The Addition of Dexfenfluramine to Fluoxetine in the Treatment of Obesity: A Randomized Clinical Trial

Current evidence demonstrates that pharmacologic agents, alone or in combination produce short-term weight-loss and may remain effective for extended periods of time in obese patients. We have evaluated the weight loss of a selective inhibitor of serotonin uptake, fluoxetine, alone as compared with combined therapeutic trial with another serotoninergic drug, dexfenfluramine. Thirty-three patients were randomly assigned in a double-blind randomized clinical trial divided to two groups: Group I [Fluoxetine 40 mg and placebo (n=13)] and Group II [Fluoxetine 40 mg plus dexfenfluramine 15 mg at night (n=20)]. Both groups had a significant weight loss at the end of 8 months (Group I, mean ± SEM 6.2 ± 2.8 kg and Group II 13.4 ± 6.3 kg, p < 0.05). Group II patients had a significantly greater weight loss as compared with Group I both in terms of mean weight loss in kg and BMI in kg/m². However significance between Group I and II related to BMI mean values and weight mean values were only achieved after, respectively, 4 and 6 months of treatment. At laboratory level there was an elevation of HDL-cholesterol and lowering of serum lipids values (cholesterol and triglycerides) in both groups. Side effects were relatively minor and no altered clinical vital signs or abnormal laboratory values were observed. We concluded that the combination of fluoxetine (daytime) and dexfenfluramine (at night) may be more effective than fluoxetine alone in weight reduction although the small size of this study does not permit broad generalization.     

Markers of inflammation and fat distribution following weight loss in African-American and white women

Changes in markers of inflammation (MOI) and fat distribution with weight loss between African-American (AA) and white (W) women have yet to be characterized. The purpose of this study was to examine potential ethnic differences in MOI and regional fat distribution with weight loss, and identify the associations between these markers and changes in regional fat distribution with weight loss among AA and W women. Subjects were 126 healthy, premenopausal women, BMI 27-30 kg/m(2). They were placed on a weight-loss intervention consisting of diet and/or exercise until a BMI <25 was achieved. Fat distribution was measured with computed tomography, and body composition with dual-energy X-ray absorptiometry. Serum concentrations of tumor necrosis factor-α (TNF-α), soluble TNF receptor-I (sTNFR-I), sTNFR-II, C-reactive protein (CRP), and interleukin-6 (IL-6) were assessed. All MOI and adiposity measures significantly decreased with weight loss. Significant ethnic differences with weight loss were observed for fat mass, body fat, intra-abdominal adipose tissue (IAAT), sTNFR-I, and sTNFR-II. Mixed-model analysis indicated that adjusting for change in IAAT explained ethnic differences in change in TNF-α and the decrease in TNF-α with weight loss, while total fat mass only explained the decrease in sTNFR-I and sTNFR-II with weight loss. In conclusion, all MOI decreased following weight loss among W, whereas only IL-6 and CRP decreased following weight loss in AA. The most distinct phenotypic difference observed was a greater impact of weight loss on TNF-α in W compared to AA, which was directly associated with IAAT in W.     

Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

Randomized trial of a multifaceted commercial weight loss program

Objective: To test whether a commercial weight loss program promotes greater weight loss in overweight or obese women compared with control conditions and to describe the effect on plasma lipids, carotenoids, hormones, and fitness. Research Methods and Procedures: Overweight or obese women were randomized to commercial weight loss program or control conditions (n = 35 each). Results: At randomization, participants were 41.1 (11.4) (mean [standard deviation]) years, BMI 34.0 (3.5) kg/m², and weight 92.0 (11.1) kg. At 6 months, change in weight by intent‐to‐treat (ITT) analysis was ?7.2 (6.7) kg and ?7.8% (7.2%) in the intervention group vs. ?0.3 (3.9) kg and ?0.3% (4.5%) in the control group (n = 35 for each; p < 0.01). One‐year ITT analysis revealed significantly greater change in weight, percent weight, BMI, and waist and hip circumferences in the intervention vs. control group. Completers at 1 year exhibited change in weight of ?7.3 (10.4) kg for the intervention group (n = 32) vs. ?0.7 (5.6) kg for controls (n = 33) (p < 0.01), and ?7.8% (11.1%) weight change for the intervention group vs. ?0.7% (6.2%) for controls (p < 0.01). High‐density lipoprotein (HDL) cholesterol concentration increased significantly in the intervention group. Fasting serum insulin decreased in the intervention but increased in the control group at 6 months (p < 0.01), remaining different at 1 year (p = 0.05). Discussion: The commercial program successfully facilitated weight loss, which was notably maintained at 1 year, and promoted favorable changes in plasma lipid and hormone concentrations.     

