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.

Effects of physical activity on blood lipids and HbA1c in healthy pregnant women: the FitMum randomized controlled trial.

OBJECTIVE: Maternal blood lipid and glucose concentrations during pregnancy affect fetal growth and the risk of pregnancy and delivery complications. We aimed to investigate the effects of physical activity (PA) during pregnancy on maternal blood lipid and hemoglobin A1c (HbA1c) concentrations. We hypothesized that higher PA was associated with improved lipid profile and glycemic control. METHODS: In a secondary analysis of a randomized controlled trial, we included 216 pregnant women before week 15+0 and tested the effects of two different PA interventions throughout pregnancy compared to standard care on maternal blood lipid and HbA1c concentrations. Additionally, we investigated the effect of PA per se measured by an activity tracker. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, and HbA1c concentrations were measured at week ≤15+0, 28+0-6, 34+0-6, and at delivery (week 32+1 to 42+0). Effects of the interventions and PA per se were tested using linear mixed effects models and linear regression analyses, respectively. RESULTS: No effects of the PA interventions were detected on maternal lipids or HbA1c during pregnancy. In PA per se analyses, more minutes per week of moderate-to-vigorous intensity PA were associated with less increase in TC (-1.3E-04, p=0.020) and LDL-C (-8.5E-05, p=0.035) as pregnancy progresses. More active kilocalories were associated with less increase in TC (-5.5E-05, p<0.001), HDL-C (-9.5E-06, p=0.024), and LDL-C (-3.2E-05, p=0.005). CONCLUSION: Whilst there were no effects of offering PA interventions, higher PA was associated with reduced increases in total cholesterol, HDL-C, and LDL-C as pregnancy progressed.

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.

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.

The effect of exercise training and motivational counselling on physical activity behaviour and psychosocial factors in pregnant women: secondary analyses of the FitMum randomised controlled trial investigating prenatal physical activity.

BACKGROUND: A physically active lifestyle is beneficial during pregnancy. However, little is known about physical activity (PA) behaviour and psychosocial factors in women during and after pregnancy. This study examined exercise behavioural regulation, exercise self-efficacy, health-related quality of life, sickness absence and musculoskeletal pain in pregnant women offered either structured supervised exercise training, motivational counselling on PA, or standard prenatal care in the FitMum randomised controlled trial. METHODS: Two hundred and eighteen healthy inactive pregnant women were randomised to structured supervised exercise training (n = 87), motivational counselling on PA (n = 86) or standard prenatal care (n = 45). The women answered the Behavioural Regulation in Exercise Questionnaire-2 (BREQ-2), the Pregnancy Exercise Self-Efficacy Scale (P-ESES-DK) and the Short Form 36 Health Survey Questionnaire (SF-36) at baseline (gestational age (GA) of max 15 weeks), GA 28 and 34 weeks, and one year after delivery. Sickness absence and low back and/or pelvic girdle pain were likewise reported in questionnaires at baseline and GA 28 weeks. RESULTS: Participants offered structured supervised exercise training or motivational counselling on PA had higher autonomous motivation for exercise during pregnancy compared with participants receiving standard prenatal care (e.g., difference in intrinsic regulation at GA 28 weeks, structured supervised exercise training vs. standard prenatal care: mean difference in score 0.39 [0.16; 0.64], p < 0.001). Participants offered structured supervised exercise training also had higher exercise self-efficacy during pregnancy (e.g., GA 28 weeks, structured supervised exercise training vs. standard prenatal care: mean difference in score 6.97 [2.05; 12.02], p = 0.005). All participants reported high exercise self-efficacy at baseline and medium exercise self-efficacy during pregnancy and one year after delivery. No differences were found between groups in health-related quality of life, sickness absence or low back and/or pelvic girdle pain during pregnancy. No group differences were found one year after delivery. CONCLUSION: Structured supervised exercise training and motivational counselling on PA had important effects on autonomous exercise motivation during pregnancy. Exercise self-efficacy was also increased with structured supervised exercise training compared to standard prenatal care. No group differences in health-related quality of life, sickness absence, or pain were found during and after pregnancy. No effects were found one year post-delivery after intervention cessation. TRIAL REGISTRATION: The study was approved by the Danish National Committee on Health Research Ethics (#H-18011067) and the Danish Data Protection Agency (#P-2019-512). The study adheres to the principles of the Helsinki declaration. Written informed consent was obtained at inclusion.

