Relationship of Mindfulness to Distress and Cortisol Response in Adolescent Girls At-Risk for Type 2 Diabetes.

Altered stress response theoretically contributes to the etiology of cardiometabolic disease. Mindfulness may be a protective buffer against the effects of stress on health outcomes by altering how individuals evaluate and respond to stress. We engaged adolescent girls at risk for developing Type 2 diabetes in a cold-pressor test in order to determine the relationship of dispositional mindfulness to cortisol response and subjective stress, including perceived pain and unpleasantness during the stressor, and negative affect following the stressor. We also evaluated mindfulness as a moderator of psychological distress (depressive/anxiety symptoms) and stress response. Participants were 119 girls age 12-17 years with overweight/obesity, family history of diabetes, and mild-to-moderate depressive symptoms. Greater mindfulness was associated with less perceived pain and negative affect, but was unrelated to cortisol response to the stressor. Regardless of mindfulness, greater depressive/anxiety symptoms related to a more blunted cortisol response. Mindfulness might promote better distress tolerance in adolescents at risk for diabetes by altering how youth perceive and relate to acute stress, rather than through altering the physiological stress response. At all levels of mindfulness, depressive/anxiety symptoms relate to greater blunting of cortisol response. Findings contribute to emerging literature on the role of mindfulness in promoting the mental and physical health and well-being of individuals at risk for Type 2 diabetes.

Mindfulness and laboratory eating behavior in adolescent girls at risk for type 2 diabetes.

Mindfulness-based intervention has become increasingly popular to address disinhibited eating in obesity and type 2 diabetes (T2D). Theoretically, present-moment attention promotes the ability to recognize and respond to internal hunger cues and to differentiate physiological hunger from other stimuli. Yet, there is limited research describing the relationship of mindfulness with disinhibited eating patterns in adolescents. In this study, we evaluated the relationship of dispositional mindfulness to laboratory eating in 107 adolescent (12-17 years) girls at risk for T2D. Adolescents reported dispositional mindfulness, were evaluated for recent loss-of-control-eating (LOC-eating) by interview, and participated in two successive, standardized laboratory test meals to assess eating when hungry as well as eating in the absence of hunger (EAH). Adolescents rated state appetite throughout the test meal paradigms. In analyses adjusting for body composition and other possible confounds, mindfulness was inversely related to caloric intake during the EAH paradigm. Mindfulness did not relate to energy intake when hungry. Instead, there was a significant interaction of reported LOC-eating by state hunger, such that girls with recent, reported LOC-eating and high state hunger consumed more calories when hungry, regardless of mindfulness. Findings suggest that in girls at risk for T2D, mindfulness may play a role in disinhibited eating. A propensity for LOC-eating may be most salient for overeating in a high hunger state.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

Mindfulness and eating behavior in adolescent girls at risk for type 2 diabetes.

OBJECTIVE: The purpose of this investigation was to examine the relationship of dispositional mindfulness to binge eating and associated eating attitudes and behaviors among adolescent girls at risk for type 2 diabetes (T2D). METHODS: Participants were 114 overweight or obese adolescents enrolled in a study of girls with a family history of T2D and mild depressive symptoms. Adolescent self-reports of mindfulness, eating in the absence of hunger, and depressive symptoms were collected. An interview was administered to determine presence of binge eating episodes and a behavioral task was used to assess the reinforcing value of food relative to other nonsnack food rewards. Body composition was assessed using dual-energy X-ray absorptiometry. RESULTS: In analyses accounting for race, percent body fat, lean mass, height, age, and depressive symptoms, dispositional mindfulness was associated with a lower odds of binge eating (p = .002). Controlling for the same potential confounds, mindfulness was also inversely associated with eating concern, eating in the absence of hunger in response to fatigue/boredom, and higher food reinforcement relative to physical activity (all p < .05). DISCUSSION: In girls with a family history of T2D, independent of body composition and depressive symptoms, intraindividual differences in mindfulness are related to binge eating and associated attitudes and behaviors that may confer risk for obesity and metabolic problems. Further research is needed to determine the extent to which mindfulness plays a role in the etiology and/or maintenance of disinhibited eating in adolescents at risk for T2D.

Evaluation of hypothalamic murine and human melanocortin 3 receptor transcript structure.

