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OBJECTIVE: The aim of this study was to investigate glucose tolerance, glucagon response, and beta cell function during a 1-year maintenance period with either exercise, the glucagon-like peptide-1 receptor agonist liraglutide, or the combination after diet-induced weight loss.METHODS: In this randomized placebo-controlled trial, adults with obesity (BMI: 32-43 kg/m 2 ) without diabetes underwent an 8-week low-calorie diet (800 kcal/d) and were randomized to 52 weeks of aerobic exercise, liraglutide 3.0 mg/d, exercise and liraglutide combined, or placebo. Change in glucose and glucagon response to a 3-hour mixed meal test and disposition index, as a measure of beta cell function, were measured. RESULTS: A total of 195 participants were randomized. After 1 year of treatment, the combination group had decreased postprandial glucose response by -9% (95% CI: -14% to -3%; p = 0.002), improved beta cell function by 49% (95% CI: 16% to 93%; p = 0.002), and decreased glucagon response by -18% (95% CI: -34% to -3%; p = 0.024) compared with placebo. Compared with placebo, liraglutide alone improved postprandial glucose response by -7% (95% CI: -12% to -1%; p = 0.018), but not beta cell function or glucagon. Exercise alone had similar postprandial glucose response, beta cell function, and glucagon response as placebo.CONCLUSIONS: Only the combination of exercise and liraglutide improved glucose tolerance, beta cell function, and glucagon responses after weight loss.

Study Objectives Insufficient sleep may attenuate weight loss, but the role of sleep in weight loss maintenance is unknown. Since weight regain after weight loss remains a major obstacle in obesity treatment, we investigated whether insufficient sleep predicts weight regain during weight loss maintenance. Methods In a randomized, controlled, two-by-two factorial study, 195 adults with obesity completed an 8-week low-calorie diet and were randomly assigned to 1-year weight loss maintenance with or without exercise and liraglutide 3.0 mg/day or placebo. Sleep duration and quality were measured before and after the low-calorie diet and during weight maintenance using wrist-worn accelerometers (GENEActiv) and Pittsburgh Sleep Quality Index (PSQI). To test associations between insufficient sleep and weight regain, participants were stratified at randomization into subgroups according to sleep duration (5). Results After a diet-induced 13.1 kg weight loss, participants with short sleep duration at randomization regained 5.3 kg body weight (p = .0008) and had less reduction in body fat percentage compared with participants with normal sleep duration (p = .007) during the 1-year weight maintenance phase. Participants with poor sleep quality before the weight loss regained 3.5 kg body weight compared with good quality sleepers (p = .010). During the weight maintenance phase, participants undergoing liraglutide treatment displayed increased sleep duration compared with placebo after 26 weeks (5 vs. −15 min/night) but not after 1 year. Participants undergoing exercise treatment preserved the sleep quality improvements attained from the initial weight loss. Conclusions Short sleep duration or poor sleep quality was associated with weight regain after weight loss in adults with obesity.

Insufficient sleep may attenuate weight loss, but the role of sleep in weight loss maintenance is unknown. Since weight regain after weight loss remains a major obstacle in obesity treatment, we investigated whether insufficient sleep predicts weight regain during weight loss maintenance.In a randomized, controlled, two-by-two factorial study, 195 adults with obesity completed an eight-week low-calorie diet and were randomly assigned to one-year weight loss maintenance with or without exercise and liraglutide 3.0mg/day or placebo. Sleep duration and quality were measured before and after the low-calorie diet and during weight maintenance using wrist-worn accelerometers (GENEActiv) and Pittsburgh Sleep Quality Index. To test associations between insufficient sleep and weight regain, participants were stratified at randomization into subgroups according to sleep duration (/≥6 h/night) or sleep quality (PSQI score ≤/5).After a diet-induced 13.1 kg weight loss, participants with short sleep duration at randomization regained 5.3 kg body weight (P=.0008) and had less reduction in body fat percentage compared with participants with normal sleep duration (P=.007) during the one-year weight maintenance phase. Participants with poor sleep quality before the weight loss regained 3.5 kg body weight compared with good quality sleepers (P=.010). During the weight maintenance phase, participants undergoing liraglutide treatment displayed increased sleep duration compared with placebo after 26 weeks (5 vs. -15 min/night) but not after one year. Participants undergoing exercise treatment preserved the sleep quality improvements attained from the initial weight loss.Short sleep duration or poor sleep quality was associated with weight regain after weight loss in adults with obesity.

