Altered Hypothalamic Signaling and Responses to Food Deprivation in Rats Fed a Low‐Carbohydrate Diet

Objective: To model how consuming a low‐carbohydrate (LC) diet influences food intake and body weight. Research Methods and Procedures: Food intake and body weight were monitored in rats with access to chow (CH), LC‐high‐fat (HF), or HF diets. After 8 weeks, rats received intracerebroventricular injections of a melanocortin agonist (melanotan‐II) and antagonist (SHU9119), and feeding responses were measured. At sacrifice, plasma hormones and hypothalamic expression of mRNA for proopiomelanocortin (POMC), melanocortin‐4 receptor, neuropeptide Y (NPY), and agouti related protein (AgRP) were assessed. A second set of rats had access to diet (chow or LC‐HF) for 4 weeks followed by 24 h food deprivation on two occasions, after which food intake and hypothalamic POMC, NPY, and AgRP mRNA expression were measured. Results: HF rats consumed more food and gained more weight than rats on CH or LC‐HF diets. Despite similar intakes and weight gains, LC‐HF rats had increased adiposity relative to CH rats. LC‐HF rats were more sensitive to melanotan‐II and less sensitive to SHU9119. LC‐HF rats had increased plasma leptin and ghrelin levels and decreased insulin levels, and patterns of NPY and POMC mRNA expression were consistent with those of food‐deprived rats. LC‐HF rats did not show rebound hyperphagia after food deprivation, and levels NPY, POMC, and AgRP mRNA expression were not affected by deprivation. Discussion: Our results demonstrate that an LC diet influences multiple systems involved in the controls of food intake and body weight. These data also suggest that maintenance on an LC‐HF diet affects food intake by reducing compensatory responses to food deprivation.     

Effects of a Low‐intensity Intervention That Prescribed a Low‐carbohydrate vs. a Low‐fat Diet in Obese,Diabetic Participants

Low‐carbohydrate diets have been associated with significant reductions in weight and HbA_1c in obese, diabetic participants who received high‐intensity lifestyle modification for 6 or 12 months. This investigation sought to determine whether comparable results to those of short‐term, intensive interventions could be achieved over a 24‐month study period using a low‐intensity intervention that approximates what is feasible in outpatient practice. A total of 144 obese, diabetic participants were randomly assigned to a low‐carbohydrate diet (<30 g/day) or to a low fat diet (≤30% of calories from fat with a deficit of 500 kcal/day). Participants were provided weekly group nutrition education sessions for the first month, and monthly sessions thereafter through the end of 24 months. Weight, HbA_1c, glucose, and lipids were measured at baseline and 6, 12, and 24 months. Of the 144 enrolled participants, 68 returned for the month 24 assessment visit. Weights were retrieved from electronic medical records for an additional 57 participants (total, 125 participants) at month 24. All participants with a baseline measurement and at least one of the three other measurements were included in the mixed‐model analyses (n = 138). The low‐intensity intervention resulted in modest weight loss in both groups at month 24. At this time, participants in the low‐carbohydrate group lost 1.5 kg, compared to 0.2 kg in the low‐fat group (P = 0.147). Lipids, glycemic indexes, and dietary intake did not differ between groups at month 24 (or at months 6 or 12) (ClinicalTrials.gov number, NCT00108459).     

The Population Cost‐Effectiveness of Weight Watchers with General Practitioner Referral Compared with Standard Care

Objective

This study aimed to assess population‐level cost‐effectiveness of the Weight Watchers (WW) program with doctor referral compared with standard care (SC) for Australian adults with overweight and obesity.

Methods

The target population was Australian adults ≥ 20 years old with BMI ≥ 27 kg/m², whose obesity status was subsequently modeled for 2015 to 2025. A microsimulation model (noncommunicable disease model [NCDMod]) was used to assess the incremental cost‐effectiveness of WW compared with SC. A health system perspective was taken, and outcomes were measured by obesity cases averted in 2025, BMI units averted for 2015 to 2025, and quality‐adjusted life years for 2015 to 2025. Univariate sensitivity testing was used to measure variations in the model parameters.

Results

The WW intervention resulted in 60,445 averted cases of obesity in 2025 (2,311 more cases than for SC), extra intervention costs of A$219 million, and cost savings within the health system of A$17,248 million (A$82 million more than for SC) for 2015 to 2025 compared with doing nothing. The modeled WW had an incremental cost‐effectiveness ratio of A$35,195 in savings per case of obesity averted in 2025. WW remained dominant over SC for the different scenarios in the sensitivity analysis.

Conclusions

The WW intervention represents good value for money. The WW intervention needs serious consideration in a national package of obesity health services.     

