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.).

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.

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.

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.

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.

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.

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.

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.

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.

Habitual physical activity is associated with lower fasting and greater glucose-induced GLP-1 response in men.

RATIONALE: The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. METHODS: Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. RESULTS: In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: -33; -3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1-2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. CONCLUSION: Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.

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.

Effects of active commuting and leisure-time exercise on appetite in individuals with overweight and obesity.

Acute exercise is associated with a transient suppression of appetite. The effects of regular exercise on appetite are not well understood. We aimed to determine the effects of active commuting and leisure-time exercise on appetite. One hundred thirty physically inactive women and men (20-45 yr) with overweight and obesity were randomized to 6 mo of habitual lifestyle (CON, n = 18), active commuting (BIKE, n = 35), or leisure-time exercise of moderate [MOD, 50% peak oxygen uptake (V̇o2peak)-reserve, n = 39] or vigorous (VIG, 70% V̇o2peak-reserve, n = 38) intensity. Appetite ratings, acylated ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and glucagon were assessed in the basal state and in response to meal and exercise challenges at baseline and 3 and 6 mo. Ad libitum energy intake was determined during test meals. Data from 90 participants (per protocol) were available, and results are comparisons with CON. At 3 mo, ad libitum energy intake was lower in VIG (-22%, P < 0.01), basal glucagon was lower in BIKE ( P < 0.05) and VIG ( P = 0.01), and postprandial ratings of prospective food consumption were lower in MOD ( P = 0.02) and VIG ( P < 0.001). In VIG, ratings of hunger ( P = 0.01) and prospective food consumption ( P = 0.03) were lower after acute exercise at 3 mo. At 6 mo, basal and postprandial GLP-1 were higher ( P ≤ 0.04) whereas postexercise PYY was lower ( P = 0.03) in VIG and postexercise CCK was lower in BIKE ( P = 0.03). Vigorous-intensity exercise training leads to a transient suppression of energy intake and subjective appetite (3 mo) but a more long-term increase in basal and postprandial GLP-1 (6 mo) in individuals with overweight and obesity. NEW & NOTEWORTHY This is the first randomized controlled trial, to our knowledge, investigating long-term effects of exercise domain and intensity on subjective and hormonal markers of appetite and ad libitum energy intake in individuals with overweight and obesity. Appetite was assessed in response to meal and exercise challenges at baseline and at 3 and 6 mo. Anorexigenic effects of exercise vary with the duration of intervention and are restricted to regular leisure-time exercise of vigorous intensity in individuals with overweight and obesity.

Glucagon-like Peptide 1 Receptor Signaling in Acinar Cells Causes Growth-Dependent Release of Pancreatic Enzymes.

Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis.

Oxyntomodulin Identified as a Marker of Type 2 Diabetes and Gastric Bypass Surgery by Mass-spectrometry Based Profiling of Human Plasma.

Low-abundance regulatory peptides, including metabolically important gut hormones, have shown promising therapeutic potential. Here, we present a streamlined mass spectrometry-based platform for identifying and characterizing low-abundance regulatory peptides in humans. We demonstrate the clinical applicability of this platform by studying a hitherto neglected glucose- and appetite-regulating gut hormone, namely, oxyntomodulin. Our results show that the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. Furthermore, we report that oxyntomodulin is co-distributed and co-secreted with the insulin-stimulating and appetite-regulating gut hormone glucagon-like peptide-1 (GLP-1), is inactivated by the same protease (dipeptidyl peptidase-4) as GLP-1 and acts through its receptor. Thus, oxyntomodulin may participate with GLP-1 in the regulation of glucose metabolism and appetite in humans. In conclusion, this mass spectrometry-based platform is a powerful resource for identifying and characterizing metabolically active low-abundance peptides.

Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine.

Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-coupled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we examined the effect of FFAR1 activation on GLP-1 secretion using isolated, perfused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 agonists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 µmol/L TAK-875, 10 µmol/L AMG 837, 1 µmol/L and 0.1 µmol/L AM-1638, 1 µmol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P < 0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-molecule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.