Sertraline and Relapse Prevention Training Following Treatment by Very-Low-Calorie Diet: A Controlled Clinical Trial

WADDEN, THOMAS A, SUSAN J BARTLETT, GARY D FOSTER, ROBERT A GREENSTEIN, BARBARA J WINGATE, ALBERT J STUNKARD AND KATHLEEN A LETIZIA. Sertraline and relapse prevention training following treatment by very-low-calorie diet: a controlled clinical trial. Obes Res. This study examined the combination of sertraline, a selective serotonin reuptake inhibitor, and relapse prevention training in the maintenance of weight loss following treatment by a very-low-calorie diet. A total of 53 women who had lost a mean (± SD) of 22.9 ± 7.1 kg from a pretreatment weight of 103.1 ± 17.8 kg were randomly assigned to a 54-week weight maintenance program that was combined with either: 1) 200 mg/d of sertraline; or 2) placebo. During the first 6 weeks, sertraline subjects lost significantly more weight and reported significantly greater reductions in hunger and preoccupation with food than did subjects on placebo. After this time, however, women in both conditions regained weight steadily. The 13 sertraline subjects who completed the 54-week study regained 17.7 ± 10.6 kg of their original 26.3 ± 7.6 kg loss, equal to a regain of 70.9 ± 41.7%. The 17 placebo completers regained 11.8 ± 9.0 kg of their 23.4 ± 7.8 kg loss, equal to a 46.5 ± 34.6% regain. End-of-treatment differences between groups in weight change were not statistically significant. Nor were there significant differences between the two conditions at any time in changes in fat-free mass, resting metabolic rate or dysphoria, all of which tended to increase with weight regain. The results are discussed in relation to findings from other long-term studies that combined diet and medication.     

Efficacy and Safety of Long-Term Fluoxetine Treatment of Obesity - Maximizing Success

Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.     

Effect of diet with and without exercise training on markers of inflammation and fat distribution in overweight women

The independent effects of exercise and weight loss on markers of inflammation (MOI) in obese individuals have not been clearly characterized. The objectives of this study were to: (i) identify the independent effects of exercise and weight loss on MOI and (ii) determine whether changes in MOI were associated with changes in fat distribution. Subjects were 126 healthy, premenopausal women, BMI 27–30 kg/m². They were randomized to one of three groups: diet only, diet + aerobic‐, or diet + resistance training until a BMI <25 kg/m² was achieved. Fat distribution was measured with computed tomography, and body composition with dual‐energy X‐ray absorptiometry. Serum concentrations of tumor necrosis factor (TNF)‐α, soluble TNF receptor 1 (sTNF‐R1), soluble TNF receptor 2 (sTNF‐R2), C‐reactive protein (CRP), and interleukin (IL)‐6 were assessed. Results of repeated‐measures ANOVA indicated a significant effect of time on MOI, such that MOI decreased with weight loss. Results of mixed‐model analysis indicated that adjusting for intra‐abdominal adipose tissue (IAAT) and total fat mass explained the decreases in TNF‐α and sTNF‐R1, whereas only total fat mass explained the decreases in sTNF‐R2, IL‐6, and CRP. In conclusion, weight loss was associated with decreases in MOI. The effect of weight loss appeared to be mediated by changes in total fat mass or IAAT. Addition of exercise did not alter the response, suggesting that weight loss has a more profound impact for reducing MOI in overweight women than exercise.     

