Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids.

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.

Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial.

Importance: A major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss. Objective: To investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined. Design, Setting, and Participants: This study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision. Interventions: After an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo. Main Outcomes and Measures: The primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population. Results: In total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, -0.006 g/cm2; 95% CI, -0.017 to 0.004 g/cm2; P = .24) and lumbar spine (-0.010 g/cm2; 95% CI, -0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, -0.013 g/cm2; 95% CI, -0.024 to -0.001 g/cm2; P = .03) and spine (mean change, -0.016 g/cm2; 95% CI, -0.032 to -0.001 g/cm2; P = .04). Conclusions and Relevance: In this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss. Trial Registration: EudraCT: 2015-005585-32.

Facilitators and barriers for implementing the PALS school-wide positive behavior support model in a Swedish municipality: A focus group study.

A research-supported model to support schools' prevention of behavior problems and promotion of a positive school climate is school-wide positive behavior support (SW-PBS), in Scandinavia adapted into "positive behavior, interactions and learning environment in school" (PALS). Facilitators and barriers for achieving and sustaining a full implementation of PALS in a Swedish primary school context have not previously been studied. The purpose of this study was to explore school staff and administrators' experiences of implementing PALS in a municipal school district in the western region of Sweden. Using a qualitative focus group design, staff with roles in the implementation and school administrators (N = 22) representing 12 schools were asked about their experiences regarding facilitators and barriers for implementing PALS. Data were analyzed using qualitative content analyses involving a combination of inductive (data-driven) and deductive (theory-driven) approaches. In the deductive, final step, the inductively derived categories were associated with the Normalization process theory core constructs coherence, cognitive participation, collective action and reflexive monitoring. The analysis resulted in nine categories in which both facilitators and barriers were identified: alignment with school mission and values; building and strengthening relationships; shared staff engagement; administrators' commitment and leadership; support and resources for adopting PALS; changed experiences of PALS work over time; positive feedback sustains motivation; learning for quality improvement; and staff continuity throughout implementation. Findings indicate that staff and administrators experienced the implementation as predominantly positive, that PALS provides a structure for relationship-based work, and fits particularly well in primary school contexts. The facilitators and barriers identified provide valuable knowledge that can inform sustainable implementations of PALS in similar contexts.

Perceptions of facilitators, barriers and solutions when preparing to implement a home visiting program in Sweden: a mixed-methods study.

Background: Although there is growing awareness that early childhood development programs are important for a sustainable society, there is a knowledge gap about how to implement such programs. Successful implementation requires attention to implementation drivers (competency, organization, and leadership) during all phases of the implementation. The purpose of this study was to describe cross-sectoral operational workgroups' perceptions of facilitators, barriers and solutions related to implementation drivers in the preparationphase of implementing an evidence-based early childhood home visiting program. Methods: Quantitative and qualitative data were collected from twenty-four participants, divided into 5 groups, during implementation planning workshops. The workshops were guided by a structured method informed by the principles of Motivational Interviewing and within a framework of implementation drivers. Groups sorted cards with statements representing implementation drivers according to perceptions of facilitators and barriers, and percentages were calculated for each type of implementation determinant, for each type of driver. The groups discussed their card sorting and wrote action plans to address barriers, yielding documentation that was analyzed using deductive qualitative content analysis. Results: A mixed-methods analysis resulted identification of facilitators, barriers, unknowns and solutions in two to three subcategories under each main category of implementation driver. A competent and confident workforce, and enthusiasm and commitment were key facilitators. Key barriers were unclear roles and responsibilities, and insufficient articulation of local vision and goals. Many factors were described as yet unknown. Specific solutions were generated to support the implementation. Conclusions: Our study furthers the scientific understanding of how to take evidence-based early childhood programs from research to practice within an implementation drivers framework. Facilitators, barriers and solutions in key areas during the preparation phase were identified with the help of a novel tool. The results provide useful knowledge for decision makers and organizations preparing similar initiatives in communities striving to attain sustainable development goals.

Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial.