The melanocortin 3 receptor (MC3R) is involved in regulation of energy homeostasis. However, its transcript structure is not well understood. We therefore studied initiation and termination sites for hypothalamic murine Mc3r and human MC3R transcripts. Rapid Amplification of cDNA Ends (RACE) was performed for the 5' and 3' ends of murine and human hypothalamic RNA. 5' RACE experiments using hypothalamic murine RNA indicated mouse hypothalamus expresses two major Mc3r transcription start sites: one with a 5' UTR approximately 368 bases in length and another previously unknown transcript with a 5' UTR approximately 440 bases in length. 5' RACE experiments using human hypothalamic RNA identified a 5' UTR beginning 533 bases upstream of the start codon with a 248 base splice. 3' RACE experiments using hypothalamic murine RNA indicated the 3' UTR terminates approximately 1286 bases after the translational stop codon, with a previously unknown 787 base splice between consensus splice donor and acceptor sites. 3' RACE experiments using human MC3R transcript indicated the 3' UTR terminates approximately 115-160 bases after the translational stop codon. These data provide insight into melanocortin 3 receptor transcript structure.

Effects of calcium supplementation on body weight and adiposity in overweight and obese adults: a randomized trial.

BACKGROUND: Some data suggest that increasing calcium intake may help prevent weight gain. OBJECTIVE: To test the hypothesis that calcium supplementation can prevent weight gain in persons who are overweight or obese. DESIGN: Randomized, placebo-controlled trial. Randomization was computer-generated, and allocation was assigned by pharmacy personnel who prepared intervention and placebo capsules. Participants, providers, and those who assessed outcomes were blinded to study group assignment. SETTING: Single research center. PARTICIPANTS: 340 overweight (body mass index [BMI], 25 to <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)) adults (mean age, 38.8 years [SD, 10.5]). INTERVENTION: Calcium carbonate (elemental calcium, 1500 mg/d) (n = 170) or placebo (n = 170) with meals for 2 years. MEASUREMENTS: Changes in body weight and fat mass (primary outcomes). RESULTS: Seventy-five percent of participants completed the trial (78% received calcium; 73% received placebo). There were no statistically or clinically significant differences between the calcium and placebo groups in change in body weight (difference, 0.02 kg [95% CI, -1.64 to 1.69 kg]; P = 0.98), BMI (difference, 0.32 kg/m(2) [CI, -0.41 to 1.02 kg/m(2)]; P = 0.39), or body fat mass (difference, 0.39 kg [CI, -1.04 to 1.92 kg]; P = 0.55). Parathyroid hormone concentrations decreased in the calcium group compared with the placebo group (difference, -0.71 pmol/L [CI, -1.28 to -0.13 pmol/L]). LIMITATION: The study took place at a research center, and its sample was mostly women. CONCLUSION: Dietary supplementation with elemental calcium, 1500 mg/d, for 2 years had no statistically or clinically significant effects on weight in overweight and obese adults. Calcium supplementation is unlikely to have clinically significant efficacy as a preventive measure against weight gain in such patients.

Obesity-related hypoferremia is not explained by differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption.

Hypoferremia is more prevalent in obese than nonobese adults, but the reason for this phenomenon is unknown. To elucidate the role dietary factors play in obesity-related hypoferremia, the intake of heme and nonheme iron and the intake of other dietary factors known to affect iron absorption were compared cross-sectionally from April 2002 to December 2003 in a convenience sample of 207 obese and 177 nonobese adults. Subjects completed 7-day food records, underwent phlebotomy for serum iron measurement, and had body composition assessed by dual-energy x-ray absorptiometry, during a 21-month period. Data were analyzed by analysis of covariance and multiple linear regression. Serum iron (mean+/-standard deviation) was significantly lower in obese than nonobese individuals (72.0+/-61.7 vs 85.3+/-58.1 microg/dL [12.888+/-11.0443 vs 15.2687+/-10.3999 micromol/L]; P<0.001). The obese cohort reported consuming more animal protein (63.6+/-34.5 vs 55.7+/-32.5 g/day; P<0.001) and more heme iron (3.6+/-2.8 vs 2.7+/-2.6 mg/day; P<0.001). Groups did not differ, however, in total daily iron consumption, including supplements. Obese subjects reported consuming less vitamin C (77.2+/-94.9 vs 91.8+/-89.5 mg/day; P=0.01), which may increase absorption of nonheme iron, and less calcium (766.2+/-665.0 vs 849.0+/-627.2 mg/day; P=0.038), which may decrease nonheme iron absorption, than nonobese subjects. Groups did not significantly differ in intake of other dietary factors that can impact absorption of iron, including phytic acid, oxalic acid, eggs, coffee, tea, zinc, vegetable protein, or copper. After accounting for demographic covariates and dietary factors expected to affect iron absorption, fat mass (P=0.007) remained a statistically significant negative predictor of serum iron. This cross-sectional, exploratory study suggests that obesity-related hypoferremia is not associated with differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption.

