Richard L. Atkinson

Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids

BACKGROUND:Human adenovirus-36 (Ad-36) increases adiposity and paradoxically lowers serum cholesterol and triglycerides in chickens, mice, and non-human primates. The role of Ad-36 in human obesity is unknown.OBJECTIVES:To determine the prevalence of Ad-36 antibodies in obese and nonobese humans. To evaluate the association of Ad-36 antibodies with body mass index (BMI) and serum lipids.DESIGN:Cohort study. Volunteers from obesity treatment programs, communities, and a research study.SUBJECTS:Obese and nonobese volunteers at the University of Wisconsin, Madison, WI, and the Bowen Center, Naples, Florida. Obese and thin volunteer research subjects and 89 twin pairs at Columbia University, New York.INTERVENTIONS:Study 1: 502 subjects; serum neutralization assay for antibodies to Ad-2, Ad-31, Ad-36, and Ad-37; serum cholesterol and triglycerides assays. Study 2: BMI and %body fat in 28 twin pairs discordant for Ad-36 antibodies.MAIN OUTCOME MEASURES:Presence of antibodies to adenoviruses, BMI, serum cholesterol and triglycerides levels.RESULTS:Significant (P<0.001) association of obesity and positive Ad-36 antibody status, independent of age, sex, and collection site. Ad-36 antibodies in 30% of obese, 11% of nonobese. Lower serum cholesterol and triglycerides (P<0.003) in Ad-36 antibody-positive vs -negative subjects. Twin pairs: antibody-positive twins had higher BMIs (24.5±5.2 vs 23.1±4.5 kg/m2, P<0.03) and %body fat (29.6±9.5% vs 27.5±9.9%, P<0.04). No association of Ad-2, Ad-31, or Ad-37 antibodies with BMI or serum lipids.CONCLUSIONS:Ad-36 is associated with increased body weight and lower serum lipids in humans. Prospective studies are indicated to determine if Ad-36 plays a role in the etiology of human obesity.

Rational design of a combination medication for the treatment of obesity.

Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro‐opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo‐controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of β‐endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.

Impact of obesity on health-related quality of life in patients with chronic illness

OBJECTIVE: To determine the association between over-weight and obesity and health-related quality of life (HRQOL) in patients with chronic conditions typical of those seen in general medical practice, after accounting for the effects of depression and medical comorbidities.DESIGN: Cross-sectional analysis of data from the Medical Outcomes Study.SETTING: Offices of physicians practicing family medicine, internal medicine, endocrinology, cardiology, and psychiatry in three U.S. cities.PATIENTS: We surveyed 2,931 patients with chronic medical and psychiatric conditions. The patients completed a self-administered questionnaire at enrollment and had complete data on height and weight.MEASUREMENTS AND MAIN RESULTS: Body mass index (BMI), chronic medical conditions, and depression were obtained by structured interview. Health-related quality of life was measured by the SF-36 Health Survey. Patients who were over-weight (BMI 25.0–29.9 kg/m2), patients with class I obesity (BMI 30.0–34.9 kg/m2), and patients with class II–III obesity (BMI ≥ 35 kg/m2) had significantly lower adjusted physical function scores (by 3.4, 7.8, and 13.8 points, respectively) compared with nonoverweight patients. Patients with class I and class II–III obesity also had significantly lower adjusted general health perceptions scores (by 2.8 and 4.4 points, respectively) and lower adjusted vitality scores (by 4.0 and 7.1 points, respectively), compared with nonoverweight patients. No significant differences between nonoverweight, overweight, and obese patients were observed for the mental health scale. Women with elevated BMI had significantly lower HRQOL scores compared with the scores of obese men in several domains. Additionally, blacks with elevated BMI had significantly lower scores than whites in several domains of HRQOL.CONCLUSIONS: Overweight and obesity have the largest association with physical function measures. Recent national standards, which have lowered the threshold for defining overweight, identify patients who are more likely to have clinically significant reductions in HRQOL and functional impairment.

Increased adiposity in animals due to a human virus

BACKGROUND: Four animal models of virus-induced obesity including adiposity induced by an avian adenovirus have been described previously. This is the first report of adiposity induced in animals by a human virus.OBJECTIVE: We investigated the adiposity promoting effect of a human adenovirus (Ad-36) in two different animal models.DESIGN: Due to the novel nature of the findings we replicated the experiments using a chicken model three times and a mammal model once. In four separate experiments, chickens and mice were inoculated with human adenovirus Ad-36. Weight matched groups inoculated with tissue culture media were used as non-infected controls in each experiment. Ad-36 inoculated and uninfected control groups were housed in separate rooms under biosafety level 2 or better containment. The first experiment included an additional weight matched group of chickens that was inoculated with CELO (chick embryo lethal orphan virus), an avian adenovirus. Food intakes and body weights were measured weekly. At the time of sacrifice blood was drawn and visceral fat was carefully separated and weighed. Total body fat was determined by chemical extraction of carcass fat.RESULTS: Animals inoculated with Ad-36 developed a syndrome of increased adipose tissue and paradoxically low levels of serum cholesterol and triglycerides. This syndrome was not seen in chickens inoculated with CELO virus. Sections of the brain and hypothalamus of Ad-36 inoculated animals did not show any overt histopathological changes. Ad-36 DNA could be detected in adipose tissue, but not skeletal muscles of randomly selected animals for as long as 16 weeks after Ad-36 inoculation.CONCLUSIONS: Data from these animal models suggest that the role of viral disease in the etiology of human obesity must be considered.