STUDY QUESTION Does diet-induced weight loss improve semen parameters, and are these possible improvements maintained with sustained weight loss? SUMMARY ANSWER An 8-week low-calorie diet-induced weight loss was associated with improved sperm concentration and sperm count, which were maintained after 1 year in men who maintained weight loss. WHAT IS KNOWN ALREADY Obesity is associated with impaired semen quality. Weight loss improves metabolic health in obesity, but there is a lack of knowledge on the acute and long-term effects of weight loss on semen parameters. STUDY DESIGN, SIZE, DURATION This is a substudy of men with obesity enrolled in a randomized, controlled, double-blinded trial (the S-LITE trial). The trial was conducted between August 2016 and November 2019. A total of 56 men were included in the study and assigned to an initial 8-week low-calorie diet (800 kcal/day) followed by randomization to 52 weeks of either: placebo and habitual activity (placebo), exercise training and placebo (exercise), the Glucagon Like Peptide 1 (GLP-1) analogue liraglutide and habitual activity (liraglutide) or liraglutide in combination with exercise training (combination). PARTICIPANTS/MATERIALS, SETTING, METHODS Inclusion criteria were men who delivered semen samples, 18 to 65 years of age, and a body mass index between 32 and 43 kg/m2, but otherwise healthy. The study was carried out at Hvidovre Hospital and at the University of Copenhagen, and the participants were from the Greater Copenhagen Area. We assessed semen parameters and anthropometrics and collected blood samples before (T0), after the 8-week low-calorie dietary intervention (T1), and after 52 weeks (T2). MAIN RESULTS AND THE ROLE OF CHANCE The men lost on average 16.5 kg (95% CI: 15.2–17.8) body weight during the low-calorie diet, which increased sperm concentration 1.49-fold (95% CI: 1.18–1.88, P LIMITATIONS, REASONS FOR CAUTION The S-LITE trial was a randomized controlled trial of weight loss maintenance. Analysis of semen was preregistered to explore the effects of weight loss and weight loss maintenance on semen parameters, but definite inferences cannot be made. WIDER IMPLICATIONS OF THE FINDINGS This study shows that sperm concentration and sperm count were improved after a diet-induced weight loss in men with obesity. Our findings indicate that either or both liraglutide and exercise as weight maintenance strategies may be used to maintain the improvements in sperm concentration and count. STUDY FUNDING/COMPETING INTEREST(S) This work is supported by an excellence grant from the Novo Nordisk Foundation (NNF16OC0019968), a Challenge Programme Grant from the Novo Nordisk Foundation (NNF18OC0033754) and a grant from Helsefonden. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). Saxenda (liraglutide) and placebo pens were provided by Novo Nordisk. Cambridge Weight Plan diet products for the 8-week low-calorie diet were provided by Cambridge Weight Plan. E.A.: shareholder, employee of ExSeed Health Ltd. Grant Recipient from ExSeed Health Ltd and listed on Patents planned, issued or pending with ExSeed Health Ltd; J.J.H.: consultant for Eli Lilly A/S and Novo Nordisk A/S. Lecture fees for Novo Nordisk A/S. Listed on Patents planned, issued or pending with the University of Copenhagen, Advocacy group for Antag Therapeutics and Bainan Biotech; S.M.: lecture fees for Novo Nordisk A/S. Recipient of Support for attending meetings from Novo Nordisk A/S. Advisory boards of Novo Nordisk A/S; Sanofi Aventis and Merck Sharp & Dohme. S.S.T.: research grant recipient Novo Nordisk. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER The trial was approved by the Ethical Committee of the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency (EudraCT Number: 2015-005585-32). ClinicalTrials.gov identifier (NCT number): NCT04122716. TRIAL REGISTRATION DATE 11 May 2016. DATE OF FIRST PATIENT’S ENROLMENT August 2016.

