8-week Low-calorie Diet Research Articles

Impact of baseline adipose tissue characteristics on change in adipose tissue volume during a low calorie diet in people with obesity—results from the LION study

Background/ObjectivesWeight loss outcomes vary individually. Magnetic resonance imaging (MRI)-based evaluation of adipose tissue (AT) might help to identify AT characteristics that predict AT loss. This study aimed to assess the impact of an 8-week low-calorie diet (LCD) on different AT depots and to identify predictors of short-term AT loss using MRI in adults with obesity.MethodsEighty-one adults with obesity (mean BMI 34.08 ± 2.75 kg/m², mean age 46.3 ± 10.97 years, 49 females) prospectively underwent baseline MRI (liver dome to femoral head) and anthropometric measurements (BMI, waist-to-hip-ratio, body fat), followed by a post-LCD-examination. Visceral and subcutaneous AT (VAT and SAT) volumes and AT fat fraction were extracted from the MRI data. Apparent lipid volumes based on MRI were calculated as approximation for the lipid contained in the AT. SAT and VAT volumes were subdivided into equidistant thirds along the craniocaudal axis and normalized by length of the segmentation. T-tests compared baseline and follow-up measurements and sex differences. Effect sizes on subdivided AT volumes were compared. Spearman Rank correlation explored associations between baseline parameters and AT loss. Multiple regression analysis identified baseline predictors for AT loss.ResultsFollowing the LCD, participants exhibited significant weight loss (11.61 ± 3.07 kg, p < 0.01) and reductions in all MRI-based AT parameters (p < 0.01). Absolute SAT loss exceeded VAT loss, while relative apparent lipid loss was higher in VAT (both p < 0.01). The lower abdominopelvic third showed the most significant SAT and VAT reduction. The predictor of most AT and apparent lipid losses was the normalized baseline SAT volume in the lower abdominopelvic third, with smaller volumes favoring greater AT loss (p < 0.01 for SAT and VAT loss and SAT apparent lipid volume loss).ConclusionsThe LCD primarily reduces lower abdominopelvic SAT and VAT. Furthermore, lower abdominopelvic SAT volume was detected as a potential predictor for short-term AT loss in persons with obesity.

Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

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. 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. 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. 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. 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. 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). 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. EudraCT: 2015-005585-32.

Low-calorie diet-induced weight loss is associated with altered brain connectivity and food desire in obesity.

The main objective of this study is to better understand the effects of diet-induced weight loss on brain connectivity in response to changes in glucose levels in individuals with obesity. A total of 25 individuals with obesity, among whom 9 had a diagnosis of type 2 diabetes, underwent functional magnetic resonance imaging (fMRI) scans before and after an 8-week low-calorie diet. We used a two-step hypereuglycemia clamp approach to mimic the changes in glucose levels observed in the postprandial period in combination with task-mediated fMRI intrinsic connectivity distribution (ICD) analysis. After the diet, participants lost an average of 3.3% body weight. Diet-induced weight loss led to a decrease in leptin levels, an increase in hunger and food intake, and greater brain connectivity in the parahippocampus, right hippocampus, and temporal cortex (limbic-temporal network). Group differences (with vs. without type 2 diabetes) were noted in several brain networks. Connectivity in the limbic-temporal and frontal-parietal brain clusters inversely correlated with hunger. A short-term low-calorie diet led to a multifaceted body response in patients with obesity, with an increase in connectivity in the limbic-temporal network (emotion and memory) and hormone and eating behavior changes that may be important for recovering the weight lost.

Association Between the Postprandial Response to an Oral Glucose Tolerance Test and Anthropometric Changes After an 8-Week Low-Calorie Formula Diet - Results From the Lifestyle Intervention (LION) Study.