On Parametric Confidence Intervals for the Cost‐Effectiveness Ratio

When comparing two competing interventions, confidence intervals for cost‐effectiveness ratios (CERs) provide information on the uncertainty in their point estimates. Techniques for constructing these confidence intervals are much debated. We provide a formal comparison of the Fieller, symmetric and Bonferroni methods for constructing confidence intervals for the CER using only the joint asymptotic distribution of the incremental cost and incremental effectiveness of the two interventions being compared. We prove the existence of a finite interval under the Fieller method when the incremental effectiveness is statistically significant. When this difference is not significant the Fieller method yields an unbounded confidence interval. The Fieller interval is always wider than the symmetric interval, but the latter is an approximation to the Fieller interval when the incremental effectiveness is highly significant. The Bonferroni method is shown to produce the widest interval. Because it accounts for the likely correlation between cost and effectiveness measures, and the intuitively appealing relationship between the existence of a bounded interval and the significance of the incremental effectiveness, the Fieller interval is to be preferred in reporting a confidence interval for the CER.     

Center‐Size as a Predictor of Weight‐Loss Outcome in Multicenter Trials Including a Low‐Calorie Diet

It has not been studied yet whether factors such as the number of subjects recruited by specialized centers for multicenter trials may influence weight loss during a low‐calorie diet (LCD). This study aimed at determining whether the number of recruited subjects per center might predict relative weight loss. This is a post hoc analysis of an existing database: 701 obese subjects (77% women, 23% men, mean BMI: 38.9 kg/m²) were enrolled at 22 sites (4–85 subjects/site) in five countries to follow a LCD providing 800–1,000 kcal/day during 8 weeks. The main outcome measure was the percentage weight loss after the 8‐week LCD. Mean weight loss differed significantly between participating centers (5.8–11.8% of the initial weight; P < 0.001). There was a significant positive correlation between relative weight loss and the number of recruited subjects per center (r = 0.38; P < 0.001). In a multiple stepwise regression analysis, the number of recruited subjects per center appeared to be the main predictive factor of weight loss (R² = 0.07; P < 0.001). As the number of participants within each center is clustered, we applied a hierarchical model to model the average weight loss vs. the number of participants included at each center. This model allows to predict that for 10 extra patients in a center, the average weight loss would increase by 0.5%. This is the first study suggesting that the number of recruited subjects per center may impact weight loss, and could therefore be considered as a new predictor for weight loss that is independent from the individual.     

Variations in Body Composition and Plasma Lipids in Response to a High‐Carbohydrate Diet

Objective: To examine the extent to which variations in body composition modulate changes in the lipid profile in response to the ad libitum consumption of a diet rich in carbohydrates (CHOs) (high‐CHO diet: 58% of energy as CHOs) or high in fat and in monounsaturated fatty acids (MUFAs) (high‐MUFA diet: 40% of energy as fat, 23% as MUFAs). Research Methods and Procedures: Sixty‐three men were randomly assigned to one of the two diets that they consumed for 6 to 7 weeks. Body composition and fasting plasma lipid levels were measured at the beginning and the end of the dietary intervention. Results: The high‐CHO and high‐MUFA diets induced significant and comparable reductions in body weight and waist circumference. These changes were accompanied by significant and comparable (p < 0.01) reductions in total plasma cholesterol and low‐density lipoprotein cholesterol levels. However, the high‐MUFA diet had more beneficial effects on plasma triglyceride concentrations (p < 0.01) and on plasma high‐density lipoprotein cholesterol levels (p = 0.02) compared with the high‐CHO diet. Diet‐induced changes in waist circumference were significantly associated with changes in low‐density lipoprotein cholesterol levels in the high‐CHO group (r = 0.39, p = 0.03) but not in the high‐MUFA group (r = 0.16, p = 0.38). Discussion: Improvements in plasma lipids induced by the ad libitum consumption of a high‐CHO diet seem to be partly mediated by changes in body weight, whereas lipid changes induced by the high‐MUFA diet seem to be independent of changes in body weight.     

Association between Low‐Molecular Weight Apolipoprotein(a) Isoforms and Obesity in Italian Women

Objective: Low‐molecular weight (MW) apolipoprotein(a) [apo(a)] isoforms are closely associated with an increased incidence of atherothrombotic disease, prevalence of which is higher in obese individuals, particularly in women. The hypothesis of this study was to assess whether there are differences in the distribution of apo(a) phenotypes between obese patients and healthy controls. Research Methods and Procedures: One hundred three obese Italian women (BMI ≥ 30.0 kg/m²) were enrolled in the study, and apo(a) phenotyping was performed in all subjects. The prevalence of low‐MW apo(a) isoforms, detected in plasma samples of our obese women, was compared with that found in a control group of 84 normal‐weight, never‐obese (BMI < 25.0 kg/m²), age‐matched women. Results: The distribution of apo(a) isoforms in the population of obese women was significantly different from that found in normal‐weight female subjects. In particular, the percentage of subjects in the obese group with at least one apo(a) isoform of low MW was significantly higher than that in the control group (51.4% vs. 32.1%, p = 0.0079). Discussion: Our results seem to suggest the possibility that small‐sized apo(a) isoforms may be used together with other traditional risk factors to better assess the overall predisposition to atherothrombotic disease in obese women.     