Background: New obesity medications result in large weight losses. However, long-term adherence in a real-world setting is challenging, and termination of obesity medication results in weight regain towards pre-treatment body weight. Therefore, we investigated whether weight loss and improved body composition are sustained better at 1 year after termination of active treatment with glucagon-like peptide-1 (GLP-1) receptor agonist, supervised exercise program, or both combined for 1 year. Methods: We conducted a post-treatment study in extension of a randomised, controlled trial in Copenhagen. Adults with obesity (aged 18-65 years and initial body mass index 32-43 kg/m2) completed an eight-week low-calorie diet-induced weight loss of 13.1 kg (week -8 to 0) and were randomly allocated (1:1:1:1) to one-year weight loss maintenance (week 0-52) with either supervised exercise, the GLP-1 receptor agonist once-daily subcutaneous liraglutide 3.0 mg, the combination of exercise and liraglutide, or placebo. 166 Participants completed the weight loss maintenance phase. All randomised participants were invited to participate in the post-treatment study with outcome assessments one year after treatment termination, at week 104. The primary outcome of the post-treatment assessment was change in body weight from after the initial weight loss (at randomisation, week 0) to one year after treatment termination (week 104) in the intention-to-treat population. The secondary outcome was change in body-fat percentage (week 0-104). The study is registered with EudraCT, 2015-005585-32, and with ClinicalTrials.gov, NCT04122716. Findings: Between Dec 17, 2018, and Dec 17, 2020, 109 participants attended the post-treatment study. From randomisation to one year after termination of combined exercise and liraglutide treatment (week 0-104), participants had reduced body weight (-5.1 kg [95% CI -10.0; -0.2]; P = 0.040) and body-fat percentage (-2.3%-points [-4.3 to -0.3]; P = 0.026) compared with after termination of liraglutide alone. More participants who had previously received combination treatment maintained a weight loss of at least 10% of initial body weight one year after treatment termination (week -8 to 104) compared with participants who had previously received placebo (odds ratio [OR] 7.2 [2.4; 21.3]) and liraglutide (OR 4.2 [1.6; 10.8]). More participants who had previously received supervised exercise maintained a weight loss of at least 10% compared with placebo (OR 3.7 [1.2; 11.1]). During the year after termination of treatment (week 52-104), weight regain was 6.0 kg [2.1; 10.0] larger after termination of liraglutide compared with after termination of supervised exercise and 2.5 kg [-1.5 to 6.5] compared with after termination of combination treatment. Interpretation: The addition of supervised exercise to obesity pharmacotherapy seems to improve healthy weight maintenance after treatment termination compared with treatment termination of obesity pharmacotherapy alone. Body weight and body composition were maintained one year after termination of supervised exercise, in contrast to weight regain after termination of treatment with obesity pharmacotherapy alone. Funding: Helsefonden and the Novo Nordisk Foundation.

Swedish parents' satisfaction and experience of facilitators and barriers with Family Check-up: A mixed methods study.

Family Check-up (FCU) was introduced in Sweden more than a decade ago. Little is known about what parents experience as FCU's key mechanisms leading to changes in parenting. The aim of this study was to investigate Swedish parents' satisfaction with FCU, and their experiences of facilitators and barriers for making changes in their parenting. A mixed methods approach was employed using a parent satisfaction questionnaire (n = 77) and focus groups (n = 15). General satisfaction with FCU was adequate, with an average rating of 4 on a five-point scale (range 3.1-4.6). The analysis of quantitative and qualitative data resulted in eight themes representing facilitators and four themes representing barriers, organized into three categories: (1) access and engagement; (2) therapeutic process; and (3) program components. Ease of access to FCU facilitated initial engagement. Individual tailoring and access to FCU during different phases of change facilitated sustained engagement and change. Therapeutic process facilitators were a meaningful, supportive relationship with the provider, psychological benefits for parents and benefits for the whole family. Program components that facilitated change in parenting were new learning of parenting strategies and use of helpful techniques such as videotaping and home practice. Negative experiences with service systems prior to starting FCU, parent psychological barriers, and parent-provider mismatch were described as potential barriers. Some parents desired other program formats that were not offered, and some felt that new learning was insufficient to improve child behavior. Understanding the parent perspective can contribute to successful future work with implementing FCU.

Weight loss maintenance with exercise and liraglutide improves glucose tolerance, glucagon response, and beta cell function.

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/m2 ) 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.

Increased meal-induced neurotensin response predicts successful maintenance of weight loss - Data from a randomized controlled trial.