Effects of Visceral Fat and Weight Loss on Lipoprotein(a) Concentration in Subjects with Obesity

ZAMBONI M, R FACCHINETTI, F ARMELLINI, E TURCATO, IA BERGAMO ANDREIS, O BOSELLO. Effects of visceral fat and weight loss on lipoprotein(a) concentration in subjects with obesity. We studied the relationships between regional body fat distribution and metabolic variables with lipoprotein(a) [Lp(a)] as well as the effects of weight loss on Lp(a) in 25 women and 9 men with obesity. Regional body fat distribution, as evaluated by the use of computed tomography; Lp(a); and fasting glucose, insulin, cholesterol, and triglycerides were analyzed before and after a very low-energy diet. No significant correlations were found between visceral, subcutaneous, and total fat and Lp(a) or between metabolic variables and Lp(a). All anthropometric variables significantly decreased after a very low-energy diet. Fasting glucose, insulin, triglycerides, and cholesterol significantly decreased after a very low-energy diet. No significant changes in Lp(a) concentration after a very low-energy diet were found. The correlation between the initial values of Lp(a) and changes of Lp(a) after a very low-energy diet was slightly significant (ρ=0.33, p<0.06). In conclusion, our study shows that Lp(a) is not influenced by obesity, visceral fat, metabolic variables, or weight loss induced by a very low-energy diet     

Recombinant human growth hormone, but not insulin-like growth factor-I, enhances central fat loss in postmenopausal women undergoing a diet and exercise program.

We examined the effect of recombinant human growth hormone (rhGH) and/or recombinant human insulin-like growth factor-I (rhIGF-l) on regional fat loss in postmenopausal women undergoing a weight loss regimen of diet plus exercise. Twenty-seven women aged 59-79 years, 20-40% above ideal body weight, completed a 12-week program consisting of resistance training 2 days/week and walking 3 days/week, while consuming a diet that was 500 kcal/day less than that required for weight maintenance. Participants were randomly assigned in a double-blind fashion to receive rhGH (0.025 mg/kg BW/day; n = 7), rhIGF-I (0.015 mg/kg BW/day; n = 7), rhGH + rhIGF-I (n = 6), or placebo (PL; n = 7). Regional and whole body fat mass were determined by dual X-ray absorptiometry. Body fat distribution was assessed by the ratios of trunk fat-to-limb fat (TrF/LimbF) and trunk fat-to-total fat (TrF/TotF). Limb and trunk fat decreased in all groups (p < 0.01). For both ratios of fat distribution, the rhGH treated group experienced an enhanced loss of truncal compared to peripheral fat (p < 0.01), with no significant change for those administered rhIGF-I or PL. There was no association between change in fat distribution and indices of cardiovascular disease risk as determined by serum lipidilipoprotein levels and maximal aerobic capacity. These results suggest that administration of rhGH facilitates a decrease in central compared to peripheral fat in older women undertaking a weight loss program that combines exercise and moderate caloric restriction, although no beneficial effects are conferred to lipid/lipoprotein profiles. Further, the effect of rhGH is not enhanced by combining rhGH with rhIGF-I administration. In addition, rhIGF-I does not augment the loss of trunk fat when administered alone.     

Effects of yo-yo diet, caloric restriction, and olestra on tissue distribution of hexachlorobenzene

Chlorinated hydrocarbons are lipophilic, toxic, and persistent in the environment and animal tissues. They enter the body in food and are stored in adipose tissue. Loss of body fat through caloric restriction mobilizes stored lipophilic xenobiotics and results in distribution to other tissues. We have studied the reversibility of this process in mice that followed a regimen of body weight cycling. Weight gain was followed by weight loss, a second gain, and a second loss ("yo-yo diet regimen"). We measured the distribution of orally gavaged [14C]hexachlorobenzene, which is sparingly metabolized. We found that weight cycling has different effects in different organs. Continued weight loss resulted in a threefold increase of 14C amount and concentration in the brain. After weight regain, 14C in the brain decreased but then increased again after a second weight loss. Weight loss resulted in an increase in the concentration of 14C in adipose tissue without changing the total amount in that tissue. Weight loss and regain resulted in an increase of 14C in the liver, which reflected an increase of fat in the liver. The regimen of weight gain and loss was repeated in mice gavaged with [14C]hexachlorobenzene, with one group receiving the nonabsorbable fat olestra in the diet. Combined dietary olestra and caloric restriction caused a 30-fold increase in the rate of excretion of 14C relative to an ad libitum diet or a reduced caloric diet alone. Distribution of 14C into the brain resulting from the restricted diet was reduced by 50% by dietary olestra.     

