Adipose tissue morphology predicts improved insulin sensitivity following moderate or pronounced weight loss.

BACKGROUND: Cross-sectional studies show that white adipose tissue hypertrophy (few, large adipocytes), in contrast to hyperplasia (many, small adipocytes), associates with insulin resistance and increased risk of developing type 2 diabetes. We investigated if baseline adipose cellularity could predict improvements in insulin sensitivity following weight loss. METHODS: Plasma samples and subcutaneous abdominal adipose biopsies were examined in 100 overweight or obese individuals before and 10 weeks after a hypocaloric diet (7±3% weight loss) and in 61 obese subjects before and 2 years after gastric by-pass surgery (33±9% weight loss). The degree of adipose tissue hypertrophy or hyperplasia (termed the morphology value) in each individual was calculated on the basis of the relationship between fat cell volume and total fat mass. Insulin sensitivity was determined by homeostasis model assessment-estimated insulin resistance (HOMAIR). RESULTS: In both cohorts at baseline, subjects with hypertrophy displayed significantly higher fasting plasma insulin and HOMAIR values than subjects with hyperplasia (P<0.0001), despite similar total fat mass. Plasma insulin and HOMAIR were normalized in both cohorts following weight loss. The improvement (delta insulin or delta HOMAIR) was more pronounced in individuals with hypertrophy, irrespective of whether adipose morphology was used as a continuous (P=0.0002-0.027) or nominal variable (P=0.002-0.047). Absolute adipocyte size associated (although weaker than morphology) with HOMAIR improvement only in the surgery cohort. Anthropometric measures at baseline (fat mass, body mass index, waist-to-hip ratio or waist circumference) showed no significant association with delta insulin or delta HOMAIR. CONCLUSIONS: In contrast to anthropometric variables or fat cell size, subcutaneous adipose morphology predicts improvement in insulin sensitivity following both moderate and pronounced weight loss in overweight/obese subjects.

Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults.

BACKGROUND: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect. OBJECTIVE: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight. DESIGN: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058). SUBJECTS: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18-65 years, body mass index (BMI) 30-40 kg m(-2)) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively). RESULTS: The intention-to-treat population comprised 561 participants (n=90-98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m(-2) (mean±s.d.)). In year 1, more participants reported ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2-3.0 mg (17-38%) than with placebo or orlistat (both 4%, P⩽0.001). Most episodes occurred during dose escalation (weeks 1-6), with 'mild' or 'moderate' symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5-5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg. CONCLUSION: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.

Nocturnal blood pressure non-dipping is prevalent in severely obese, prepubertal and early pubertal children.

AIM: To investigate the prevalence of nocturnal blood pressure dipping among obese prepubertal and early pubertal children and to analyse the relationship between dipping and measures of insulin-glucose metabolism or sleep-disordered breathing. METHODS: We studied 76 obese children (41% girls) under clinical care, with an average age of 10.4 ± 1.7 and a body mass index Z-score (BMI Z-score) of 6.2 ± 1.6. We performed a 24-h ambulatory blood pressure measurement. Non-dipping was defined as a nocturnal blood pressure reduction of <10%. We calculated measures of insulin-glucose metabolism from the performed frequently sampled intravenous glucose-tolerance test and from fasting blood samples. Overnight sleep polygraph recordings were performed to assess sleep-disordered breathing. RESULTS: Forty-two percent of the children were systolic non-dippers, and 17% were diastolic non-dippers. There were no associations between systolic or diastolic dipping and measures of insulin-glucose metabolism after adjustments for BMI Z-score, gender and pubertal status. There were no associations between dipping and measures of sleep-disordered breathing. CONCLUSION: Nocturnal non-dipping was two times higher among severely obese, prepubertal and early pubertal children, compared to previous reports among children in general. There were no associations between nocturnal dipping and insulin-glucose metabolism or measures of sleep-disordered breathing in this group.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

OBJECTIVE: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. DESIGN: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. SUBJECTS: A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. RESULTS: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. CONCLUSION: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Increased physical activity in abdominally obese women through support for changed commuting habits: a randomized clinical trial.