Weight regain after weight loss is a major problem in the treatment of persons with obesity.In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group.A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).

Background Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. Objectives The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. Methods A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. Results Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. Conclusions These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183 )

Introduction: Improved cardiorespiratory fitness (CRF) is associated with reduced mortality. Each metabolic equivalent (MET) increase in CRF is associated with 10-25 % improvements in survival. The aim was to explore changes in fitness during weight maintenance with the glucagon-like peptide-1 receptor agonist liraglutide and/or exercise. Methods: Women and men with obesity (18-65 years, BMI 32-43 kg/m2) who achieved ≥ 5 % weight loss during an 8-week very low-calorie diet (VLCD) were randomized to (1) liraglutide 3 mg/day (LIRA), (2) exercise 150 min/week + placebo (EX), (3) exercise 150 min/week + liraglutide 3 mg/day (LIRA+EX), or (4) placebo (PLA) for one year. CRF was measured as peak oxygen consumption using indirect calorimetry during an incremental bicycle test. Physical functioning was evaluated as time to ascend/descend an 11-step stairway twice. Results: A total of 215 participants were included. Changes in fitness after VLCD and 1-year weight maintenance program are presented in Table 1. Conclusion: Exercise alone and in combination with liraglutide exert clinically relevant improvements in cardiorespiratory fitness and improve physical functioning. Thus, adding liraglutide does not interfere with the ability to improve fitness with exercise, supporting the combined use in weight maintenance. Disclosure S. Jensen: None. C. Janus: Research Support; Spouse/Partner; Mercodia, Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Research Support; Spouse/Partner; Novo Nordisk Foundation. Speaker’s Bureau; Spouse/Partner; Merck Sharp < Dohme Corp. J.R. Lundgren: None. C.R. Juhl: None. M.B. Blond: None. B. Stallknecht: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp < Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp < Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. Funding Novo Nordisk Foundation (NNF16OC0019968, NNF15SA0018486); University of Copenhagen; Helsefonden; Danish Diabetes Academy

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide and risk factors include obesity, physical inactivity, hypertension, and dyslipidemia. Our aim was to investigate changes in CVD risk factors after an initial weight loss followed by 1 year of treatment with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide and/or exercise. Method: The trial included 215 individuals with obesity (BMI 36.6 kg/m2, age 42 years). This was a double-blinded trial with an initial 8-week weight loss phase (800 kcal/day) and subsequent randomization (n=195) to placebo, placebo + exercise (150 min/week), liraglutide 3.0 mg/day or liraglutide 3.0 mg/day + exercise (150 min/week) for 1 year. Trial identifier: NCT 04122716 Results: The table shows changes in CVD risk factors after an 8-week weight loss phase followed by 1 year of treatment. Conclusion: A 13 kg weight loss acutely improved all CVD risk factors. With liraglutide and exercise treatment combined, body weight was further reduced. Fasting glucose and HbA1c were additionally improved with the combined treatments compared to placebo and exercise alone. Interestingly, when exercise was added to liraglutide treatment there was no increase in resting heart rate as opposed to liraglutide treatment alone. Disclosure J.R. Lundgren: None. E. Bladbjerg: None. C. Janus: Research Support; Spouse/Partner; Mercodia, Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Research Support; Spouse/Partner; Novo Nordisk Foundation. Speaker’s Bureau; Spouse/Partner; Merck Sharp & Dohme Corp. L. Gliemann: None. L.M. Olsen: None. C.R. Juhl: None. S.B.K. Jensen: None. R. Thirumathyam: Research Support; Self; Boehringer Ingelheim International GmbH. R.M. Christensen: None. A. Andresen: None. B. Stallknecht: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. J.D. Hove: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C. Antoniades: Board Member; Self; Caristo Diagnostics. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. Funding Novo Nordisk Foundation (NNF16OC0019968, NNF15SA0018486); University of Copenhagen; Helsefonden; Danish Diabetes Academy

