia. PLoS One 2012;7:e47813.
    
45. 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.
    
46. Jiang S, Gavrikova TA, Pereboev A, Messina JL. Adenovirus infection results in alterations of insulin signaling and glucose homeostasis. Am J Physiol Endocrinol Metab 2010;298:E1295-304.
    
47. 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.
    
48. 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) 2008;32:397-406.
    
49. Bouwman JJ, Visseren FL, Bouter KP, Diepersloot RJ. Infectioninduced inflammatory response of adipocytes in vitro. Int J Obes (Lond) 2008;32:892-901.
    
50. 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.
    
51. 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.
    
52. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002;277:48115-21.
    
53. Na HN, Dubuisson O, Hegde V, Nam JH, Dhurandhar NV. Human adenovirus Ad36 and its E4orf1 gene enhance cellular glucose uptake even in presence of inflammatory cytokines. Obesity Week; 2013 Nov 11-16; Atlanta, USA.