Baseline Predictors of Success When Comparing Two Treatments

Since few medications are equally effective in all patients, physicians can maximize the risk/benefit ratio of therapy for their patients by limiting exposure based on baseline predictors of success. Traditional procedures typically evaluate the response of patients receiving the same treatment regimen without evaluating a comparator. However, when treatments are compared, such as in clinical trials, traditional procedures of identifying predictors must be modified to analyze the treatment effect on the primary outcome variable. We focus on clinical and statistical considerations that arise when developing baseline predictors through models which consider treatment differences. To illustrate an application of this method, we used data from 1,026 patients completing at least 6 months of double-blind therapy in clinical trials comparing fluoxetine (N=522) with placebo (N=504) for weight loss. Stepwise regression procedures were used to identify baseline variables which were predictive of a beneficial fluoxetine treatment effect on last-visit-carried-forward (LVCF) weight change. In this example, age, smoking activity, and uric acid concentration were the best baseline predictors of long-term treatment effect relative to LVCF weight change. Patients were more likely to achieve long-term benefit with fluoxetine if they were older, and/or were nonsmokers, and/or had high concentrations of uric acid at baseline. These predictors, developed through models keying on treatment effect, can be used to identify patients who are more likely to accrue benefits with active therapy beyond those expected with placebo therapy, thus enriching the treatment population so that a higher proportion of treated patients are successful.     

Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects

Objective: To evaluate the efficacy and safety of the selective dopamine D1/D5 antagonist ecopipam for the treatment of obesity. Research Methods and Procedures: Four randomized, double‐blind, multicenter trials compared ecopipam (n = 1667) and placebo (n = 1118) in obese subjects including type 2 diabetic subjects. Subjects received oral ecopipam 10, 30, or 100 mg daily for 12 weeks (Phase 2) or 50 or 100 mg daily for 52 weeks (Phase 3) combined with a weight loss program. Primary efficacy variables were the proportion of subjects with ≥5% weight loss from baseline at 12 weeks (Phase 2) or the distribution of percentage weight loss from baseline at 52 weeks (Phase 3). Results: In the Phase 2 study, 26% of subjects administered ecopipam 100 mg vs. 6% of placebo subjects achieved ≥5% weight loss after 12 weeks (p < 0.01). In the Phase 3 studies, ecopipam 100 mg produced a 3.1% to 4.3% greater weight loss than placebo at 52 weeks. More subjects administered ecopipam vs. placebo achieved a 5% to 10% or >10% weight loss in two non‐diabetic phase 3 trials. Ecopipam‐treated subjects also maintained more weight loss compared with placebo subjects at 52 weeks. Phase 3 studies were discontinued because of unexpected psychiatric adverse events (ecopipam 31% vs. placebo 15%), including depression, anxiety, and suicidal ideation. Discussion: Ecopipam was effective for achieving and maintaining weight loss in obese subjects, including type 2 diabetic subjects; however, the adverse effects on mood observed in the Phase 3 studies exclude its projected use in weight management.     

Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity

We studied whether cannabinoid receptor (CB1) blockade with rimonabant has an anti-inflammatory effect in obese mice, and whether this effect depends on weight loss and/or diet consumption. High-fat diet (HFD)-induced obese mice were treated orally with rimonabant (HFD-R) or vehicle (HFD-V) for 4 weeks. Paired-feeding was conducted in two additional groups of obese mice to achieve either the same body weight (HFD-BW) or the same HFD intake (HFD DI) as HFD-R. All these groups of mice were maintained on HFD throughout, with mice on normal diet (ND) throughout as lean controls. Rimonabant treatment of obese mice induced marked diet-intake reduction and weight loss during the first week, which was followed by maintenance of low body weight but not diet-intake reduction. Lower HFD intake was required to reach the same degree of weight loss in HFD-BW. HFD-DI had similar weight loss initially, but then started to gain weight, reaching a higher body weight than HFD-R. Despite the same degree of weight loss, HFD-R had less fat mass and lower adipogenic gene expression than HFD-BW. Compared to HFD-V or HFD-DI, HFD-R had reduced inflammation in adipose tissue (AT) and/or liver indicated primarily by lower monocyte chemoattractant protein-1 (MCP-1) levels. However, MCP-1 levels were not significantly different between HFD-R and HFD-BW. In vitro incubation of rimonabant with AT explants did not change MCP-1 levels. Thus, rimonabant induced weight loss in obese mice by diet-intake-dependent and -independent fashions. Rimonabant decreased inflammation in obese mice, possibly through a primary effect on weight reduction.     