Topiramate: Long‐Term Maintenance of Weight Loss Induced by a Low‐Calorie Diet in Obese Subjects

Objective: To examine the safety and efficacy of topiramate (TPM) for maintaining weight following a low‐calorie diet. Research Methods and Procedures: Obese subjects (30 ≤ BMI < 50 kg/m²) 18 to 75 years old received a low‐calorie diet for 8 weeks. Those who lost ≥8% of their initial weight received TPM (96 or 192 mg/d) or placebo; all were on a lifestyle modification plan. Sixty weeks of medication were planned. Sponsor ended study early to develop a new controlled‐release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Efficacy was analyzed in subjects who completed 44 weeks of treatment before study termination. Results: Of the 701 subjects enrolled, 80% lost ≥8% of their initial body weight and were randomized; 293 were analyzed for efficacy. Most withdrawals were due to premature termination of the study. Subjects receiving TPM lost 15.4% (96 mg/d) and 16.5% (192 mg/d) of their enrollment weight by week 44, compared with 8.9% in the placebo group (p < 0.001). Subjects on TPM continued to lose weight after the run‐in, whereas those on placebo regained weight. Significantly more TPM subjects lost 5%, 10%, or 15% of their randomization weight than placebo. Most adverse events were related to the central nervous system. Discussion: During a treatment period of 44 weeks, TPM was generally well tolerated, and subjects maintained weight loss initially achieved by a low‐calorie diet—and produced additional clinically significant weight loss beyond that achieved by a low‐calorie diet.     

Treatment of Morbid Obesity in Low‐income Adolescents: Effects of Parental Self‐monitoring

Objective: This study examined the extent to which consistency of self‐monitoring by participants and their parents was related to weight control over an initial period of 3 months within the context of a treatment program for morbidly obese low‐income minority adolescents. Research Methods and Procedures: Eighty‐three obese adolescents (mean age, 13.0 years; 51% boys; 92% African American; mean BMI, 43.0 kg/m²; mean BMI z‐score, 6.0) and at least one parent participated in a long‐term treatment program that included a very‐low‐fat dietary focus, weekly group cognitive‐behavior therapy, monthly nutrition education classes, a 12‐week physical therapy class, and medical monitoring. Results: Participants who self‐monitored on the majority of days compared with those who did not self‐monitor at all or who self‐monitored infrequently attended more sessions and generally lost more weight over the first 3 months. Although parents signed behavioral contracts committing to self‐monitor their own eating and exercising over the first month, only 12% did so. Nonetheless, participants whose parents self‐monitored were much more likely to self‐monitor consistently and lose weight during the first 3 months. Discussion: These results indicate that self‐monitoring is a cornerstone of successful weight control even for morbidly obese low‐income minority adolescents; targeting consistency of self‐monitoring among these high‐risk weight controllers and their parents should be just as important as it is for more affluent and less overweight adolescents.     

Enhanced Erythrocyte Adhesiveness/Aggregation in Obesity Corresponds to Low‐Grade Inflammation

Objective: Previous studies have suggested that obesity enhances the inflammatory response, producing macromolecules involved in the induction and/or maintenance of increased erythrocyte aggregation. The objectives of this study were to evaluate the correlation between inflammation markers, erythrocyte adhesiveness/aggregation, and the degree of obesity and to assess phosphatidylserine expression on erythrocyte surface membrane of obese vs. nonobese individuals. Research Methods and Procedures: Erythrocyte adhesiveness/aggregation in the peripheral venous blood was evaluated by using a new biomarker, phosphatidylserine expression was assessed by means of flow cytometry, and markers of inflammation were measured in 65 subjects: 30 obese [body mass index (BMI) = 41 ± 7.7 kg/m²] and 35 nonobese (BMI = 24 ± 2.7 kg/m²) individuals. Pearson correlations and Student's t test were performed. Results: A highly significant difference was noted in the degree of erythrocyte adhesiveness/aggregation and markers of inflammation between the study groups. BMI correlated with erythrocyte adhesiveness/aggregation (r = 0.42, p = 0.001), erythrocyte sedimentation rate (r = 0.42, p = 0.001), high‐sensitive C‐reactive protein (r = 0.55, p < 10^?4), fibrinogen (r = 0.37, p = 0.004), and white blood cell count (r = 0.45, p < 10^?4). The degree of erythrocyte adhesiveness/aggregation correlated with erythrocyte sedimentation rate (r = 0.5, p < 10^?4), high‐sensitive C‐reactive protein (r = 0.56, p < 10^?4), fibrinogen (r = 0.54, p < 10^?4), and white blood cell count (r = 0.32, p = 0.01). Discussion: Our results suggest that obesity‐related erythrocyte adhesiveness/aggregation is probably mediated through increased concentrations of adhesive macromolecules in the circulation and not necessarily through hyperlipidemia or phosphatidylserine exposure on erythrocyte's membrane.