Natural infection of human adenovirus 36 in rhesus monkeys is associated with a reduction in fasting glucose 36.

Experimental infection of the human adenovirus Ad36 increases adiposity, yet improves glycemic control in rodents. In humans, natural Ad36 infection is crosssectionally and temporally associated with adiposity and better glycemic control. In vitro studies indicate that the early gene 4, open reading frame 1 (E4orf1) gene of Ad36 is necessary and sufficient to improve cellular glucose disposal. Consequentially, E4orf1 protein offers an excellent template to develop antidiabetic drugs. Considering the human relevance of a rhesus monkey model for preclinical drug development, we determined the associations of natural Ad36 infection with changes in glycemic control in rhesus monkeys. For this study, serum samples were obtained from 20 male rhesus monkeys (Macaca mulatta; 7–13 years of age) enrolled in an ongoing study described earlier. Briefly, all rhesus monkeys received a diet high in fat and sugar (42% kcal from fat, 27% kcal from sucrose; HFS) and were randomized to two experimental groups (n = 10 in each group), one on the HFS diet and the other on the HFS diet with resveratrol treatment (RESV). The resveratrol dose was 80 mg/day for 0–12 months and 480 mg/day for 13–24 months. All procedures were approved by the Animal Care and Use Committee of the National Institute of Aging Intramural Program. Serum samples obtained at 12 months were screened for neutralizing antibodies to Ad36 by a serum neutralization assay. A general linear model approach was used to examine the association of resveratrol treatment and Ad36 infection on body weight, total body fat, and fasting glucose over 1 year in rhesus monkeys fed the HFS diet. Here, body fat was determined by dual-energy X-ray absorptiometry (DPX-α X-ray Bone Densitometer; Lunar, Madison, WI, USA) and fasting blood glucose was determined with an Ascensia Breeze 2 Blood Glucose Monitor (Bayer HealthCare, Mishawaka, IN, USA). For the present analysis, samples obtained at 12 months served as baseline measures. Change data (values at 24 months – values at baseline) were log transformed to increase normality and homoscedasticity. Statistical analyses included separate twoway analysis of covariance for each dependent variable, with Ad36 status and resveratrol as fixed factors and baseline measures as covariates. Data from two rhesus monkeys were removed from all analyses because of extreme values. At baseline, there were no differences in HFS and RESV groups for body weight, body fat, or fasting glucose (Table 1). In the HFS group, four rhesus monkeys were Ad36 seropositive (POS) and four were negative (NEG). In the RESV group, five were POS. At baseline, Ad36 status was not significantly associated with body weight, body fat, or fasting glucose. Documentation of food consumption by individual rhesus monkeys throughout the study indicated that there was no difference in average consumption between groups on a per kg body weight basis. When examining the descriptive data, we found that there was a slight increase in body weight across all groups during the 1-year time period, but the difference did not reach statistical significance. In addition, body fat for those rhesus monkeys identified as Ad36 POS increased from a mean ± SD) of 4.80 ± 1.11 kg at baseline to 6.03 ± 1.32 kg 1 year later. Those rhesus monkeys that remained Ad36 NEG throughout the 1-year testing period also had a non-significant increase in body fat (from 4.02 ± 0.75 to 4.80 ± 0.67 kg). Although the Ad36 POS group gained fat, the magnitude of the change in body fat was not significantly different between the Ad36 POS and NEG groups. Correspondence Nikhil V. Dhurandhar, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. Tel.: +1225 763 2741 Fax: +1225 763 3030 Email: [email protected]