BACKGROUND: Abdominally obese women can reduce their health risk through regular physical activity. There is, however, little evidence on the effectiveness of interventions that promote physical activity long-term, such as cycling and walking to and from work. METHODS: This intervention focused on physically active commuting (cycling and walking) in middle-aged (30-60 years), abdominally obese (waist circumference > or = 88 cm) women (n=120), recruited by newspaper advertisement. The intervention group was a moderate-intensity programme with physician meetings, physical activity prescriptions, group counselling and bicycles. The control group was a low-intensity group support programme with pedometers. We used a randomized, controlled, 2-armed design with 18 months duration and intention-to-treat analysis (data collection 2005-2006). Treatment success was defined as bicycling > or = 2 km/d (primary) or walking 10,000 steps per day (secondary). RESULTS: At baseline, mean (s.d.) age was 48.2 years (7.4), waist circumference 103.8 cm (7.8), walking 8471 steps per day (2646), bicycling 0 km per day. Attrition at 18 months was 10% for the intervention group and 25% in the control group (P=0.03). The intervention group was more likely to achieve treatment success for cycling than controls: 38.7 vs 8.9% (odds ratio (OR)=7.8 (95% confidence interval=4.0 to 15.0, P<0.001)), but with no difference for compliance with the walking recommendation: 45.7 vs 39.3% (OR=1.2 (95% CI=0.7 to 2.0, P=0.50)). Commuting by car and public transport were reduced by 34% (P<0.01) and 37% (P<0.001), respectively, with no differences between groups. Both groups attained similar waist reductions (-2.1 and -2.6 cm, P=0.72). CONCLUSIONS: Abdominally obese women can increase PA long-term through moderate-intensity behavioural support aimed at changing commuting habits.

Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans.

BACKGROUND: The A risk allele of rs9939609 of the fat mass- and obesity-associated gene (FTO) increases body fat mass. OBJECTIVE: To examine whether FTO rs9939609 affects obese individuals' response to a high-fat, low-carbohydrate (CHO) (HF) or low-fat, high-CHO (LF), hypo-energetic diet and whether the effect of the FTO variant depends on dietary fat and CHO content. DESIGN: In a 10-week, European, multi-centre dietary intervention study 771 obese women and men were randomized to either LF (20-25% of energy (%E) from fat, 60-65%E from CHO) or HF (40-45%E from fat, 40-45%E from CHO), hypo-energetic diet (measured resting metabolic rate multiplied by 1.3-600 kcal day(-1)). Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation as % of REE (FatOx), insulin release (HOMA-beta) and a surrogate measure of insulin resistance (HOMA-IR) were measured at baseline and after the intervention. In all, 764 individuals were genotyped for FTO rs9939609. RESULTS: For A-allele carriers the drop-out rate was higher on HF than LF diet (in AT, P=0.002; in AT/AA combined, P=0.003). Among those individuals completing the intervention, we found no effect of FTO rs9939609 genotype on Deltaweight, DeltaFM, DeltaFFM, DeltaWC or DeltaFatOx. However, participants with TT had a smaller reduction in REE on LF than on HF diet (75 kcal/24 h; interaction: P=0.0055). These individuals also showed the greatest reduction in HOMA-beta and HOMA-IR (interaction: P=0.0083 and P=0.047). CONCLUSION: The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways; carriers of the A allele on LF diet appear to have a lower risk for drop out, and TT individuals have a smaller decrease in REE and greater decrease in HOMA-beta and HOMA-IR on LF than on HF diet.

Sexual function in obese women: impact of lower urinary tract dysfunction.

OBJECTIVE: To assess the impact on sexual function attributed to lower urinary tract dysfunction in a female obese population. DESIGN: We performed a case-control study based on the registry of a university hospital obesity unit. A consecutive sample of women with body mass index(BMI) >or=30 (obese) was randomly matched by age, gender and residential county to control subjects using the computerized Register of the Total Population. Data were collected by a self-reported postal survey including the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). RESULTS: The questionnaire was completed and returned by 279/446 patients (62%) and 430/892 control subjects (48%). Obese women reported significantly lesser satisfaction with their sexual life, more frequent symptoms of urinary incontinence at intercourse, more often fear of urine leakage at intercourse, a higher tendency toward avoiding intercourse and more frequent feelings of guilt and disgust during intercourse (P<0.001). While considering sexual function in a subset of women with urge or stress urinary incontinence, the overall PISQ-12 scores were significantly lower in obese women compared to their age-matched nonobese controls for both the conditions (P<0.001). In an adjusted multivariate analysis, a BMI >30 was independently associated with a significantly increased risk for sexual dysfunction (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.1-2.9), as were symptoms of urge or stress urinary incontinence (OR, 2.0; 95% CI, 1.3-3.1 and OR, 2.6; 95% CI, 1.7-4.0), respectively. CONCLUSION: Urge and stress urinary incontinences are more common and have greater impact on sexual function in obese women.