Mediators of Weight Loss in a Family‐Based Intervention Presented over the Internet

Objective: To assess the process variables involved in a weight loss program for African‐American adolescent girls. Several process variables have been identified as affecting success in in vivo weight loss programs for adults and children, including program adherence, self‐efficacy, and social support. The current study sought to broaden the understanding of these process variables as they pertain to an intervention program that is presented using the Internet. It was hypothesized that variables such as program adherence, dietary self‐efficacy, psychological factors, and family environment factors would mediate the effect of the experimental condition on weight loss. Research Methods and Procedures: Participants were 57 adolescent African‐American girls who joined the program with one obese parent; family pairs were randomized to either a behavioral or control condition in an Internet‐based weight loss program. Outcome data (weight loss) are reported for the first 6 months of the intervention. Results: Results partially supported the hypotheses. For weight loss among adolescents, parent variables pertaining to life and family satisfaction were the strongest mediating variables. For parental weight loss, changes in dietary practices over the course of 6 months were the strongest mediators. Discussion: The identification of factors that enhance or impede weight loss for adolescents is an important step in improving weight loss programs for this group. The current findings suggest that family/parental variables exert a strong influence on weight loss efforts for adolescents and should be considered in developing future programs.     

Interaction of competing fungi with fly larvae

Saprophytic fungi have degradative abilities and interspecific interactions which suggest that resource use and yield should increase as species number increases, but previous studies show the opposite. As a test of the possibility that invertebrate activity changes fungal resource use patterns, we grew coprophilous fungi on rabbit feces at the same initial density singly or in mixtures of 2, 4, or 6 species, with or without activity of larvalLycoriella mali (Diptera: Sciaridae). Fungi in mixtures without larvae caused less weight loss in one mixture, and greater weight loss in 2 mixtures than when growing alone; fungi in 4 of 6 mixtures produced fewer spores than when growing alone. Overall, without larvae, weight loss did not increase as number of fungal species increased. Larvae did not change the pattern of weight loss or proportions of spores caused by mixing fungal species. Numbers of larvae surviving to pupate rose as fungal species numbers increased; as a result, weight loss increased with fungal species number in cultures with larvae.     

Obesity: overview of pathogenesis and treatment

This paper presents an overview of selected current concepts of the pathogenesis and treatment of obesity. It has been estimated using the 1981 Canada Fitness Survey data that 14.1% of Canadian adult men and 20.6% of women are greater than 20% above reference table weight. Recent advances in adipocyte metabolism and control have shown that hyperplastic obesity can occur at any age and that there are differences in the replicative rate of adipocyte precursor cells from the massively obese. Furthermore, a number of the complications of obesity, including hypertension, have been related to regional body fat distribution, independent of total body fat. It is suggested that some of the controversy on the relationship between body weight/weight loss and hypertension may be due to failure to account for this. There is now suggestive evidence that abnormalities in diet-induced thermogenesis and (or) brown adipose tissue may result in human obesity. The roles of the major treatment modalities (diet, behaviour therapy, and exercise) are reviewed as are the potential hazards of the weight loss process.     