Validation of three food frequency questionnaires to assess dietary calcium intake in adults.

OBJECTIVE: To assess the accuracy of three self-administered food frequency questionnaires (FFQs) to measure dietary calcium intake in healthy adults. DESIGN: Estimates of dietary calcium intake from one previously validated and two recently developed FFQs were compared with those from 7-day food records. SUBJECTS/SETTING: Healthy adults enrolled in an outpatient study of calcium supplementation completed the 36-page Dietary History Questionnaire (DHQ), a 3-page Calcium Questionnaire, and a 1-page Short Calcium Questionnaire. Subjects then completed a 7-day food record. MAIN OUTCOME MEASURES: Differences between calcium intake reported on FFQs and calcium intake from food records were compared. STATISTICAL ANALYSES: Spearman correlations were used to measure associations among variables; Bland-Altman pairwise comparisons were conducted to assess systematic and magnitude biases. RESULTS: We studied 341 subjects, 74.5% female, mean (+/-standard deviation) age of 38+/-11 years and body mass index (calculated as kg/m(2)) of 31.8+/-7.1. Mean (+/-standard deviation) food record calcium intake was 896+/-380 mg/day; data from all three FFQs were positively related to food record calcium intake, but accounted for <40% of the variance in food record dietary calcium intake (DHQ: r(2)=0.21; Calcium Questionnaire: r(2)=0.33; Short Calcium Questionnaire: r(2)=0.37; all P<0.001). The DHQ underestimated daily calcium intake (systematic bias: -94 mg/day, P<0.001; magnitude bias r=-0.40; P<0.001), whereas the Calcium Questionnaire overestimated calcium intake (systematic bias +177 mg/day, P<0.001), but had no significant magnitude bias (r=-0.09; P=0.11). The Short Calcium Questionnaire showed minimal systematic bias (+34 mg/day, P=0.09), but had magnitude bias (r=-0.33; P<0.001). CONCLUSIONS: All three FFQs performed reasonably well at estimating dietary calcium intake compared to food records; each may be appropriate for use in select clinical and research settings.

The prevalence of hypovitaminosis D and secondary hyperparathyroidism in obese Black Americans.

CONTEXT: Both obesity (body mass index, BMI > or = 30 kg/m2) and Black race are associated with a higher risk of vitamin D deficiency and secondary hyperparathyroidism. We hypothesized the risk of hypovitaminosis D would therefore be extraordinarily high in obese Black adults. OBJECTIVE: To study the effects of race and adiposity on 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (iPTH). DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of 379 Black and White adults from the Washington D.C. area. BMI ranged from 19.9 to 58.2 kg/m2. MAIN OUTCOME MEASURES: Prevalence of hypovitaminosis D [25(OH)D < 37.5 nmol/l] and secondary hyperparathyroidism [25(OH)D < 37.5 nmol/l with iPTH > 4.2 pmol/l]. RESULTS: Obese Black subjects had lower mean 25(OH)D, 40.3 (SD, 20.3) nmol/l, compared with obese Whites, 64.5 (29.7), P < 0.001, nonobese Blacks, 53.3 (26.0), P = 0.0025 and nonobese Whites, 78.0 (33.5), P < 0.001. The prevalence of hypovitaminosis D increased with increasing BMI, and was greater (P < 0.001) in Blacks than Whites within all BMI categories examined. Among subjects with BMI > or = 35 kg/m2, 59% of Blacks vs 18% of Whites had hypovitaminosis D (odds ratio 6.5, 95% confidence interval 3.0-14.2). iPTH was negatively correlated with 25(OH)D (r = -0.31, P < 0.0001), suggesting those with hypovitaminosis D had clinically important vitamin D deficiency with secondary hyperparathyroidism. For secondary hyperparathyroidism 35.2% of Blacks met the criteria, compared to 9.7% of Whites (OR 3.6, CI 1.5-98.8). CONCLUSIONS: Obese Black Americans are at particularly high risk for vitamin D deficiency and secondary hyperparathyroidism. Physicians should consider routinely supplementing such patients with vitamin D or screening them for hypovitaminosis D.

