Although human adenovirus-36 (Ad-36) has been reported to be associated with obesity in US adults and children, Korean children and the Italian population, the association has not been found in Dutch or Belgian populations or in US military subjects. Therefore, we examined whether Ad-36 infection is associated with obesity in Korean adults.
A total of 540 age- and sex-matched individuals, who were normal weight, overweight or obese, were selected from participants in routine health examinations at the Ewha Womans University Medical Center. Overweight participants were defined as those with a body mass index (BMI) of 23⩽BMI<25 kg m−2 and obese subjects were those with BMI⩾25 kg m−2, according to the International Obesity Task Force definition. Ad-36 antibody was measured using a serum neutralization assay.
Although more overweight participants than normal or obese subjects tested positive for the Ad-36 antibody (40%, 32.8% and 30%, respectively), the differences were not significant. The participants who tested positive for Ad-36 antibody had lower levels of triglycerides (TG) in each of the three groups, higher total cholesterol (TC) in the obese group and higher high-density lipoprotein-cholesterol (HDL-C) in both the normal and obese groups. The odds ratio (OR) for Ad-36 antibody positivity was greater in overweight than in normal subjects (OR=2.03; 95% confidence interval (CI), 1.16–3.55) after adjusting for age, sex and waist circumference. However, this OR was non-significant in the obese group (OR=1.56; 95% CI, 0.67–3.67).
Ad-36 seems to be strongly associated with overweight, but not obese, Korean adults.
The prevalence of obesity is increasing in most parts of the world.1 Based on recent data from the Korean National Health and Nutrition Examination Survey III, an estimated 32% of Korean adults (>19 years) are obese,2 which is a similar finding to that for the US adults.3 As obesity appears to be a factor in many adverse health conditions, including dyslipidemia, hypertension, coronary heart disease, stroke and some types of cancer,3 intervention to address obesity is an important public health issue in many countries. Therefore, the causal factors associated with obesity should be identified to prevent obesity-related diseases. Dietary patterns characterized by high fat and sugar or a meat-based diet (known as the Western diet pattern) and a low level of physical activity are well known to be associated with increased risks of obesity. In the last two decades, infectious agents such as viruses and bacteria have been also shown to be associated with obesity in humans and other animals, a concept that is known as ‘infectobesity’.4
There is considerable evidence showing that various types of adenovirus cause obesity in animal models and accelerate the differentiation of pre-adipocytes to adipocytes in 3T3-L1 cells. For example, Ad-5 and Ad-37 cause obesity in chickens and mice, and human adenovirus-36 (Ad-36) increases 3T3-L1 differentiation.5 However, antibodies to other adenovirus except Ad-36 have not been found in human populations.5 Support for Ad-36 as a contributor to human obesity has been accumulating for several years. Atkinson et al.6 reported that obese adults in the USA have a higher prevalence of serum antibodies against Ad-36 compared with non-obese adults (30% vs 11%, respectively). Atkinson et al.7 also found that the body mass index (BMI) z-score was significantly higher in Ad-36-infected Korean children compared with uninfected controls, suggesting that human Ad-36 has a role in obesity in Korean children. In consistent, Trovato et al.8 found a significant association between Ad-36 seropositivity and obesity in the Italian population. A cross-sectional study of 8–18-year olds in the USA also showed a clear association between Ad-36 seropositivity and obesity and body weight.9 Although these results provide compelling support for the infectobesity concept, other studies do not support this concept. A study of Dutch and Belgian people found that Ad-36 infection was unlikely to be associated with obesity.10 Another recent study showed no association between Ad-36 seropositivity and US military personnel.11 The reasons for these inconsistent results are not known. Atkinson emphasized recently the importance of differences in Ad-36 seroprevalence.12 The prevalence of Ad-36 in human blood ranges from <5 to >40% depending on factors such as ethnicity, age, obesity and perhaps Ad-36 detection methods.12 We used a serum anti-Ad-36 neutralization test in samples from Korean schoolchildren and found that obese children were more Ad-36 antibody positive than were non-obese children, but this association disappeared when we analyzed the data using multiple regression.13 As our data are not completely consistent with the data of adults in the USA and another study of Korean children, we reexamined whether Ad-36 is associated with obesity in the relatively homogeneous South Korean adult population.