Counselling on physical activity in Danish antenatal care: A qualitative study of experiences from both the pregnant woman's and the care provider's perspective.

OBJECTIVES: Physical activity during pregnancy is beneficial to maternal and fetal health, but most pregnant women do not achieve the recommended level of physical activity. To investigate how antenatal care can promote physical activity during pregnancy, this study explores experiences of physical activity counselling from the perspectives of pregnant women and antenatal care providers. METHODS: In a qualitative design with an inductive approach individual semi-structured interviews with 19 pregnant women and seven antenatal care providers were performed and analyzed using thematic analysis. RESULTS: The themes "Experiencing inadequate counselling", "Benefiting from individualized guidance", and "Voicing a need for enhanced support" cover the perspectives from the participating pregnant women. They often experienced insufficient physical activity counselling that left them insecure about proper physical activity during pregnancy. The pregnant women desired individualized and concrete advice and early and continuous support. From antenatal care providers the themes "Providers' perceived barriers in counselling", "Balancing the act of counselling", and "Acknowledging potential for enhanced counselling" were identified. They perceived barriers towards counselling including time restraints, lack of interest, and doubts about certain physical activity during pregnancy but expressed trying to adjust the counselling to meet the woman's individual situation. They acknowledged that continuous support during pregnancy and updated knowledge and increased focus among providers might improve physical activity counselling. CONCLUSIONS: Pregnant women received scarce counselling on physical activity in antenatal care, while care providers described several barriers towards counselling on physical activity. Both pregnant women and antenatal care providers recognized opportunities for enhanced physical activity counselling.

Predicting the HbA1c level following glucose-lowering interventions in individuals with HbA1c-defined prediabetes: a post-hoc analysis from the randomized controlled PRE-D trial.

PURPOSE: To investigate whether the prediction of post-treatment HbA1c levels can be improved by adding an additional biomarker of the glucose metabolism in addition to baseline HbA1c. METHODS: We performed an exploratory analysis based on data from 112 individuals with prediabetes (HbA1c 39-47 mmol) and overweight/obesity (BMI ≥ 25 kg/m2), who completed 13 weeks of glucose-lowering interventions (exercise, dapagliflozin, or metformin) or control (habitual living) in the PRE-D trial. Seven prediction models were tested; one basic model with baseline HbA1c as the sole glucometabolic marker and six models each containing one additional glucometabolic biomarker in addition to baseline HbA1c. The additional glucometabolic biomarkers included: 1) plasma fructosamine, 2) fasting plasma glucose, 3) fasting plasma glucose × fasting serum insulin, 4) mean glucose during a 6-day free-living period measured by a continuous glucose monitor 5) mean glucose during an oral glucose tolerance test, and 6) mean plasma glucose × mean serum insulin during the oral glucose tolerance test. The primary outcome was overall goodness of fit (R2) from the internal validation step in bootstrap-based analysis using general linear models. RESULTS: The prediction models explained 46-50% of the variation (R2) in post-treatment HbA1c with standard deviations of the estimates of ~2 mmol/mol. R2 was not statistically significantly different in the models containing an additional glucometabolic biomarker when compared to the basic model. CONCLUSION: Adding an additional biomarker of the glucose metabolism did not improve the prediction of post-treatment HbA1c in individuals with HbA1c-defined prediabetes.

Effects of Two Physical Activity Interventions on Sleep and Sedentary Time in Pregnant Women.

Pregnancy is often associated with poor sleep and high sedentary time (SED). We investigated the effect of physical activity (PA) interventions on sleep and SED in pregnant women. A secondary analysis of a randomized controlled trial (n = 219) explored the effect of structured supervised exercise training (EXE) or motivational counseling on PA (MOT) compared to standard prenatal care (CON) on sleep and SED during pregnancy. Three times during pregnancy, sleep was determined by the Pittsburgh Sleep Quality Index (PSQI) and SED by the Pregnancy Physical Activity Questionnaire (PPAQ). Also, a wrist-worn consumer activity tracker measured sleep and SED continuously. Data from the activity tracker confirmed that sleep time decreases, and SED increases by approx. 30 and 24 min/day, respectively, from baseline (maximum gestational age (GA) week 15) to delivery. Compared to CON, the global PSQI score was better for EXE in GA week 28 (-0.8 [-1.5; -0.1], p = 0.031) and for both EXE and MOT in GA week 34 (-1 [-2; -0.5], p = 0.002; -1 [-2; -0.1], p = 0.026). In GA week 28, SED (h/day) from PPAQ was lower in EXE compared to both CON and MOT (-0.69 [-1; -0.0], p = 0.049; -0.6 [-1.0; -0.02], p = 0.042). In conclusion, PA interventions during pregnancy improved sleep quality and reduced SED.