Calcium intake and adiposity.

Limited epidemiologic and experimental data support the possibility that dietary calcium intake plays a role in human body weight regulation. The aim of this review was to present the data from human studies that link calcium and dairy intake to body weight, describe the existing evidence for an effect of calcium intake on body weight from animal models of obesity, present evidence of a role for intracellular calcium in the regulation of lipogenesis and lipolysis, elucidate the potential suggested relation between dietary calcium intake and intracellular calcium concentrations, and outline the effects of calcium supplementation on dietary fat absorption. We suggest that these data support the need for large, population based clinical trials to assess the effects of supplemental calcium and other components of dairy products on human body weight.

Three-month tolerability of orlistat in adolescents with obesity-related comorbid conditions.

OBJECTIVE: To study the safety, tolerability, and potential efficacy of orlistat in adolescents with obesity and its comorbid conditions. RESEARCH METHODS AND PROCEDURES: We studied 20 adolescents (age, 14.6 +/- 2.0 years; body mass index, 44.1 +/- 12.6 kg/m(2)). Subjects were evaluated before and after taking orlistat (120 mg three times daily) and a multivitamin for 3 months. Subjects were simultaneously enrolled in a 12-week program emphasizing diet, exercise, and strategies for behavior change. RESULTS: Participants who completed treatment (85%) reported taking 80% of prescribed medication. Adverse effects were generally mild, limited to gastrointestinal effects observed in adults, and decreased with time. Three subjects required additional vitamin D supplementation despite the prescription of a daily multivitamin containing vitamin D. Weight decreased significantly (-4.4 +/- 4.6 kg, p < 0.001; -3.8 +/- 4.1% of initial weight), as did body mass index (-1.9 +/- 2.5 kg/m(2); p < 0.0002). Total cholesterol (-21.3 +/- 24.7 mg/dL; p < 0.001), low-density lipoprotein-cholesterol (-17.3 +/- 15.8 mg/dL; p < 0.0001), fasting insulin (-13.7 +/- 19.0 microU/mL; p < 0.02), and fasting glucose (-15.4 +/- 7.4 mg/dL; p < 0.003) were also significantly lower after orlistat. Insulin sensitivity, assessed by a frequently sampled intravenous glucose-tolerance test, improved significantly (p < 0.02). DISCUSSION: We conclude that, in adolescents, short-term treatment with orlistat, in the context of a behavioral program, is well-tolerated and has a side-effect profile similar to that observed in adults, but its true benefit versus conventional therapy remains to be determined in placebo-controlled trials.

Effects of orlistat on fat-soluble vitamins in obese adolescents.

STUDY OBJECTIVES: To determine whether orlistat causes fat-soluble vitamin deficiencies in African-American and Caucasian adolescents. DESIGN: Prospective, open-label pilot study. SETTING: Warren Grant Magnuson Clinical Center of the National Institutes of Health. PATIENTS: Seventeen adolescents with body mass indexes above the 95th percentile for age, race, and gender who also had at least one obesity-related comorbid condition. INTERVENTION: Subjects received orlistat 120 mg 3 times/day and a daily multivitamin supplement containing vitamin A 5000 IU, vitamin D 400 IU, vitamin E 300 IU, and vitamin K 25 microg. MEASUREMENTS AND MAIN RESULTS: During 3-6 months of orlistat treatment, acute absorption of retinol (vitamin A) was not significantly altered, but absorption of alpha-tocopherol (vitamin E) was significantly reduced compared with baseline levels (p<0.001). Serum levels of vitamins A and E did not change significantly; however, there was a nonsignificant decrease in vitamin K. Mean vitamin D levels were significantly reduced compared with baseline (p<0.02) after 1 month of orlistat, despite multivitamin supplementation. CONCLUSION: It may be prudent to monitor vitamin D concentrations in adolescents who take orlistat, even when a multivitamin is prescribed.