Robert I. Berkowitz

The Look AHEAD study: a description of the lifestyle intervention and the evidence supporting it.

The Look AHEAD (Action for Health in Diabetes) study is a multicenter, randomized controlled trial designed to determine whether intentional weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. The study began in 2001 and is scheduled to conclude in 2012. A total of 5145 participants have been randomly assigned to a lifestyle intervention or to an enhanced usual care condition (i.e., diabetes support and education). This article describes the lifestyle intervention and the empirical evidence to support it. The two principal intervention goals are to induce a mean loss ≥ 7% of initial weight and to increase participants’ moderately intense physical activity to ≥175 min/wk. For the first 6 months, participants attend one individual and three group sessions per month and are encouraged to replace two meals and one snack a day with liquid shakes and meal bars. From months 7 to 12, they attend one individual and two group meetings per month and continue to replace one meal per day (which is recommended for the studys duration). Starting at month 7, more intensive behavioral interventions and weight loss medication are available from a toolbox, designed to help participants with limited weight loss. In Years 2 to 4, treatment is provided mainly on an individual basis and includes at least one on‐site visit per month and a second contact by telephone, mail, or e‐mail. After Year 4, participants are offered monthly individual visits. The intervention is delivered by a multidisciplinary team that includes medical staff who monitor participants at risk of hypoglycemic episodes.

Parental feeding attitudes and styles and child body mass index: prospective analysis of a gene-environment interaction.

Background. Parental feeding styles were linked to child weight in cross-sectional studies, which were unable to test the direction of effect. Prospective studies can best establish causal relationships among such variables. Objective. We tested the 2-year stability of parental feeding attitudes and styles and investigated whether these variables predict child body mass index (BMI) z scores 2 years later. We evaluated whether these associations were dependent on children’s predisposition to obesity. Methods. Participants were 57 families enrolled in an Infant Growth Study of children born at high risk or low risk for obesity, on the basis of maternal prepregnancy overweight or leanness. Children were evaluated for weight and height at 3, 5, and 7 years of age. Measures of parental feeding attitudes and styles were ascertained with the Child Feeding Questionnaire at 5 and 7 years of age. Correlation and multiple regression analyses tested whether parental feeding styles at age 5 predicted increased child BMI z scores 2 years later. Results. Parental feeding attitudes and styles were stable for child ages of 5 to 7 years. With respect to feeding attitudes, perceived responsibility at age 5 predicted reduced child BMI z scores at age 7 among low-risk families, whereas child weight concern and perceived child weight predicted increased child BMI z scores among high-risk families. With respect to feeding styles, monitoring predicted reduced child BMI z scores at age 7 among low-risk children. In contrast, restriction predicted higher BMI z scores and pressure to eat predicted reduced BMI z scores among high-risk children. These associations remained significant after controlling for child weight status at age 3. Conclusions. The relationship between parental feeding styles and child BMI z scores depends on child obesity predisposition, suggesting a gene-environment interaction. Among children predisposed to obesity, elevated child weight appears to elicit restrictive feeding practices, which in turn may produce additional weight gain. Parenting guidelines for overweight prevention may benefit from consideration of child characteristics such as vulnerability to obesity and current weight status.

A Two-Year Randomized Trial of Obesity Treatment in Primary Care Practice

BACKGROUND Calls for primary care providers (PCPs) to offer obese patients behavioral weight-loss counseling have not been accompanied by adequate guidance on how such care could be delivered. This randomized trial compared weight loss during a 2-year period in response to three lifestyle interventions, all delivered by PCPs in collaboration with auxiliary health professionals (lifestyle coaches) in their practices. METHODS We randomly assigned 390 obese adults in six primary care practices to one of three types of intervention: usual care, consisting of quarterly PCP visits that included education about weight management; brief lifestyle counseling, consisting of quarterly PCP visits combined with brief monthly sessions with lifestyle coaches who instructed participants about behavioral weight control; or enhanced brief lifestyle counseling, which provided the same care as described for the previous intervention but included meal replacements or weight-loss medication (orlistat or sibutramine), chosen by the participants in consultation with the PCPs, to potentially increase weight loss. RESULTS Of the 390 participants, 86% completed the 2-year trial, at which time, the mean (±SE) weight loss with usual care, brief lifestyle counseling, and enhanced brief lifestyle counseling was 1.7±0.7, 2.9±0.7, and 4.6±0.7 kg, respectively. Initial weight decreased at least 5% in 21.5%, 26.0%, and 34.9% of the participants in the three groups, respectively. Enhanced lifestyle counseling was superior to usual care on both these measures of success (P=0.003 and P=0.02, respectively), with no other significant differences among the groups. The benefits of enhanced lifestyle counseling remained even after participants given sibutramine were excluded from the analyses. There were no significant differences between the intervention groups in the occurrence of serious adverse events. CONCLUSIONS Enhanced weight-loss counseling helps about one third of obese patients achieve long-term, clinically meaningful weight loss. (Funded by the National Heart, Lung, and Blood Institute; POWER-UP ClinicalTrials.gov number, NCT00826774.).