Who will lose weight on sibutramine and orlistat? Psychological correlates for treatment success.

AIM: To study the associations between weight loss with sibutramine and orlistat with psychological aspects that may interact with patients' response to these drugs. METHODS: A total of 478 obese patients with a mean body mass index of 42 +/- 12 kg/m(2) gave self-reported, retrospective data on different types of previous weight loss treatments (sibutramine and orlistat, and Weight Watchers used as a control condition) including the amount of weight lost with these treatments, eating behaviour (Dutch Eating Behaviour Questionnaire) and personality (NEO Personality Inventory - Revised). RESULTS: Greater weight loss with sibutramine was associated with lower levels of restrained eating and higher levels of 'neuroticism', in particular 'anxiety' and 'depression'. Greater weight loss with orlistat was associated with aspects of the personality dimension 'conscientiousness' (e.g. 'order' and 'deliberation'). CONCLUSION: Sibutramine may exert its greatest effect in patients whose eating is a 'natural' response to hunger rather than regulated by cognitions and conscious controls. Patients with low levels of restraint could be more sensitive to the satiety-enhancing effect of sibutramine. They may be able to reduce their food intake without cognitive interference and/or start to control their eating most radically in response to enhanced satiety. Enhanced satiety may also help patients withstand a wish to eat triggered by psychological distress. Possible central nervous system effects on mood could also have reduced eating, which was related to distress. The administration regimen of orlistat is more demanding, requiring greater adherence. This can account for the finding that personality attributes such as conscientiousness are important for success.

Eating habits in relation to body fatness and gender in adolescents--results from the 'SWEDES' study.

OBJECTIVE: To investigate if eating habits among adolescents are related to body fatness and gender. DESIGN: Cross-sectional study. SETTING: Obesity Unit, Huddinge University Hospital, Sweden, 2001-2002. SUBJECTS: Two hundred and seventy-five girls and 199 boys, aged 16-17 years. METHOD: Questionnaires were used for dietary intake and meal frequency, BodPod for measuring body fatness (BF%). In all, 169 girls and 128 boys were classified as adequate reporters (AR) of energy intake, and were used in the dietary analyses. The whole sample was used in the meal frequency analyses. RESULTS: The correlation between reported energy intake and weight in the AR group was 0.23 (P<0.01) for girls and 0.36 for boys (P<0.001). The correlations were inverse or not significant in the whole sample. The following variables correlated significantly with a high BF% (r (s)=+/-0.2): a low intake of milk in both girls and boys, a high intake of fibre and alcohol and a low intake of sugar in girls and a low intake of breakfast cereals in boys. Those with regular breakfast habits had healthier food choices than others, but this was not related to BF%. Boys had more meals per day (4.9 vs 4.6, P=0.02), especially early in the morning and late at night, whereas girls reported a higher relative intake of light meals and fruit and a lower intake of milk than boys. CONCLUSIONS: A few associations between eating habits and body fatness were found, but without any obvious patterns. The true differences in eating habits between lean and overweight adolescents are probably very small.

Type 1 diabetic serum interferes with pancreatic beta-cell Ca2+-handling.

The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic beta-cell cytoplasmic free Ca(2+) concentration, [Ca(2+)](i), and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca(2+)](i) , upon depolarization, were measured in beta-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic beta-cell Ca(2+)-handling. This effect on beta-cell [Ca(2+)](i) could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca(2+)-handling may aggravate development of beta-cell destruction.

Prevalence of obesity in Sweden.