Effects of prenatal exercise on gestational weight gain, obstetric and neonatal outcomes: FitMum randomized controlled trial.

BACKGROUND: To investigate the effects of two different exercise interventions during pregnancy on gestational weight gain (GWG) and obstetric and neonatal outcomes compared to standard care. Additionally, we aimed to improve standardization of GWG measurements by developing a model to estimate GWG for a standardized pregnancy period of 40 weeks and 0 days accounting for individual differences in gestational age (GA) at delivery. METHODS: In a randomized controlled trial we compared the effects of structured supervised exercise training (EXE) three times per week throughout pregnancy versus motivational counselling on physical activity (MOT) seven times during pregnancy with standard care (CON) on GWG and obstetric and neonatal outcomes. Uniquely, to estimate GWG for a standardized pregnancy period, we developed a novel model to predict GWG based on longitudinally observed body weights during pregnancy and at admission for delivery. Observed weights were fitted to a mixed effects model that was used to predict maternal body weight and estimate GWG at different gestational ages. Obstetric and neonatal outcomes, among them gestational diabetes mellitus (GDM) and birth weight, were obtained after delivery. GWG and the investigated obstetric and neonatal outcomes are secondary outcomes of the randomized controlled trial, which might be underpowered to detect intervention effects on these outcomes. RESULTS: From 2018-2020, 219 healthy, inactive pregnant women with median pre-pregnancy BMI of 24.1 (21.8-28.7) kg/m2 were included at median GA 12.9 (9.4-13.9) weeks and randomized to EXE (n = 87), MOT (n = 87) or CON (n = 45). In total 178 (81%) completed the study. GWG at GA 40 weeks and 0 days did not differ between groups (CON: 14.9 kg [95% CI, 13.6;16.1]; EXE: 15.7 kg [14.7;16.7]; MOT: 15.0 kg [13.6;16.4], p = 0.538), neither did obstetric nor neonatal outcomes. For example, there were no differences between groups in the proportions of participants developing GDM (CON: 6%, EXE: 7%, MOT: 7%, p = 1.000) or in birth weight (CON: 3630 (3024-3899), EXE: 3768 (3410-4069), MOT: 3665 (3266-3880), p = 0.083). CONCLUSIONS: Neither structured supervised exercise training nor motivational counselling on physical activity during pregnancy affected GWG or obstetric and neonatal outcomes compared to standard care. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03679130; 20/09/2018.

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.

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.

Effects of acute exercise and exercise training on plasma GDF15 concentrations and associations with appetite and cardiometabolic health in individuals with overweight or obesity - A secondary analysis of a randomized controlled trial.

Growth Differentiation Factor 15 (GDF15) is seemingly involved in appetite control. Acute exercise increases GDF15 concentrations in lean humans, but acute and long-term effects of exercise on GDF15 in individuals with overweight/obesity are unknown. We investigated the effects of acute exercise and exercise training on GDF15 concentrations in individuals with overweight/obesity and associations with appetite and cardiometabolic markers. 90 physically inactive adults (20-45 years) with overweight/obesity were randomized to 6-months habitual lifestyle (CON, n=16), or isocaloric exercise of moderate (MOD, n=37) or vigorous intensity (VIG, n=37), 5 days/week. Testing was performed at baseline, 3, and 6 months. Plasma GDF15 concentrations, other metabolic markers, and subjective appetite were assessed fasted and in response to acute exercise before an ad libitum meal. Cardiorespiratory fitness, body composition, insulin sensitivity, and intraabdominal adipose tissue were measured. At baseline, GDF15 increased 18% (95%CI: 4; 34) immediately after acute exercise and 32% (16; 50) 60 min post-exercise. Fasting GDF15 increased 21% (0; 46) in VIG after 3 months (p=0.045), but this attenuated at 6 months (13% (-11; 43), p=0.316) and was unchanged in MOD (11% (-6; 32), p=0.224, across 3 and 6 months). Post-exercise GDF15 did not change in MOD or VIG. GDF15 was not associated with appetite or energy intake. Higher GDF15 was associated with lower cardiorespiratory fitness, central obesity, dyslipidemia, and poorer glycemic control. In conclusion, GDF15 increased in response to acute exercise but was unaffected by exercise training. Higher GDF15 concentrations were associated with a less favorable cardiometabolic profile but not with markers of appetite. This suggests that GDF15 increases in response to acute exercise independent of training state. Whether this has an impact on free-living energy intake and body weight management needs investigation.