Obesity as a Disease: A White Paper on Evidence and Arguments Commissioned by the Council of The Obesity Society

tative bodies that it is reasonable to call obesity a disease. The panel reviewed three broad classes of argument as to whether obesity is rightly classified as a disease.The first, the scientific approach, pro-ceeds in two conceptually simple steps: i) identify the characteristics that entities must have to be considered diseases and ii) examine empirical evidence to deter-mine whether obesity possesses those characteristics. The scientific approach would be well suited to answering the question “is obesity a disease?” rather than “should we consider obesity a disease?,” were the former question answerable. However, after much deliberation, the panel concluded that the former question is ill posed and does not admit an answer. This is not because of a lack of agreement or understanding about obesity but rather because of a lack of a clear, specific, widely accepted, and scientifically applicable defi-nition of “disease” that allows one to objec-tively and empirically determine whether specific conditions are diseases.The second type of argument, the foren-sic approach, entailed looking to the public statements of authoritative bodies as evi-dence of whether obesity is a disease or should be considered a disease. A nearly of the statements made by ostensibly authoritative bodies made apparent that there is a clear and strong majority lean-ing—although not complete consensus—toward obesity being a disease. However, although some authoritative bodies have offered statements that obesity is (or is not) a disease, very few of them have published a thorough and rigorous argument or evi-dential basis in support of the statement. Moreover, and far more importantly, the panel held that the opinions of authorita-tive bodies tell us—at most—what is law-ful, consistent with mainstream opinions, or likely to be supported by others. Such opinions are insufficient to tell us what is true or what is right. The panel strongly endorsed the position that there can be no higher authority than reason. Hence, the forensic approach was judged to be inad-equate to help us determine either whether obesity is a disease or whether it should be considered a disease.The third approach to this question we termed the utilitarian approach. Recognizing that there is no clear agreed-on definition of disease with precise, assessable criteria that can be articulated, it seems that conditions that produce adverse health outcomes come to be considered diseases as the result of a social process when it is assessed to be beneficial to the greater good that they be so judged. Such judgments about likely benefit to the greater good are utilitarian judgments that may take empirical input but must also assume certain values. We considered the

Effects of long‐term therapy with naltrexone on body weight in obesity

The endogenous opiate system is thought to be associated with the regulation of food intake and body weight. Opiate antagonists decrease food intake in animals, but there are no controlled studies in obese man to evaluate body weight response to naltrexone. Sixty obese people were randomized into three groups and given 0, 50, or 100 mg of the opiate antagonist naltrexone for 8 weeks in an outpatient, double‐blind study. Weight loss was not significant in either the 50 or 100 mg groups as compared with placebo. However, when broken down by sex, women had a significant (P < 0.05) weight loss of 1.7 kg, while men did not lose weight. Side effects were modest, but six subjects had one or more abnormal liver function test results; in one subject these abnormalities appeared to be clinically significant. The effects of naltrexone on weight loss were less than expected in light of prior animal studies, but further studies with a wider dose range of naltrexone may be indicated.

Transmissibility of adenovirus-induced adiposity in a chicken model.

BACKGROUND: We previously reported that human adenovirus Ad-36 induces adiposity and paradoxically lower levels of serum cholesterol (CHOL) and triglycerides (TG) in animals.OBJECTIVE: To evaluate the transmissibility of Ad-36 and Ad-36 induced adiposity using a chicken model.DESIGN: Experiment 1—four chickens were housed (two per cage) and one from each cage was inoculated with Ad-36. Duration of presence of Ad-36 DNA in the blood of all chickens was monitored. Experiment 2—two groups of chickens were intranasally inoculated with Ad-36 (infected donors, I-D) or media (control donors, C-D). Blood drawn 36 h later from I-D and C-D groups was inoculated into wing veins of recipient chickens (infected receivers, I-R, and control receivers, C-R, respectively). On sacrifice, 5 weeks post-inoculation, blood was drawn, body weight noted and visceral fat was separated and weighed.RESULTS: Experiment 1—Ad-36 DNA appeared in the blood of the inoculated chickens and that of uninoculated chickens (cage mates) within 12 h of inoculation and the viral DNA persisted up to 25 days in the blood. Experiment 2—compared with C-D, visceral and total body fat were significantly greater and CHOL significantly lower for the I-D and I-R. TG were significantly lower for the I-D. Ad-36 was isolated from 12 out of 16 blood samples of the I-D that were used for inoculating I-R chickens. Ad-36 DNA was present in the blood and the adipose tissue of the I-D and I-R but not in the skeletal muscles of animals selected randomly for testing.CONCLUSION: As seen in experiment 1, Ad-36 infection can be transmitted horizontally from an infected chicken to another chicken sharing the cage. Additionally, experiment 2 demonstrated blood-borne transmission of Ad-36-induced adiposity in chickens. Transmissibility of Ad-36-induced adiposity in chicken model raises serious concerns about such a possibility in humans that needs further investigation.