Although the prevalence of obesity in Sweden still is low in an international perspective, the development during the last decades is alarming in adults, adolescents and children alike. The prevalence of obesity [body mass index (BMI) > 30 kg m-2] in adults has doubled during the last two decades and is now approximately 10% in both men and women, according to estimates based on self-reported BMI from repeated random samples of the population. However, prevalence estimates based on measured BMI from the WHO MONICA study indicate that the self-reported data result in underestimates. In military conscripts, the prevalence of obesity (BMI > 30 kg m-2) almost quadrupled to 3.2% from 1971 to 1995, while the overweight fraction (BMI > 25 kg m-2) more than doubled to 16.3%. The development in younger age groups seems to be similar; the prevalence of overweight [International Obesity Task Force (IOTF)/Cole] in children aged 10 years in Gothenburg has doubled to 18% (2.9% obese) during the last decade, and similar figures have been reported in other studies. However, most reports on childhood overweight stem from the larger metropolitan areas, and hence may be underestimates because of the urban-rural influence on obesity-status. Recent data from non-urban areas in the northern part of Sweden estimate the prevalence of overweight (BMI > 20 kg m-2) in 10-year-olds to above 30%. In the most comprehensive study in children, including both rural and urban areas, BMI was measured among all children aged 10 years (n = 5517; 92.7% of the population) in the county of Ostergotland, and the prevalence of overweight (IOTF/Cole) was 22% in both boys and girls, of which 4% and 5% were obese respectively.

A comparison of effects of fish and beef protein on satiety in normal weight men.

BACKGROUND: Previous studies have indicated that fish protein may have a greater effect on satiety compared to other protein sources of animal origin. OBJECTIVE: To compare the effects of fish protein and beef protein meals on hunger and satiety. DESIGN: Twenty-three normal non-smoking, healthy males aged 20-32 years, body mass index 22.5+/-1.8 (s.d.) kg/m(2) participated in a study, with within-subjects design and 1 week between test days. In the morning of the test days, subjects received a standardized breakfast. Four hours after breakfast, subjects were served an iso-energetic protein-rich (40 energy % protein) lunch meal, consisting of either a fish protein dish or a beef protein dish. Four hours after the start of the lunch meals, an ad libitum standardized evening meal was served and the intake of food was measured. Appetite was rated by visual analogue scales (VAS) immediately before and after the meals, as well as every hour between the meals. After the evening meal until bedtime, subjects were asked to record in detail foods and drinks consumed. RESULTS: The repeated VAS-ratings of hunger, satiety and prospective consumption were modelled in a random effects model, taking pre-lunch VAS-ratings into account. After the fish meal, the point estimates were lower for hunger (-2+/-4.8), higher for satiety (8.7+/-6.0) and lower for prospective consumption (-4.9+/-4.7), but they did not reach statistical significance (P satiety=0.88; P hunger=0.15; P prospective=0.30). However, the energy intake at the evening meal displayed significant differences with subjects eating less after the fish protein lunch (2765 vs 3080 KJ, P<0.01) without feeling less satiated. No later energy compensation after the evening meal was found on the test day. CONCLUSION: Although no significant differences in VAS-ratings of satiety or hunger were detected, subjects displayed an 11% reduction in energy intake at the subsequent evening meal.

Influence of diffusion on models for nonequilibrium wetting.

It is shown that the critical properties of a recently studied model for nonequilibrium wetting are robust if one extends the dynamic rules by single-particle diffusion on terraces of the wetting layer. Examining the behavior at the critical point and along the phase transition line, we identify a special point in the phase diagram where detailed balance of the dynamical processes is partially broken.

The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling.