A Statewide Intervention Reduces BMI in Adults: Shape Up Rhode Island Results

Given the epidemic of obesity, approaches to weight loss that can be applied on a community, state, or national level are needed. We report results from Shape Up Rhode Island 2007 (SURI), a statewide Internet‐based program involving team‐based competition to increase physical activity and achieve weight loss. A total of 4,717 adults (84% women; mean BMI = 29.6 kg/m²) enrolled in the 16‐week weight loss competition of SURI and 3,311 completed at least 12 weeks. Completers reported losing 3.2 ± 3.4 kg, and 30% achieved a clinically significant weight loss of ≥5%. Although modest, these weight losses shifted the BMI distribution from a mean BMI of 29.4 to a mean of 28.2 kg/m² and reduced the population that was obese from 39 to 31%. More conservative intent‐to‐treat analyses and analysis of 132 participants with objective weights still showed a significant reduction in BMI of ?0.8 units. These findings suggest that statewide weight loss campaigns can produce modest weight losses in large numbers of participants. These data provide a benchmark that can be used for comparisons with other statewide campaigns. Research on ways to improve such campaigns is needed.     

Effect of weight loss on lactate transporter expression in skeletal muscle of obese subjects.

The effects of weight loss on skeletal muscle lactate transporter [monocarboxylate transporter (MCT)] expression in obese subjects were investigated to better understand how lactate transporter metabolism is regulated in insulin-resistant states. Ten obese subjects underwent non-macronutrient-specific energy restriction for 15 wk. Anthropometric measurements and a needle biopsy of the vastus lateralis muscle before and after the weight loss program were performed. Enzymatic activity, fiber type distribution, and skeletal muscle MCT protein expression were measured. Muscle from nonobese control subjects was used for comparison of MCT levels. The program induced a weight loss of 9.2 +/- 1.6 kg. Compared with controls, muscle from obese subjects showed a strong tendency (P = 0.06) for elevated MCT4 expression (+69%) before the weight loss program. MCT4 expression decreased (-7%) following weight loss to reach levels that were not statistically different from control levels. There were no differences in MCT1 expression between controls and obese subjects before and after weight loss. A highly predictive regression model (R2 = 0.93), including waist circumference, citrate synthase activity, and percentage of type 1 fibers, was found to explain the highly variable MCT1 response to weight loss in the obese group. Therefore, in obesity, MCT1 expression appears linked both to changes in oxidative parameters and to changes in visceral adipose tissue content. The strong tendency for elevated expression of muscle MCT4 could reflect the need to release greater amounts of muscle lactate in the obese state, a situation that would be normalized with weight loss as indicated by decreased MCT4 levels.     

Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin or adiponectin multimeric complexes

It has been suggested that changes in adiponectin levels may contribute to improved insulin sensitivity in insulin-resistant individuals both after weight loss and after treatment with thiazolidinedione compounds. If this is correct, then changes in total circulating adiponectin and/or distribution of its multimeric complexes should coincide with improvements in insulin sensitivity after both interventions. To address this issue, fasting adiponectin concentrations and distribution of adiponectin complexes were measured in plasma samples in 24 insulin-resistant, nondiabetic subjects before and after 3-4 mo of treatment with either rosiglitazone or caloric restriction. The degree of insulin resistance in each group of 12 subjects was equal at baseline and improved to a similar extent ( approximately 30%) after each therapy. Whereas total adiponectin levels increased by nearly threefold and the relative amount of several higher molecular weight adiponectin complexes increased significantly in the rosiglitazone treatment group, there were no discernible changes in adiponectin levels or in the distribution between high or low molecular weight complexes in the weight loss group. These data indicate that, although changes in total adiponectin and several specific adiponectin complexes paralleled improvements in insulin resistance in thiazolidinedione-treated subjects, neither circulating adiponectin concentrations nor multimeric complexes changed in association with enhanced insulin sensitivity after moderate weight loss in 12 insulin-resistant, obese individuals.     

Treatment of Obese Non-Diabetic Patients with Phenformin. A Double-Blind Cross-Over Trial

The effect of 50 mg. of sustained release phenformin capsules administered twice daily was compared with a placebo as an aid to weight reduction in obese non-diabetic patients. Phenformin and placebo were administered alternately in two three-month periods.Weight loss on a 1,200-calorie diet was greater in the first three months than in the second three months regardless of treatment. There was no difference in weight loss between the phenformin and placebo groups in either the first or second three-month period. Serum cholesterol levels tended to fall in association with weight loss, but not apparently in relation to the size of the weight loss or to the treatment.