Effects of Sibutramine Treatment in Obese Adolescents: A Randomized Trial

Context Few trials have evaluated drugs for obesity in adolescents. Contribution This 12-month randomized, double-blind trial evaluated behavioral therapy plus either sibutramine or placebo in 498 very obese adolescents who were 12 to 16 years of age. Sibutramine reduced mean body mass index (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 8.4 kg) more than placebo. Sibutramine also improved some lipid and glycemic measures and was associated with tachycardia. Cautions Only 76% and 62% of the sibutramine and placebo recipients, respectively, completed the trial. Implications Sibutramine plus behavioral therapy for 1 year can reduce weight and improve metabolic risk factors in some very obese adolescents. The Editors Adolescent obesity is a major public health problem, with 15.5% of U.S. adolescents 12 to 19 years of age defined as overweight (>95th percentile for age- and sex-specific measures for body mass index [BMI]) (1, 2). Overweight often leads to serious health consequences during childhood, such as hypertension, depression, and social exclusion (3). Recently, the incidence of type 2 diabetes, typically an adult disease, has dramatically increased in the pediatric population (46). Cardiovascular risk factors, such as dyslipidemia, insulin sensitivity, and hypertension, are also more prevalent in adolescents with a BMI greater than the 95th percentile than in those with a BMI less than the 85th percentile (7). Management of adult obesity relies on a range of options, including diet, physical activity, behavior modification, pharmacotherapy, and surgery (8, 9). The serotonin and norepinephrine reuptake inhibitor sibutramine facilitates weight loss and weight maintenance in obese adults with commensurate improvements in metabolic variables for up to 2 years of treatment (1012). Prevention is the optimal approach; however, effective treatment in children with a BMI greater than the 95th percentile is needed. Comprehensive behavioral methods have shown weight loss benefit in younger children (13). In most studies, adolescents typically remain overweight after therapy (14). In an earlier single-center, 6-month controlled trial, sibutramine and a comprehensive behavioral program induced statistically significantly more weight loss in obese adolescents than the behavioral program alone (15). Overall, sibutramine is well tolerated; however, increases in mean blood pressure and pulse rate have been reported in some adults (10, 16) and adolescents (15). Our large multicenter study examined the longer-term effects on weight loss by adding sibutramine to behavior therapy in obese adolescents. Methods Design Overview The protocol-designated objective of our 12-month, double-blind study was to evaluate the efficacy and safety of sibutramine in addition to behavior therapy in obese adolescents. At baseline, we randomly assigned participants (3:1 randomization ratio) to sibutramine or placebo (Figure 1). The randomization schedule was stratified by center and baseline BMI (37 kg/m2 or >37 kg/m2) and was computer-generated in blocks of 4 by the sponsor. Each site was responsible for assigning sequential treatments within each stratum. The sponsor kept allocation codes sealed and secure until the database was locked before analysis. Participants, their parents, and study personnel were blinded to treatment. All participants received a behavior therapy program that included lifestyle modification instructions to improve nutrition and increase physical activity. We conducted the study from July 2000 to February 2002 at 33 U.S. weight loss clinics. Individual sites were responsible for recruitment, and we selected eligible participants from the sites clinical database or from responses to advertisements of the study. We obtained approval from individual institutional review boards. Figure 1. Study flow diagram. P P P Participants We included adolescents 12 to 16 years of age with a BMI (calculated as weight [kg] divided by height [m2]) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex (17) and was not more than 44 kg/m2. Contraindications included cardiovascular disease (including arrhythmias), type 1 or 2 diabetes mellitus, major psychiatric disorders, pregnancy, use of a weight loss medication or participation in structured weight loss programs for more than 2 weeks, medication use promoting weight gain or contraindicated with sibutramine (16), or cigarette smoking. We excluded candidates with systolic blood pressure greater than 130 mm Hg, diastolic blood pressure greater than 85 mm Hg, or pulse rate greater than 95 beats/min. We included candidates with stable hypertension who were receiving therapy. Participants completed behavioral assessments conducted by a staff psychologist or psychiatrist. We obtained written, informed consent from the parent and assent from the adolescent. Interventions Behavioral Protocol Participants received instruction in a center-specific behavior