The increased expression and/or abnormal processing of the amyloid precursor protein (APP) is associated with the formation of amyloid plaques and cerebrovascular amyloid deposits, which are one of the major morphological hallmarks of Alzheimer's disease (AD). Among the processes regulating APP metabolism, the proteolytic cleavage of APP into amyloidogenic or nonamyloidogenic fragments is of special interest. The cleavage of the APP by the alpha-secretase within the beta-amyloid sequence generates nonamyloidogenic C-terminal APP fragments and soluble APPs alpha, which has neurotrophic and neuroprotective activities. Proteolytic processing of APP by beta-secretase, on the other hand, exposes the N-terminus of beta-amyloid, which is liberated after gamma-secretase cleavage at the variable amyloid C-terminus. The resulting 39-43 amino acid beta-amyloid may be neurotoxic and disrupt neuronal connectivity after its accumulation in senile plaques. In this review, we discuss evidence derived from in vitro experiments, suggesting that the stimulation of protein kinase C (PKC)-coupled M1/M3 muscarinic acetylcholine receptors increases the nonamyloidogenic, secretory pathway of APP processing. It has also been shown in animal models that under conditions of reduced M1/M3 muscarinic acetylcholine receptor stimulation the secretory pathway of APP processing is inhibited and that constitutive upregulation of M1/M3-associated PKC increases APP secretion. Thus, the cortical cholinergic hypoactivity characteristic of AD may inhibit the nonamyloidogenic APP processing pathway and lead to increased beta-amyloid generation. It has been shown in vitro that nerve growth factor (NGF)-associated signaling also influences the expression and catabolism of APP. Recent experiments with NGF-responsive cells revealed a specific role for the high-affinity NGF receptor, TrkA, in the increases in secretory APP processing and a role for the low-affinity neurotrophin receptor, p75NTR, in the transcriptional regulation of APP. Therefore, treatments with NGF could ameliorate cortical cholinergic dysfunction in AD. These findings may influence the design of therapeutic strategies aimed at stimulating cholinergic function and at increasing nonamyloidogenic APP processing without elevating APP expression.

Early Changes in Hippocampal Neurogenesis in Transgenic Mouse Models for Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the Western world and is characterized by a progressive loss of cognitive functions leading to dementia. One major histopathological hallmark of AD is the formation of amyloid-beta plaques, which is reproduced in numerous transgenic animal models overexpressing pathogenic forms of amyloid precursor protein (APP). In human AD and in transgenic amyloid plaque mouse models, several studies report altered rates of adult neurogenesis, i.e. the formation of new neurons from neural stem and progenitor cells, and impaired neurogenesis has also been attributed to contribute to the cognitive decline in AD. So far, changes in neurogenesis have largely been considered to be a consequence of the plaque pathology. Therefore, possible alterations in neurogenesis before plaque formation or in prodromal AD have been largely ignored. Here, we analysed adult hippocampal neurogenesis in amyloidogenic mouse models of AD at different points before and during plaque progression. We found prominent alterations of hippocampal neurogenesis before plaque formation. Survival of newly generated cells and the production of new neurons were already compromised at this stage. Moreover and surprisingly, proliferation of doublecortin (DCX) expressing neuroblasts was significantly and specifically elevated during the pre-plaque stage in the APP-PS1 model, while the Nestin-expressing stem cell population was unaffected. In summary, changes in neurogenesis are evident already before plaque deposition and might contribute to well-known early hippocampal dysfunctions in prodromal AD such as hippocampal overactivity.

Who succeeds in maintaining weight loss? A conceptual review of factors associated with weight loss maintenance and weight regain.

Weight loss is difficult to achieve and maintaining the weight loss is an even greater challenge. The identification of factors associated with weight loss maintenance can enhance our understanding for the behaviours and prerequisites that are crucial in sustaining a lowered body weight. In this paper we have reviewed the literature on factors associated with weight loss maintenance and weight regain. We have used a definition of weight maintenance implying intentional weight loss that has subsequently been maintained for at least 6 months. According to our review, successful weight maintenance is associated with more initial weight loss, reaching a self-determined goal weight, having a physically active lifestyle, a regular meal rhythm including breakfast and healthier eating, control of over-eating and self-monitoring of behaviours. Weight maintenance is further associated with an internal motivation to lose weight, social support, better coping strategies and ability to handle life stress, self-efficacy, autonomy, assuming responsibility in life, and overall more psychological strength and stability. Factors that may pose a risk for weight regain include a history of weight cycling, disinhibited eating, binge eating, more hunger, eating in response to negative emotions and stress, and more passive reactions to problems.

Evidence for a major role of skeletal muscle lipolysis in the regulation of lipid oxidation during caloric restriction in vivo.