Background: Physical inactivity and obesity are associated with short sleep duration and poor quality of sleep. The aim was to explore the impact on sleep habits of a diet-induced weight loss followed by three weight maintenance strategies: Exercise training, GLP-1 receptor agonist (liraglutide), and the combination of both treatments. Methods: Exploratory analyses from the randomized weight maintenance trial S-LITE (NCT 04122716). Participants with obesity (BMI 32-43 kg/m2) were included to 8 weeks on a very low-calorie diet (VLCD) of 800 kcal/day followed by 1-year of treatment with 1) exercise 150 min/week + placebo (EX), 2) liraglutide 3 mg/day (LIRA), 3) liraglutide 3 mg/day + exercise 150 min/week (LIRA + EX), or 4) placebo (PLA). Sleep duration and sleep efficiency (sleep time/time in bed * 100) were measured by 7-day wrist-worn accelerometry (GENEactiv) at inclusion, after weight loss at randomization, and after the intervention. Self-reported sleep quality was assessed by the validated Pittsburgh Sleep Questionnaire Index (PSQI) with higher scores denoting worse sleep. Results: The VLCD resulted in a mean weight loss of 13.1 kg in 195 participants (64% women, mean (SD) age 42 (12) yrs) and improved sleep: Longer sleep duration (14.5 min/night, 95% CI: 6.9 to 22.2), higher sleep efficiency (2.1%, 1.2 to 3.0), and improved self-rated sleep quality (-0.76, -1.16 to -0.37). After one year, improvements in sleep quality were sustained only in the exercise groups despite all three intervention groups having maintained or further reduced body weight. Higher sleep efficiency was sustained in all four groups. Conclusion: A large, rapid diet-induced weight loss exerts improvements in sleep duration and self-reported sleep quality; however, only weight maintenance including exercise sustains self-reported sleep quality for one year. Disclosure C. Janus: Research Support; Spouse/Partner; Mercodia, Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Research Support; Spouse/Partner; Novo Nordisk Foundation. Speaker’s Bureau; Spouse/Partner; Merck Sharp & Dohme Corp. S. Jensen: None. J.R. Lundgren: None. C. Juhl: None. L.M. Olsen: None. B. Stallknecht: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. Funding Novo Nordisk Foundation (NNF16OC0019968); Novo Nordisk Center for Metabolic Research; Helsefonden

Background: Weight loss decreases energy expenditure and increases appetite, leading to weight regain. Energy expenditure can be targeted with exercise, and appetite with the glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide.The objective was to investigate 1-year weight loss maintenance and change in body composition with liraglutide, exercise, and the combination in individuals with obesity after a very low-calorie diet (VLCD). Methods: Double-blinded, randomized placebo-controlled trial. Following 8-weeks of VLCD (800 kcal/day), inducing a body weight loss of ≥ 5%, the participants were randomized to 1-year of treatment with 1) liraglutide 3.0 mg/day (LIRA), 2) exercise 150 min/week + placebo (EX), 3) exercise 150 min/week + liraglutide 3.0 mg/day (LIRA + EX), or 4) placebo (PLA). Results: Participants with obesity were included (n = 215, 64% women, age 42 years (IQR 30.7 to 51.9), BMI 36.6 kg/m2 (34.5 to 39.2)). See Table 1 for all results. Conclusion: The combination of liraglutide and exercise was superior to placebo and exercise alone, and numerically better to liraglutide, in weight loss maintenance and further weight reduction. Fat percentage loss with the combination treatment was superior to liraglutide and exercise alone, supporting the combined treatment for healthy weight loss maintenance. Disclosure C. Janus: Research Support; Spouse/Partner; Mercodia, Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Research Support; Spouse/Partner; Novo Nordisk Foundation. Speaker’s Bureau; Spouse/Partner; Merck Sharp & Dohme Corp. J.R. Lundgren: None. S. Jensen: None. L.M. Olsen: None. C. Juhl: None. M.B. Blond: None. R.M. Christensen: None. K.N. Bojsen-Moller: None. M.S. Svane: None. T. Bandholm: Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J.B. Jensen: None. B. Stallknecht: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. Funding Novo Nordisk Foundation (NNF16OC0019968); Novo Nordisk Center for Metabolic Research; Helsefonden