Interindividual variations in postprandial metabolism and weight loss outcomes have been reported. The literature suggests links between postprandial metabolism and weight regulation. Therefore, the study aims to evaluate if postprandial glucose metabolism after a glucose load predicts anthropometric outcomes of a weight loss intervention. Anthropometric data from adults with obesity (18-65 years, body mass index [BMI] 30.0-39.9kgm-2) are collected pre- and post an 8-week formula-based weight loss intervention. An oral glucose tolerance test (OGTT) is performed at baseline, from which postprandial parameters are derived from glucose and insulin concentrations. Linear regression models explored associations between these parameters and anthropometric changes (∆) postintervention. A random forest model is applied to identify predictive parameters for anthropometric outcomes after intervention. Postprandial parameters after an OGTT of 158 participants (63.3% women, age 45 ± 12, BMI 34.9 ± 2.9kgm-2) reveal nonsignificant associations with changes in anthropometric parameters after weight loss (p>0.05). Baseline fat-free mass (FFM) and sex are primary predictors for ∆ FFM [kg]. Postprandial glucose metabolism after a glucose load does not predict anthropometric outcomes after short-term weight loss via a formula-based low-calorie diet in adults with obesity.

Evaluating Sex-specific Differences in Abdominal Fat Volume and Proton Density Fat Fraction at MRI Using Automated nnU-Net-based Segmentation.

Sex-specific abdominal organ volume and proton density fat fraction (PDFF) in people with obesity during a weight loss intervention was assessed with automated multiorgan segmentation of quantitative water-fat MRI. An nnU-Net architecture was employed for automatic segmentation of abdominal organs, including visceral and subcutaneous adipose tissue, liver, and psoas and erector spinae muscle, based on quantitative chemical shift-encoded MRI and using ground truth labels generated from participants of the Lifestyle Intervention (LION) study. Each organ's volume and fat content were examined in 127 participants (73 female and 54 male participants; body mass index, 30-39.9 kg/m2) and in 81 (54 female and 32 male participants) of these participants after an 8-week formula-based low-calorie diet. Dice scores ranging from 0.91 to 0.97 were achieved for the automatic segmentation. PDFF was found to be lower in visceral adipose tissue compared with subcutaneous adipose tissue in both male and female participants. Before intervention, female participants exhibited higher PDFF in subcutaneous adipose tissue (90.6% vs 89.7%; P < .001) and lower PDFF in liver (8.6% vs 13.3%; P < .001) and visceral adipose tissue (76.4% vs 81.3%; P < .001) compared with male participants. This relation persisted after intervention. As a response to caloric restriction, male participants lost significantly more visceral adipose tissue volume (1.76 L vs 0.91 L; P < .001) and showed a higher decrease in subcutaneous adipose tissue PDFF (2.7% vs 1.5%; P < .001) than female participants. Automated body composition analysis on quantitative water-fat MRI data provides new insights for understanding sex-specific metabolic response to caloric restriction and weight loss in people with obesity. Keywords: Obesity, Chemical Shift-encoded MRI, Abdominal Fat Volume, Proton Density Fat Fraction, nnU-Net ClinicalTrials.gov registration no. NCT04023942 Supplemental material is available for this article. Published under a CC BY 4.0 license.

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

BackgroundThe 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. MethodsIn 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. ResultsIn 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). ConclusionDiet-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

BackgroundIdentifying 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.MethodsThis 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.ResultsThe 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).ConclusionThe 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.

Insufficient sleep may attenuate weight loss, but the role of sleep in weight loss maintenance is unknown. Since weight regain after weight loss remains a major obstacle in obesity treatment, we investigated whether insufficient sleep predicts weight regain during weight loss maintenance. In a randomized, controlled, two-by-two factorial study, 195 adults with obesity completed an 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 (</≥6 h/night) or sleep quality (PSQI score ≤/>5). After a diet-induced 13.1 kg weight loss, participants with short sleep duration at randomization regained 5.3 kg body weight (p = .0008) and had less reduction in body fat percentage compared with participants with normal sleep duration (p = .007) during the 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. Short sleep duration or poor sleep quality was associated with weight regain after weight loss in adults with obesity.