A lipolytic process in skeletal muscle has recently been demonstrated. However, the physiological importance of this process is unknown. We investigated the role of skeletal muscle lipolysis for lipid utilization during caloric restriction in eight obese women before and after 11 days of very low-calorie diet (VLCD) (2.2 MJ per day). Subjects were studied with indirect calorimetry and microdialysis of skeletal muscle and adipose tissue in order to analyze substrate utilization and glycerol (lipolysis index) in connection with a two-step euglycemic-hyperinsulinemic (12 and 80 mU/m(2). min) clamp. Local blood flow rates in the two tissues were determined with (133)Xe-clearance. Circulating free fatty acids and glycerol decreased to a similar extent during insulin infusion before and during VLCD, and there was a less marked insulin-induced reduction in lipid oxidation during VLCD. Adipose tissue glycerol release was hampered by insulin infusion to the same extent ( approximately 40%) before and during VLCD. Skeletal muscle glycerol release was not influenced by insulin before VLCD. However, during VLCD insulin caused a marked (fivefold) (P < 0.01) increase in skeletal muscle glycerol release. The effect was accompanied by a fourfold stimulation of skeletal muscle blood flow (P < 0.01). We propose that, during short-term caloric restriction, the reduced ability of insulin to inhibit lipids, despite a preserved antilipolytic effect of the hormone in adipose tissue, is caused by an augmented mobilization of fat from skeletal muscle, and that a physiological role of muscle lipolysis provides a local source of fatty acids.

Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue.

Some animal models suggest that tumor necrosis factor (TNF)-alpha is a key component in obesity-linked insulin resistance because it inhibits insulin receptor signaling and glucose transport in insulin-sensitive tissues. However, in vivo data in humans have given conflicting results regarding the relationship between circulating TNF-alpha levels and insulin sensitivity. In the present study, the potential local role of TNF-alpha on insulin action in human subcutaneous adipose tissue was studied in 42 obese women (BMI 39+/-10 kg/m2). We found a strong inverse correlation between adipose TNF-alpha secretion and maximum insulin-stimulated glucose transport in adipocytes that was independent of fat cell volume, age, and BMI (P < 0.001, r = 0.58). As much as one-third of the variation in insulin-stimulated glucose transport could be accounted for by variations in TNF-alpha secretion. There was no significant correlation (r = 0.11) between secretion of adipose plasminogen activator inhibitor 1 and glucose transport. Furthermore, subcutaneous adipose tissue of 4 obese women (BMI 40+/-4) incubated with TNF-A for 24 h showed a one-third concentration-dependent inhibition of insulin-stimulated glucose transport (P < 0.01). In conclusion, adipose TNF-alpha may be an important specific and local factor in adipose tissue that influences the ability of insulin to stimulate glucose transport in human fat cells, at least in obese women.

Allergic laryngospasm on initiating oral propranolol therapy.

A 29-year-old woman suffered acute laryngospasm on taking the initial dose of propranolol hydrocholoride for the treatment of hypertension associated with a hyperdynamic circulatory state. Hypersensitivity to the tartrazine additive used as a stabilizing agent in oral propranolol appeared the likely cause of anaphylaxis, although a direct hypersensitivity to propranolol itself could not be excluded.

In Vivo Longitudinal Monitoring of Changes in the Corpus Callosum Integrity During Disease Progression in a Mouse Model of Alzheimer's Disease.

The corpus callosum is the largest commissural fiber connecting left and right hemisphere of the brain. Emerging evidence suggests that a variety of abnormalities detected in the microstructure of this white matter fiber can be an early event in Alzheimer's disease (AD) pathology. However, little is known about tissue characteristics of these abnormalities and how these abnormalities evolve during AD progression. In this study, we measured in vivo magnetic resonance transverse relaxation times (T2) to longitudinally monitor changes in tissue integrity and abnormalities related to myelination and demyelination processes in corpus callosum of AD mouse models. The most striking finding of our study was a significant elongation of T2 values in the corpus callosum at 10, 14, 16 and 18 months of age compared to age-matched wild-type mice. In contrast, the gray matter regions surrounding the corpus callosum, such as the cortex and hippocampus, showed a significant T2 decrease compared to wild-type mice. Histological analyses clearly revealed demyelination, gliosis and amyloid-plaque deposition in the corpus callosum. Our results suggest that demyelinating and inflammatory pathology may result in prolonged relaxation time during AD progression. To our knowledge, this is the first in vivo T2 study assessing the microstructural changes with age in the corpus callosum of the Tg2576 mouse model and it demonstrates the application of T2 measurement to noninvasively detect tissue integrity of the corpus callosum, which can be an early event in disease progression.