therapy program. Individual centers implemented flexible lifestyle modification approaches that were specific to the participants needs. This included self-monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, contingency management, cognitive restructuring, and social support. Counseling at each visit promoted increased physical activity and reduced sedentary behavior. Nutritional counseling encouraged development of healthy eating habits and promoted dietary consumption based on a 500-kcal/d deficit. Medication Protocol At baseline, we randomly assigned participants (3:1 randomization ratio) to receive 10 mg of sibutramine or placebo daily. At month 6, doses of all participants who had not lost more than 10% of their initial BMI were uptitrated (blinded) to 15 mg of sibutramine or placebo. Abbott (previously Knoll Pharmaceuticals) manufactured and provided all capsules. Placebo and sibutramine capsules appeared identical and were dispensed similarly. We discontinued therapy for or closely monitored the participants with systolic blood pressure, diastolic blood pressure, or pulse rate that increased at a single visit to more than 150 mm Hg or by more than 20 mm Hg, to 95 mm Hg or by more than 15 mm Hg, or to 110 beats/min or by more than 20 beats/min, respectively, until acceptable values returned. We used a protocol-driven algorithm for repeating visits or withdrawing participants whose values did not return to specified limits. In the case of intolerance, participants were to be withdrawn from the study. Measurements and Follow-up Procedures The primary efficacy measure was absolute change from baseline in BMI. Secondary outcomes included percentage change in BMI, proportion of patients achieving reductions in BMI of 5% or more or 10% or more, absolute and percentage changes in body weight and lipid and glycemic variables, and absolute change in waist circumference. Participants had weekly visits for the first 2 weeks, visits every 2 weeks until week 12, and monthly visits thereafter. At each visit, we recorded weight to the nearest 0.1 kg, with the participant in light clothing and without shoes, and height to the nearest 0.5 cm. We measured waist circumference monthly. We evaluated medication adherence by capsule count. We assessed growth by using a pediatric growth chart (18) and performed full physical examinations at screening and at months 3, 6, and 12 (or at discontinuation). We assessed sexual maturation by self-reported changes in Tanner staging (19). We determined fasting lipid and glycemic variables at major assessments (Clinical Reference Laboratory, Lenexa, Kansas). We performed electrocardiography before treatment and at month 12 or at discontinuation. We obtained blood pressure (manually) and pulse rate (by palpation of the radial or brachial artery) at all visits. We withheld study medication until blood samples were obtained for laboratory assessments at months 3, 6, and 12. The investigator recorded all adverse events, both observed and volunteered, on the appropriate case report form, as well as in the participants clinic, office, or hospital chart. For each event, the investigator provided information on severity, start and stop dates, relationship to study drug, actions taken, and outcome. The investigator also recorded adverse events resulting from concomitant illnesses, reactions to concomitant medications, or progression of disease states. Statistical Analysis The planned sample size was approximately 400 participants with a 3:1 randomization ratio of sibutramine to placebo. On the basis of previous 12-month adult trials, we determined that 300 participants in the sibutramine group would be adequate to assess safety and exposure, allowing an overall dropout rate of approximately 50% and a probability that approximately 50% of participants receiving 10 mg of sibutramine would lose 10% or more of initial BMI at 6 months. The inflated sample size ensured enough participants with echocardiograms, ambulatory blood pressure monitoring, and dual-energy x-ray absorptiometry measurements (minimum of 120, 80, and 100 participants, respectively, at baseline) since these assessments would be performed in subsets. Although the protocol did not document a formal sample size calculation for efficacy, approximately 132 adolescents (99 in the sibutramine group and 33 in the placebo group) would allow a between-group difference in BMI of 2 kg/m2, with 90% power (2-sided level of 0.05) to be statistically significant, assuming a common SD of 3 kg/m2. We documented the prespecified statistical analysis methods while all study and sponsor personnel, including the statistician, were blinded to treatment. The primary efficacy variable was the absolute change from baseline in BMI. Secondary efficacy variables determined from baseline included percentage change in BMI, proportions of participants achieving 5%

Exercise in the Treatment of Obesity Effects of Four Interventions on Body Composition, Resting Energy Expenditure, Appetite, and Mood