Study population and blood sampling
This study was performed using participants from routine health examinations at the Health Promotion Center of the Ewha Womans University Medical Center (EWUMC). From a total of 1715 participants (1047 men, 668 women) admitted from April 2006 to June 2007, we randomly collected equal numbers of 180 subjects (90 men and 90 women; mean age, 44.3±7.04 years; range, 30–59 years) from those who were normal, overweight and obese. The groups were matched by age and sex. Demographic and anthropometric data and blood lipid levels were available for all subjects. The examinations were performed in accordance with the standard protocol, which has been well described elsewhere.14 Informed written consent for participation was obtained from each individual, and the study design was approved by the Institutional Review Board at the EWUMC. A peripheral venous blood sample was collected from each participant after 12 h of fasting. After blood coagulation, serum was separated by centrifugation, collected and kept frozen at −80 °C until analysis.
BMI was calculated as weight (kg) divided by the square of height (m2). Overweight and obese were defined as 23⩽BMI<25 kg m−2 and BMI⩾25 kg m−2, respectively, in accordance with the International Obesity Task Force definitions as described previously.15 Blood pressure was measured as previously described.13 Fasting glucose, total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C) and other biomarkers were measured with a Hitachi-7600 analyzer (Hitachi Ltd, Tokyo, Japan).
Detection of Ad-36 antibody in serum
All procedures for Ad-36 antibody analysis were as described in a previous report,6, 13 but with some minor modifications. Human Ad-36 from the American Type Culture Collection (ATCC, Manassas, VA, USA) was grown on A549 cells, a human bronchial carcinoma tissue culture line. The tissue culture infectious dose 50 (TCID-50), the dose of virus that had a cell cytotoxic effect (CPE) in 50% of wells, was determined using standard methods. Serum-neutralizing assays for Ad-36 antibodies in serum were performed using the constant virus-decreasing serum method. Serum samples that did not induce a CPE in dilutions of 1:8 or more were considered positive for the presence of neutralizing antibodies to Ad-36 and evidence of prior infection with Ad-36.
Data are expressed as means±s.d. or as numbers and percentages. Differences between groups across the categories of BMI were evaluated using analysis of variance(proc GLM) or χ2-test. Differences according to the presence of Ad-36 antibody among the BMI groups were evaluated using the Wilcoxon rank sum test or the χ2-test. Logistic regression analysis was conducted to determine the odds ratio (OR) for obesity according to the presence of the Ad-36 antibody. Statistical analyses were performed using SAS software (SAS 9.1; SAS Institute, Cary, NC, USA). Statistical significance was defined as P<0.05.
Characteristics of study groups
The characteristics of Korean adults according to BMI are shown in Table 1. There were no significant differences in age and sex between the three BMI groups. Overweight and obese individuals were significantly heavier than normal weight individuals. BMI, waist circumference and TC/HDL-C were significantly higher in overweight and obese subjects than in those of normal body weight. Significant lower HDL-C level was found in overweight and obese individuals; however, although there appeared to be slightly more participants with positive Ad-36 antibodies in the overweight group than in the two other groups, there was no statistically significant difference across the three BMI groups.
Characteristics of subjects according to the presence of Ad-36 antibody
The characteristics of overweight and obese adults according to Ad-36 antibody status are shown in Table 2. In both the overweight and obese groups, adults who were Ad-36 antibody positive were shorter and weighed less than those who were Ad-36 antibody negative. However, no differences in height and weight according to Ad-36 antibody status were found in the normal weight group. No significant differences in BMI according to Ad-36 antibody status were observed in the three BMI groups. In the overweight group, adults who were Ad-36 antibody positive had significantly smaller waists (P=0.001), lower TG level (P=0.004) and lower TC/HDL-C (P=0.018) than did those who were Ad-36 antibody negative. In both the normal weight and obese groups, subjects who were Ad-36 antibody positive had significantly lower TG level, lower TC/HDL-C and higher HDL-C level than did those who were Ad-36 antibody negative. Only in the obese group, subjects who were Ad-36 antibody positive had significantly higher levels of TC than those who were Ad-36 antibody negative. After adjusting for age, we compared parameters such as blood pressure and glucose and lipids levels between the Ad-36-negative and Ad-36-positive groups, and the two groups did not differ significantly.
OR and 95% confidence intervals (CI) for overweight or obese participants according to the presence of Ad-36 antibody
The unadjusted OR for Ad-36 antibody status was not significantly different for Korean adults who were overweight (OR=1.37; 95% CI, 0.89–2.10) and those who were obese (OR=0.88; 95% CI, 0.56–1.37) (Table 3). The non-significant OR for the obese group did not change after adjusting for the putative risk factors tested. However, the OR for the overweight group significantly increased twofold in adults who were Ad-36 antibody positive after adjustment for waist circumference (OR=2.03; 95% CI, 1.16–3.55).