BACKGROUND: The gut derived anorexigenic hormone neurotensin (NT) is upregulated after bariatric surgery which may contribute to the sustained weight loss. In contrast, diet-induced weight loss is most often followed by weight regain. We therefore investigated whether diet-induced weight loss impacts levels of circulating NT in mice and humans and whether NT levels predicts body weight change after weight loss in humans. METHODS: In vivo mice study: Obese mice were fed ad-libitum or a restricted diet (40-60 % of average food intake) for 9 days to obtain similar weight loss as observed in the human study. At termination, intestinal segments, the hypothalamus and plasma were collected for histological, real time PCR, and radioimmunoassay (RIA) analysis. CLINICAL TRIAL: Plasma samples from 42 participants with obesity, completing an 8-week low-calorie diet in a randomized controlled trial, were analyzed. Plasma NT was measured by RIA at fasting and during a meal test before and after diet-induced weight loss and after one year of intended weight maintenance. RESULTS: In obese mice, food restriction-induced body weight loss of 14 % was associated with a 64 % reduction in fasting plasma NT (p < 0.0001). In the mouse duodenum (p = 0.07) and jejunum (p < 0.05), NT tissue concentration was decreased without tissue atrophy indicative of a physiological downregulation. In the mouse hypothalamus a downregulation of Pomc (p < 0.01) along with upregulation of Npy (p < 0.001) and Agrp (p < 0.0001) expression was found after restricted feeding in support of increased hunger after diet-induced weight loss. Therefore, we investigated the NT response in humans undergoing weight loss maintenance. In humans, similar to the mice, the low-calorie diet induced weight loss of 13 % body weight was associated with 40 % reduction in fasting plasma NT levels (p < 0.001). Meal-induced NT peak responses were greater in humans who lost additional weight during the 1 year maintenance phase compared to participants who regained weight (p < 0.05). CONCLUSION: Diet-induced weight loss decreased fasting plasma NT levels in both humans and mice with obesity, and regulated hunger-associated hypothalamic gene expression in mice. Meal-induced NT responses were greater in humans who lost additional weight during the 1 year maintenance phase compared to participants who regained weight. This indicates that increased peak secretion of NT after weight loss may contribute to successful maintenance of weight loss. CLINICAL TRIAL REGISTRATION NUMBER: NCT02094183.

Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial.

BACKGROUND: Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. METHODS: This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo, moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model. RESULTS: The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (- 0.37, 95% CI - 0.58 to - 0.16, P < 0.001) and the combination treatment (- 0.48, 95% CI - 0.70 to - 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). CONCLUSION: The combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments. Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716.

Insufficient sleep predicts poor weight loss maintenance after 1 year.

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.

Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment.

Weight regain after weight loss remains a major challenge in obesity treatment and may involve alteration of eating and sedentary behavior after weight loss. In this randomized, controlled, double-blind trial, adults with obesity were randomized, in a 1:1:1:1 ratio stratified by sex and age group (<40 years and ≥40 years), to one-year weight loss maintenance with exercise, the GLP-1 receptor agonist liraglutide, or the combination, as compared with placebo, after low-calorie diet-induced weight loss. Primary outcome was change in body weight, which has been published. Here, we investigated the effects of weight loss maintenance with exercise, liraglutide, or the combination on weight loss-induced changes in the pre-specified explorative outcomes, eating and sedentary behavior in 130 participants who completed the trial according to the study protocol (exercise (n = 26), liraglutide (n = 36), combination (n = 29), and placebo (n = 39)). One year after weight loss, the placebo group had decreased postprandial appetite suppression score by 14%, and increased sedentary time by 31 min/day and regained weight. Liraglutide prevented the decrease in postprandial appetite suppression score compared with placebo (0% vs. -14%; P = 0.023) and maintained weight loss. Exercise after weight loss did not increase appetite or sedentary behavior compared with placebo, despite increased exercise energy expenditure and maintained weight loss. The combination of exercise and liraglutide increased cognitive restraint score (13% vs. -9%; P = 0.042), reflecting a conscious restriction of food intake, and decreased sedentary time by 41 min/day (-10 vs. 31 min/day; 95%CI, -82.3 to -0.2; P = 0.049) compared with placebo, which may have facilitated the additional weight loss. Targeting both eating and sedentary behavior could be the most effective for preventing weight regain.Trial registration: EudraCT number, 2015-005585-32; clinicaltrials.gov number, NCT04122716.

Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial.

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 < 0.01) and sperm count 1.41-fold (95% CI: 1.07-1.87, P < 0.01). These improvements were maintained for 52 weeks in men who maintained the weight loss, but not in men who regained weight. Semen volume, sperm motility and motile sperm count did not change. 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.

Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined.

BACKGROUND: Weight regain after weight loss is a major problem in the treatment of persons with obesity. METHODS: 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. RESULTS: 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; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). 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. CONCLUSIONS: 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.).

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease.

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).

Facilitators and Barriers in Cross-Country Transport of Evidence-based Preventive Interventions: a Case Study Using the Family Check-Up.

This study is a qualitative analysis of facilitators and barriers in the dissemination of Family Check-Up (FCU), a U.S.-developed preventive intervention in Sweden. The FCU is inherently culturally flexible because it was designed to be tailored to each family's needs and context, including cultural norms and values. We present the FCU implementation framework (IF) as a conceptual framework for cross-country transport of the FCU and evidence-based programs (EBP) more generally. The FCU IF draws from implementation science literature and involves specifying barriers and facilitators related to implementation drivers (e.g., competency) at each implementation phase and applying these data to inform phase-specific, readiness-building activities for each driver. In addition to driver-related influences, barriers and facilitators specific to the FCU and the collaborative partnership between the U.S. and Swedish purveyors emerged in the data. The partnership's reliance on a hybrid bottom-up, top-down approach that balanced the Swedish purveyor's autonomy and cultural expertise with guidance from the U.S. purveyor facilitated adaptation of the FCU for Sweden. Relying on previously collected data, we also explored similarities and differences in barriers and facilitators to FCU scale-up in the United States versus Sweden. In general, across drivers, the same barriers and facilitators were salient. This study suggests that dissemination of culturally flexible EBPs guided by a dynamic implementation framework can facilitate cross-country transport of EBPs. This study promotes a culture of prevention by highlighting barriers, facilitators, and readiness-building strategies that influence the cross-cultural transportability of EBPs that prevent the onset and escalation of child problem behavior.

Protocol for a randomised controlled trial of the combined effects of the GLP-1 receptor agonist liraglutide and exercise on maintenance of weight loss and health after a very low-calorie diet.

INTRODUCTION: The 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 ANALYSIS: This 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 DISSEMINATION: The 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 NUMBER: 2015-005585-32.

Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures.

BACKGROUND AND AIM: Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD. METHODS: This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex. RESULTS: A greater GLP-1 response was associated with lower central systolic and diastolic BP of - 1.17 mmHg (95% confidence interval (CI) - 2.07 to - 0.27 mmHg, P = 0.011) and - 0.74 mmHg (95% CI - 1.29 to - 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of - 1.27 mmHg (95% CI - 2.20 to - 0.33 mmHg, P = 0.008) and - 1.00 (95% CI - 1.56 to - 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: - 4.94 (95% CI - 8.56 to - 1.31) mmHg, central diastolic BP: - 3.05 (95% CI - 5.29 to - 0.80) mmHg, brachial systolic BP: - 5.18 (95% CI - 8.94 to - 1.42) mmHg, and brachial diastolic BP: - 2.96 (95% CI - 5.26 to - 0.67) mmHg). CONCLUSION: Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005.

Instrumentalization of Eating Improves Weight Loss Maintenance in Obesity.

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.

Proteomics reveals the effects of sustained weight loss on the human plasma proteome.

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 < 10-13), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten-protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases.

Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36.

OBJECTIVE: The 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. DESIGN: The 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. METHODS: Twenty 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). RESULTS: Weight loss was successfully maintained for 52 weeks. iAUC for GLP-1 increased by 44% after weight loss (P<0.04) and increased to 72% at week 52 (P=0.0001). iAUC for PYY3-36 increased by 74% after weight loss (P<0.0001) and by 36% at week 52 (P=0.02). tAUC for ghrelin increased by 23% after weight loss (P<0.0001), but at week 52, the increase was reduced to 16% compared with before weight loss (P=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. CONCLUSIONS: Meal responses of GLP-1 and PYY3-36 remained 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.