O-018 Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomised controlled trial

Abstract 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 count, which was maintained after one year in men who maintained weight loss. What is known already Obesity is associated with impaired semen parameters. 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 randomised, controlled, double-blinded trial (the S-LITE trial). The trial was conducted between August 2016 and November 2019. A total of 56 men was included in the study and assigned to an initial 8-week low-calorie diet (800 kcal/day) followed by randomisation to 52 weeks of either: placebo, exercise training, and placebo (exercise), the GLP-1 analogue liraglutide (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 to 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, anthropometrics and collected blood samples before (T0) and 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) bodyweight during the low-calorie diet, which increased sperm concentration 1.49 fold (95% CI: 1.18-1.88, P&amp;lt;0.01) and sperm count 1.41 fold (95% CI: 1.07-1.87, P&amp;lt;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 randomised 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. Due to the small sample size, 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 both liraglutide and exercise as weight maintenance strategies may be used to maintain the improvements in sperm concentration and count. Trial registration number H-16027082

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

STUDY QUESTIONDoes diet-induced weight loss improve semen parameters, and are these possible improvements maintained with sustained weight loss?SUMMARY ANSWERAn 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 ALREADYObesity 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, DURATIONThis 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, METHODSInclusion 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 CHANCEThe 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 CAUTIONThe 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 FINDINGSThis 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 NUMBERThe 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 DATE11 May 2016.DATE OF FIRST PATIENT’S ENROLMENTAugust 2016.

Changes in Circulating Metabolites during Weight Loss and Weight Loss Maintenance in Relation to Cardiometabolic Risk.

(1) Background: There is a substantial lack of knowledge of the biochemical mechanisms by which weight loss and weight regain exert their beneficial and adverse effects, respectively, on cardiometabolic outcomes. We examined associations between changes in circulating metabolites and changes in cardiometabolic risk factors during diet-induced weight loss and weight loss maintenance. (2) Methods: This prospective analysis of data from the Satiety Innovation (SATIN) study involved adults living with overweight and obesity (mean age=47.5). One hundred sixty-two subjects achieving ≥8% weight loss during an initial 8-week low-calorie diet (LCD) were included in a 12-week weight loss maintenance period. Circulating metabolites (m=123) were profiled using a targeted multiplatform approach. Data were analyzed using multivariate linear regression models. (3) Results: Decreases in the concentrations of several phosphatidylcholines (PCs), sphingomyelins (SMs), and valine were consistently associated with decreases in total (TChol) and low-density lipoprotein cholesterol (LDL-C) levels during the LCD. Increases in PCs and SMs were significantly associated with increases in TChol and LDL-C during the weight loss maintenance period. Decreases and increases in PCs during LCD and maintenance period, respectively, were associated with decreases in the levels of triglycerides. (4) Conclusions: The results of this study suggest that decreases in circulating PCs and SMs during weight loss and the subsequent weight loss maintenance period may decrease the cardiovascular risk through impacting TChol and LDL-C.

Abstract 13393: Liraglutide Improves Myocardial Redox State in Humans by Regulating the Adipose Tissue-Derived Long-Chain Ceramides

Introduction: A notable reduction in major adverse cardiovascular events and cardiovascular mortality was observed in several cardiovascular studies via treatment with liraglutide, which have been suggested to be mediated through several mechanisms including inhibition of oxidative stress. Hypothesis: We hypothesised that treatment with liraglutide reduces oxidative stress via modulating circulating levels of long-chain ceramides. Methods: We measured vascular superoxide production using lucigenin-enhanced chemiluminescence and levels of circulating ceramides using LC-MS/MS in 633 participants of the Oxford Heart Vessels and Fat (OxHVF) cohort. We also measured 33 sphingolipid species (SPL) in plasma from 32 obese individuals (average BMI 33.5±2.5kg/m 2 at inclusion) participating in a randomized clinical trial (RCT) of low calorie diet and liraglutide. Results: We found a significant association between superoxide production by internal mammary arteries (IMA) and circulating levels of long-chain ceramides (C16:0, C17:0, C18:0, C18:1) (A-D) . In the RCT, all participants adhered to an 8-week low-calorie diet (800 kcal/day) (E) , during which they lost 9.9±6.0 kg of body weight exhibiting a significant reduction in BMI ( p &lt;0.0001), which was paralleled by significant effects on the circulating levels of SPL (F) . Following this initial phase, the patients were randomised to liraglutide treatment (1.2 mg daily) or no treatment, for a period of 52 weeks. Liraglutide treatment differentially affected several SPL species compared to the control group despite no significant changes in BMI in any of the two groups (G-J) . Conclusions: In this study, we observed for the first time in human a regulatory effect of liraglutide on the circulating levels of long-chain ceramides that are shown to be associated with vascular oxidative stress suggesting a promising mechanistic link that justifies further exploration.