Aim: The purpose of this study was to identify psychosocial determinants for maintaining weight loss. Methods: 42 obese individuals who achieved a 12% weight loss before entering a 52-week weight maintenance program were interviewed qualitatively. Psychosocial factors related to weight loss maintenance were identified in two contrasting groups: weight reducers and weight regainers. Groups were defined by health-relevant weight maintenance (additional weight loss > 3% at week 52, n = 9 versus weight gain > 3%, at week 52, n = 20). Results: Weight reducers reported structured meal patterns (p = 0.008), no comfort eating (p = 0.016) and less psychosocial stress (p = 0.04) compared to weight regainers. The ability to instrumentalize eating behavior emerged as an important factor (p = 0.007). Nutritional knowledge, motivation or exercise level did not differ between groups (p > 0.05). Conclusions: Successful weight loss maintenance was associated with an interplay between behavioral, affective and contextual changes. ‘Instrumentalization of eating behavior' seems to be an important element in long-term weight maintenance. Aim: The purpose of this study was to identify psychosocial determinants for maintaining weight loss. Methods: 42 obese individuals who achieved a 12% weight loss before entering a 52-week weight maintenance program were interviewed qualitatively. Psychosocial factors related to weight loss maintenance were identified in two contrasting groups: weight reducers and weight regainers. Groups were defined by health-relevant weight maintenance (additional weight loss > 3% at week 52, n = 9 versus weight gain > 3%, at week 52, n = 20). Results: Weight reducers reported structured meal patterns (p = 0.008), no comfort eating (p = 0.016) and less psychosocial stress (p = 0.04) compared to weight regainers. The ability to instrumentalize eating behavior emerged as an important factor (p = 0.007). Nutritional knowledge, motivation or exercise level did not differ between groups (p > 0.05). Conclusions: Successful weight loss maintenance was associated with an interplay between behavioral, affective and contextual changes. ‘Instrumentalization of eating behavior' seems to be an important element in long-term weight maintenance.

IntroductionThe success rate of weight loss maintenance is limited. Therefore, the purpose of this study is to investigate the maintenance of weight loss and immunometabolic health outcomes after diet-induced weight loss followed by 1-year treatment with a glucagon-like peptide-1 receptor agonist (liraglutide), physical exercise or the combination of both treatments as compared with placebo in individuals with obesity.Methods and analysisThis is an investigator-initiated, randomised, placebo-controlled, parallel group trial. We will enrol expectedly 200 women and men (age 18–65 years) with obesity (body mass index 32–43 kg/m2) to adhere to a very low-calorie diet (800 kcal/day) for 8 weeks in order to lose at least 5% of body weight. Subsequently, participants will be randomised in a 1:1:1:1 ratio to one of four study groups for 52 weeks: (1) placebo, (2) exercise 150 min/week+placebo, (3) liraglutide 3.0 mg/day and (4) exercise 150 min/week+liraglutide 3.0 mg/day. The primary endpoint is change in body weight from randomisation to end-of-treatment.Ethics and disseminationThe trial has been approved by the ethical committee of the Capital Region of Denmark and the Danish Medicines Agency. The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.Trial registration number2015-005585-32