Physical activity in pregnancy: a mixed methods process evaluation of the FitMum randomised controlled trial interventions.

BACKGROUND: Physical activity (PA) at moderate intensity is recommended for healthy pregnant women. The three-arm FitMum randomised controlled trial showed that it was possible to increase PA level during pregnancy with structured supervised exercise training (EXE) compared to standard care. Motivational counselling on PA (MOT) did not increase PA. This process evaluation aims to understand the implementation and mechanisms of impact of EXE and MOT. METHODS: A mixed methods process evaluation was conducted using the UK Medical Research Council's process evaluation framework by assessing implementation (reach, fidelity, and dose) and mechanisms of impact of the two interventions provided to pregnant women in FitMum. Data was collected both quantitatively (n = 220) and qualitatively (n = 20). RESULTS: The FitMum trial reached educated pregnant women (80% having an educational level ≥ bachelor's degree) with high autonomy of everyday life. Most participants (58%) were recruited at their first-trimester ultrasonic scan. Reasons to participate were personal (91%) and altruistic (56%). The intervention dose was delivered as intended with high fidelity in the original physical intervention setup and in the altered online setup during the COVID-19 restrictions. A low dose received in EXE (1.3 [95% CI, 1.1; 1.5] sessions/week) was partly explained by the pre-scheduled EXE sessions favouring participants with a flexible everyday life and a supportive social network. Dose received in EXE increased during online intervention delivery. Participants in MOT received 5.2 [4.7; 5.7] of 7 sessions. Mechanisms of impact comprised a perception of intervention commitment among participants in EXE due to the scheduled EXE sessions, whereas participants in MOT considered themselves as PA self-determined. PA was considered as constrained activities in EXE and included in daily activities in MOT. CONCLUSION: The FitMum interventions was delivered with high fidelity. During COVID-19, the dose received in EXE increased compared to the previous physical setup. Mechanisms of impact as commitment, perception of empowerment and perception of PA as well as the paradox between prioritising PA and family and the need of a flexible everyday life need to be considered when offering pregnant women PA interventions. Future interventions should consider a combination of physical and online exercise training for pregnant women.

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.

Effects of Structured Supervised Exercise Training or Motivational Counseling on Pregnant Women's Physical Activity Level: FitMum - Randomized Controlled Trial.

BACKGROUND: Physical activity (PA) during pregnancy is an effective and safe way to improve maternal health in uncomplicated pregnancies. However, compliance with PA recommendations remains low among pregnant women. OBJECTIVE: The purpose of this study was to evaluate the effects of offering structured supervised exercise training (EXE) or motivational counseling on PA (MOT) during pregnancy on moderate-to-vigorous intensity physical activity (MVPA) level. Additionally, complementary measures of PA using the Pregnancy Physical Activity Questionnaire (PPAQ) and gold standard doubly labeled water (DLW) technique were investigated. The hypotheses were that both EXE and MOT would increase MVPA in pregnancy compared with standard care (CON) and that EXE would be more effective than MOT. In addition, the association between MVPA and the number of sessions attended was explored. METHODS: A randomized controlled trial included 220 healthy, inactive pregnant women with a median gestational age of 12.9 (IQR 9.4-13.9) weeks. A total of 219 women were randomized to CON (45/219), EXE (87/219), or MOT (87/219). The primary outcome was MVPA (minutes per week) from randomization to the 29th gestational week obtained by a wrist-worn commercial activity tracker (Vivosport, Garmin International). PA was measured by the activity tracker throughout pregnancy, PPAQ, and DLW. The primary outcome analysis was performed as an analysis of covariance model adjusting for baseline PA. RESULTS: The average MVPA (minutes per week) from randomization to the 29th gestational week was 33 (95% CI 18 to 47) in CON, 50 (95% CI 39 to 60) in EXE, and 40 (95% CI 30 to 51) in MOT. When adjusted for baseline MVPA, participants in EXE performed 20 (95% CI 4 to 36) minutes per week more MVPA than participants in CON (P=.02). MOT was not more effective than CON; EXE and MOT also did not differ. MVPA was positively associated with the number of exercise sessions attended in EXE from randomization to delivery (P=.04). Attendance was higher for online (due to COVID-19 restrictions) compared with physical exercise training (P=.03). Adverse events and serious adverse events did not differ between groups. CONCLUSIONS: Offering EXE was more effective than CON to increase MVPA among pregnant women, whereas offering MOT was not. MVPA in the intervention groups did not reach the recommended level in pregnancy. Changing the intervention to online due to COVID-19 restrictions did not affect MVPA level but increased exercise participation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03679130; https://clinicaltrials.gov/ct2/show/NCT03679130. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2020-043671.