Although many reports have shown Ad-36 antibody positive status to be associated with obesity, they are predominantly limited to data from the United States6, 7, 9 and Italy.8 Using Korean children and adolescents, we like Atkinson et al.7, 13 found a strong relationship between Ad-36 antibody positive status and obesity. However, this relationship became statistically non-significant when other lipid variables such as TC and TG were included in the analysis. In the present study, we reexamined carefully the data to evaluate the possible association in a relatively homogeneous Korean adult population. Our data show that Ad-36 is independently associated with being overweight, but not with being obese.
The prevalence of the Ad-36 antibody in overweight individuals in our population of Korean adults appeared to be higher than in either the normal or obese groups, but the differences were not statistically significant (overweight=40.0%, normal=32.8%, obese=30%, P=0.1189). All these Ad-36 seroprevalences are similar to those found for obese subjects in US adults, but are significantly higher than for normal Korean subjects. We previously found that 28.6% of our sample of obese Korean schoolchildren were Ad-36 antibody positive compared with 13.6% of normal individuals. Although samples from our two Korean studies are not directly comparable because of different experimental conditions, the dramatic increase in seroprevalence (from 13.6% in schoolchildren to 32.8% in adults) was found only in normal subjects; however, the exact mechanism is still unknown. It is possible that Ad-36 seropositivity increases with age because of a cumulative increase in Ad-36 infection through the respiratory tract. In this regard, Ad-36 seropositivity increases from <5% in subjects up to 30 years of age to >10% in those over 50 years in the Netherlands and Belgium.10 Nonetheless, we failed to find any increase in Ad-36 seropositivity in obese subjects with age (28.6% in schoolchildren and 30% in adults). At present, it is not known if an age-specific increase in Ad-36 seropositivity occurs only in normal Korean individuals.
As in studies on US adults and Korean schoolchildren, we also found significant differences in TG and TC levels according to Ad-36 antibody positivity. However, the results are mixed, showing that Korean adults who were Ad-36 antibody positive had lower levels of TG, which is consistent with US data but not with data from Korean schoolchildren. Korean obese adults who were Ad-36 antibody positive had higher TC levels than those who were Ad-36 antibody negative, which is consistent with Korean schoolchildren but not with the US adults. Furthermore, a significant difference in HDL-C levels was also found in normal and obese Korean adults according to Ad-36 seropositivity. Taken together, these results indicate that Ad-36 is associated with lipid abnormality in human samples. Whether the effect of Ad-36 on lipid abnormality is causal or consequential warrants further investigation. In this study, we also found that both overweight and obese subjects who were Ad-36 antibody positive were shorter and lighter than their Ad-36 antibody-negative counterparts. Although these data are interesting, further studies are needed to clarify this finding.
We also conducted multiple logistic regression analysis to determine if Ad-36 is independently associated with obesity in Korean adults. Our data show that the adjusted OR for Ad-36 antibody positivity was considerably elevated in overweight individuals (OR=2.03; 95% CI, 1.16–3.55), but was not significant in obese adults (OR=1.56; 95% CI, 0.67–3.67). These results indicate that Ad-36 may be associated predominantly with an early stage of obesity development. They also imply that factors other than Ad-36 infection, such as excessive calorie intake and physical inactivity, may be more important in the later stages of the obesity process. Although it seems that Ad-36 infection and its pathogenesis may differ according to age and the pathophysiological state of the human body, a more detailed study is required for clarification. Nonetheless, if this is correct, it is important to intervene before Ad-36 infection in order to prevent Ad-36-derived obesity development; thus, immunization against Ad-36 is likely to be a challenging research area in the future.
Our study has limitations. As our results were obtained from a cross-sectional design, we could not define a causal relationship between Ad-36 infection and being overweight. A large-scale longitudinal study should be conducted to evaluate the causal relationship. Another limitation is that we used a relatively small sample. Nonetheless, as far as we know, this study is well designed; we randomly selected and stratified our sample into three groups, normal, overweight and obese, among large cohort samples in Korea. In conclusion, we found, for the first time, that Ad-36 infection is independently associated with being overweight, but not with obesity, in Korean adults.
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This study was supported by grants from the Seoul R & BD Program, Republic of Korea (10526), the Catholic University of Korea Research Fund 2010, the GRRC of the Catholic University of Korea, the Biogreen21 Program (PJ007186) of Rural Development of Administration, and MKE and KOTEF through the Human Resource Training Project for Strategic Technology.
The authors declare no conflict of interest.
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Na, HN., Kim, J., Lee, H. et al. Association of human adenovirus-36 in overweight Korean adults. Int J Obes 36, 281–285 (2012). https://doi.org/10.1038/ijo.2011.102
- human adenovirus-36
- Korean adults
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