ObjectiveThe hormones glucagon-like peptide 1 (GLP-1), peptide YY3-36(PYY3–36), ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon have all been implicated in the pathogenesis of obesity. However, it is unknown whether they exhibit adaptive changes with respect to postprandial secretion to a sustained weight loss.DesignThe study was designed as a longitudinal prospective intervention study with data obtained at baseline, after 8 weeks of weight loss and 1 year after weight loss.MethodsTwenty healthy obese individuals obtained a 13% weight loss by adhering to an 8-week very low-calorie diet (800kcal/day). After weight loss, participants entered a 52-week weight maintenance protocol. Plasma levels of GLP-1, PYY3–36, ghrelin, GIP and glucagon during a 600-kcal meal were measured before weight loss, after weight loss and after 1 year of weight maintenance. Area under the curve (AUC) was calculated as total AUC (tAUC) and incremental AUC (iAUC).ResultsWeight loss was successfully maintained for 52 weeks. iAUC for GLP-1 increased by 44% after weight loss (PP=0.0001). iAUC for PYY3–36increased by 74% after weight loss (PP=0.02). tAUC for ghrelin increased by 23% after weight loss (PP=0.005). iAUC for GIP increased by 36% after weight loss (P=0.001), but returned to before weight loss levels at week 52. Glucagon levels were unaffected by weight loss.ConclusionsMeal responses of GLP-1 and PYY3–36remained increased 1 year after weight maintenance, whereas ghrelin and GIP reverted toward before-weight loss values. Thus, an increase in appetite inhibitory mechanisms and a partly decrease in appetite-stimulating mechanisms appear to contribute to successful long-term weight loss maintenance.

Context: Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. Objective: To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. Design: Randomized control study. Setting: Outpatient research hospital clinic. Participants: Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m2 and age 46 ± 2 years. Intervention: After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. Main Outcome Measures: Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)...

Background: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. Methods: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. Results: Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml−1 (−3.0 (95% confidence interval (CI)=−0.5 to −5.5)), P

Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill‐defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry‐based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual‐specific protein levels with wide‐ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte‐secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of −16% and +37%, respectively (P

Increased levels of circulating branched chain amino acids (BCAAs), as well as phenylalanine, and tyrosine have been suggested to be involved in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unknown how these metabolites are affected by weight loss, and during weight-maintaining treatment with glucagon-like peptide-1 receptor agonist (GLP-1 RA). We aimed to characterize changes in metabolites related to protein turnover and glycolysis after a weight loss intervention followed by long term weight maintenance with/without GLP-1 RA. Fifty-eight obese individuals underwent a diet-induced 12 % body weight loss during 8 weeks. Participants were randomized to weight maintenance with or without administration of the GLP-1 RA liraglutide (1.2 mg/day) for 52 weeks. Metabolomic profiling by high-throughput proton nuclear magnetic resonance spectroscopy was used for quantification of metabolites. The weight loss was maintained in both groups and was associated with 9–20 % decreases in plasma concentrations of alanine, phenylalanine, histidine, tyrosine and the BCAAs leucine, isoleucine and valine (p

Obesity is associated with increased all-cause mortality, but weight loss may not decrease cardiovascular events. In fact, very low calorie diets have been linked to arrhythmias and sudden death. The QT interval is the standard marker for cardiac repolarization, but T-wave morphology analysis has been suggested as a more sensitive method to identify changes in cardiac repolarization. We examined the effect of a major and rapid weight loss on T-wave morphology.Twenty-six individuals had electrocardiograms (ECG) taken before and after eight weeks of weight loss intervention along with plasma measurements of fasting glucose, HbA1c, and potassium. For assessment of cardiac repolarization changes, T-wave Morphology Combination Score (MCS) and ECG intervals: RR, PR, QT, QTcF (Fridericia-corrected QT-interval), and QRS duration were derived. The participants lost on average 13.4% of their bodyweight. MCS, QRS, and RR intervals increased at week 8 (p0.01), while QTcF and PR intervals were unaffected. Fasting plasma glucose (p0.001) and HbA1c both decreased at week 8 (p10(-5)), while plasma potassium was unchanged. MCS but not QTcF was negatively correlated with HbA1c (p0.001) and fasting plasma glucose (p0.01).Rapid weight loss induces changes in cardiac repolarization. Monitoring of MCS during calorie restriction makes it possible to detect repolarization changes with higher discriminative power than the QT-interval during major rapid weight loss interventions. MCS was correlated with decreased HbA1c. Thus, sustained low blood glucose levels may contribute to repolarization changes.