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.

Menopausal transition does not influence skeletal muscle capillary growth in response to cycle training in women.

The influence of the menopausal transition, with a consequent loss of estrogen, on capillary growth in response to exercise training remains unknown. In the present study, we evaluated the effect of a period of intense endurance training on skeletal muscle angiogenesis in late premenopausal and recent postmenopausal women with an age difference of <4 yr. Skeletal muscle biopsies were obtained from the thigh muscle before and after 12 wk of intense aerobic cycle training and analyzed for capillarization, fiber-type distribution, and content of vascular endothelial growth factor (VEGF). At baseline, there was no difference in capillary per fiber ratio (C:F; 1.41 ± 0.22 vs. 1.40 ± 0.30), capillary density (CD; 305 ± 61 vs. 336 ± 52 mm2), muscle fiber area (MFA; 4,889 ± 1,868 vs. 4,195 ± 749), or distribution of muscle fiber type I (47.3% ± 10.1% vs. 49.3% ± 15.1%), between the pre- and postmenopausal women, respectively. There was a main effect of training on the C:F ratio (+9.2% and +12.1%, for the pre- and postmenopausal women, respectively) and the CD (+6.9% and +8.9%, for the pre- and postmenopausal women, respectively). MFA and fiber-type distribution were unaltered by training. Skeletal muscle VEGF protein content was similar between groups at baseline, and there was a main effect of training (+21.1% and +27.2%, for the pre- and postmenopausal women, respectively). In conclusion, the loss of estrogen per se at menopause does not influence the capillary growth response to intense aerobic exercise training.NEW & NOTEWORTHY We evaluated the effect of 12 wk of intense aerobic exercise training on skeletal muscle angiogenesis in late pre- and recent postmenopausal women, with <4 yr of age difference. There was a main effect of training on capillary per fiber ratio, capillary density, and muscle VEGF protein content, with no difference between groups. It is concluded that the loss of estrogen per se at menopause does not influence the capillary growth response to intense aerobic training.

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.).

Effect of exercise training on skeletal muscle protein expression in relation to insulin sensitivity: Per-protocol analysis of a randomized controlled trial (GO-ACTIWE).

Exercise training improves peripheral insulin sensitivity and leads to molecular adaptations in the skeletal muscle. We investigated changes in the expression of key muscle proteins in the glucose metabolic pathway following active commuting by bike or leisure-time exercise at two different intensities. In addition, potential associations between insulin sensitivity and muscle protein expression were examined. This per-protocol analysis included 72 out of 130 physically inactive, healthy women and men (20-45 years) with overweight/obesity (BMI: 25-35 kg/m2 ) who completed 6 months of no intervention (CON, n = 12), active commuting by bike (BIKE, n = 14), or leisure-time exercise of moderate (MOD, n = 28) or vigorous (VIG, n = 18) intensity. Exercise was prescribed 5 days/week with a weekly exercise energy expenditure of 1,600 kcal for women and 2,100 kcal for men. Insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp and skeletal muscle biopsies were obtained from m. vastus lateralis and analyzed for protein expression at baseline and after 3 and 6 months of intervention. We found an increased expression of pyruvate dehydrogenase (PDH) in the exercise groups compared with the control group following 6 months of training. No differential effects were observed on the protein expression following moderate versus vigorous intensity exercise. In addition, we found a positive association between insulin sensitivity and the expression of glucose transporter type 4 as well as PDH. The positive association and the increase in expression of PDH after exercise training points toward a role for PDH in the training-induced enhancement of insulin sensitivity.