Self-help weight loss versus a structured commercial program after 26 weeks: a randomized controlled study.

PURPOSE There have been few randomized controlled trials of commercial weight-loss programs. This ongoing study compares the effects of a self-help program and a commercial program on weight loss and other measures of obesity in overweight and obese men and women. SUBJECTS AND METHODS We report the results of the first 26 weeks of a multicenter, randomized, 2-year study of 423 subjects who had a body mass index of 27 to 40 kg/m(2). Subjects were randomly assigned to either a self-help program, consisting of two 20-minute sessions with a nutritionist and provision of printed materials and other self-help resources, or to attendance at meetings of a commercial program (Weight Watchers). Outcome measures were changes in body weight, body mass index, waist circumference, and body fat. Changes in serum homocysteine levels were measured in a subsample of participants during the first 12 weeks. RESULTS After 26 weeks, subjects in the commercial program, as compared with those in the self-help program, had greater decreases in body weight [mean (+/- SD) -4.8+/-5.6 vs -1.4+/-4.7 kg] and body mass index (-1.7+/-1.9 vs -0.5+/-1.6 kg/m(2), both P<0.001) in intention-to-treat analyses. Among subjects measured at week 26, mean waist circumference (-4.3+/-10.5 vs -0.7+/-12.7 cm) and fat mass (-3.8 +/-7.0 vs -1.5+/-7.6 kg, both P<0.05) also decreased more among subjects in the commercial program. Mean serum homocysteine levels improved in the commercial program compared with self-help (-0.5+/-1.3 vs 0.9+/-1.8 microM, P<0.05). CONCLUSIONS A structured commercial weight-loss program is more likely to be effective for managing moderately overweight patients than brief counseling and self-help.

ICF CORE SETS FOR OBESITY

OBJECTIVE To report on the results of the consensus process integrating evidence from preliminary studies to develop the first version of the Comprehensive ICF Core Set and the Brief ICF Core Set for obesity. METHODS A formal decision-making and consensus process integrating evidence gathered from preliminary studies was followed. Preliminary studies included a Delphi exercise, a systematic review and an empirical data collection. After training in the ICF and based on these preliminary studies relevant ICF categories were identified in a formal consensus process by international experts from different backgrounds. RESULTS The preliminary studies identified a set of 219 ICF categories at the second, third and fourth ICF levels with 87 categories on body functions, 34 on body structures, 53 on activities and participation and 45 on environmental factors. Twenty-one experts attended the consensus conference on obesity (18 physicians with various sub-specializations and 3 physical therapists). Altogether 109 categories (108 second-level and one third-level categories) were included in the Comprehensive ICF Core Set with 30 categories from the component body functions, 18 from body structures, 28 from activities and participation and 33 from environmental factors. The Brief ICF Core Set included a total of 9 second-level categories with 3 on body functions, 4 on activities and participation and 2 on environmental factors. No body-structures categories were included in the Brief ICF Core Set. CONCLUSION A formal consensus process integrating evidence and expert opinion based on the ICF framework and classification led to the definition of ICF Core Sets for obesity. Both the Comprehensive ICF Core Set and the Brief ICF Core Set were defined.

Human adenovirus-36 antibody status is associated with obesity in children.

BACKGROUND Human adenovirus-36 (Ad-36) is thought to induce obesity by a direct effect of the viral E4orf1 gene on lipogenic enzymes in host adipocytes. Ad-36 prevalence is 30% in obese adults, but prevalence has not been reported in childhood obesity. OBJECTIVES To determine the prevalence of Ad-36 infection in obese Korean children (age 14.8 +/- 1.9; range 8.3-6.3 years); correlation of infection with BMI z-score and other obesity measures. METHODS Blood was drawn at the annual school physical exam or clinic visit; Ad-36 status was determined by serum neutralization assay; and routine serum chemistry values. RESULTS A total of 30% of subjects were positive (N = 25) for Ad-36; 70% were negative (N = 59). Significantly higher BMI z-scores (1.92 vs. 1.65, p < 0.01) and waist circumferences (96.3 vs. 90.7 cm, p = 0.05) were found in infected versus uninfected children. Cardiovascular risk factors were not significantly different. CONCLUSIONS Ad-36 infection is common in obese Korean children and correlates highly with obesity. Ad-36 may have played a role in the obesity and Type 2 diabetes epidemic in children.