This study investigated changes in body composition, resting energy expenditure (REE), appetite, and mood in 128 obese women who were randomly assigned to 1 of 4 treatment conditions: diet alone, diet plus aerobic training, diet plus strength training, or diet combined with aerobic and strength training (i.e., combined training). All women received the same 48-week group behavioral program and were prescribed the same diet. Exercising participants were provided 3 supervised exercise sessions per week for the first 28 weeks and 2 sessions weekly thereafter. Participants across the 4 conditions achieved a mean weight loss of 16.5 +/- 6.8 kg at Week 24, which decreased to 15.1 +/- 8.4 kg at Week 48. There were no significant differences among conditions at any time in changes in weight or body composition. Women who received aerobic training displayed significantly smaller reductions in REE at Week 24 than did those who received strength training. There were no other significant differences among conditions at any time on this variable or in changes in appetite and mood.

Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP.

Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI≥95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r2 = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08–1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91–1.21; P = 0.49) and of 1.31 (95% CI 1.050–1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.

The role of obesity-associated loci identified in genome wide association studies in the determination of pediatric BMI

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome‐wide association (GWA) studies. In this study, we examined 25 single‐nucleotide polymorphisms (SNPs) corresponding to 13 previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13, and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z‐score. We conclude that among 13 loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.

Eating in the Absence of Hunger: A Genetic Marker for Childhood Obesity in Prepubertal Boys?

Objective: Eating in the absence of hunger (EAH) may be a behavioral trait through which obesity‐promoting genes promote positive energy balance. The primary aim of this study was to compare children born at high vs. low risk for obesity with respect to EAH at 5 years of age.

Role of BMI-associated loci identified in GWAS meta-analyses in the context of common childhood obesity in European Americans.

Obesity is a serious health concern for children and adolescents, particularly in Western societies, where its incidence is now considered to have reached epidemic proportions. A number of genetic determinants of adult BMI have already been established through genome wide association studies (GWAS), most recently from the GIANT meta‐analysis of such datasets combined. In this current study of European Americans, we examined the 32 loci detected in that GIANT study in the context of common childhood obesity within a cohort of 1,097 cases (defined as BMI ≥95th percentile), together with 2,760 lean controls (defined as BMI <50th percentile), aged between 2 and 18 years old. Nine of these single‐nucleotide polymorphims (SNPs) yielded at least nominal evidence for association with common childhood obesity, namely at the FTO, TMEM18, NRXN3, MC4R, SEC16B, GNPDA2, TNNI3K, QPCTL, and BDNF loci. However, overall 28 of the 32 loci showed directionally consistent effects to that of the adult BMI meta‐analysis. We conclude that among the 32 loci that have been reported to associate with adult BMI in the largest meta‐analysis of BMI to date, at least nine also contribute to the determination of common obesity in childhood in European Americans, as demonstrated by their associations in our pediatric cohort.

Sleep Architecture and Glucose and Insulin Homeostasis in Obese Adolescents

OBJECTIVE Sleep deprivation is associated with increased risk of adult type 2 diabetes mellitus (T2DM). It is uncertain whether sleep deprivation and/or altered sleep architecture affects glycemic regulation or insulin sensitivity or secretion. We hypothesized that in obese adolescents, sleep disturbances would associate with altered glucose and insulin homeostasis. RESEARCH DESIGN AND METHODS This cross-sectional observational study of 62 obese adolescents took place at the Clinical and Translational Research Center and Sleep Laboratory in a tertiary care children’s hospital. Subjects underwent oral glucose tolerance test (OGTT), anthropometric measurements, overnight polysomnography, and frequently sampled intravenous glucose tolerance test (FSIGT). Hemoglobin A1c (HbA1c) and serial insulin and glucose levels were obtained, indices of insulin sensitivity and secretion were calculated, and sleep architecture was assessed. Correlation and regression analyses were performed to assess the association of total sleep and sleep stages with measures of insulin and glucose homeostasis, adjusted for confounding variables. RESULTS We found significant U-shaped (quadratic) associations between sleep duration and both HbA1c and serial glucose levels on OGTT and positive associations between slow-wave sleep (N3) duration and insulin secretory measures, independent of degree of obesity, pubertal stage, sex, and obstructive sleep apnea measures. CONCLUSIONS Insufficient and excessive sleep was associated with short-term and long-term hyperglycemia in our obese adolescents. Decreased N3 was associated with decreased insulin secretion. These effects may be related, with reduced insulin secretory capacity leading to hyperglycemia. We speculate that optimizing sleep may stave off the development of T2DM in obese adolescents.