Network Analyses Reveal Negative Link Between Changes in Adipose Tissue GDF15 and BMI During Dietary-induced Weight Loss.

Adipose tissue (AT) transcriptome studies provide holistic pictures of adaptation to weight and related bioclinical settings changes. To implement AT gene expression profiling and investigate the link between changes in bioclinical parameters and AT gene expression during 3 steps of a 2-phase dietary intervention (DI). AT transcriptome profiling was obtained from sequencing 1051 samples, corresponding to 556 distinct individuals enrolled in a weight loss intervention (8-week low-calorie diet (LCD) at 800 kcal/day) followed with a 6-month ad libitum randomized DI. Transcriptome profiles obtained with QuantSeq sequencing were benchmarked against Illumina RNAseq. Reverse transcription quantitative polymerase chain reaction was used to further confirm associations. Cell specificity was assessed using freshly isolated cells and THP-1 cell line. During LCD, 5 modules were found, of which 3 included at least 1 bioclinical variable. Change in body mass index (BMI) connected with changes in mRNA level of genes with inflammatory response signature. In this module, change in BMI was negatively associated with changes in expression of genes encoding secreted protein (GDF15, CCL3, and SPP1). Through all phases of the DI, change in GDF15 was connected to changes in SPP1, CCL3, LIPA and CD68. Further characterization showed that these genes were specific to macrophages (with LIPA, CD68 and GDF15 expressed in anti-inflammatory macrophages) and GDF15 also expressed in preadipocytes. Network analyses identified a novel AT feature with GDF15 upregulated with calorie restriction induced weight loss, concomitantly to macrophage markers. In AT, GDF15 was expressed in preadipocytes and macrophages where it was a hallmark of anti-inflammatory cells.

Changes in Circulating Metabolites During Weight Loss are Associated with Adiposity Improvement, and Body Weight and Adiposity Regain During Weight Loss Maintenance: The SATIN Study.

To examine the relationship between changes in circulating metabolites during diet-induced weight loss and changes of adiposity. This study also investigates changes in these metabolites in relation to body weight and adiposity regain during a weight loss maintenance period. This cohort study is nested within the Satiety Innovation (SATIN) study. Participants (n = 162) achieving ≥8% weight loss during an initial 8-week low-calorie formula diet (LCD) are included in a 12-week weight loss maintenance period. A targeted metabolite profiling (123metabolites) approach is applied using three different platforms (proton nuclear magnetic resonance, liquid chromatography mass spectrometry, gas chromatography mass spectrometry). Changes in several lipid species and citric acid are significantly associated with greater reduction of body weight, total fat, and abdominal adiposity distribution during the LCD. Decreases in the concentrations of lysophosphatidylcholines (LPCs) 14:0, LPC 20:3, phosphatidylcholine (PC) 32:2, PC 38:3, sphingomyelin (SM) 32:2, and increases in citric acid concentrations during the LCD are associated with adiposity regain and loss, respectively, during the weight loss maintenance period. The results show that weight loss is associated with changes in lipid species and citric acid. These changes are related to subsequent weight and adiposity regain identifying the adipose lipid metabolism as an important factor for the maintenance of lost weight and adiposity.

Physical Activity, Weight Loss, and Weight Maintenance in the DiOGenes Multicenter Trial.

In this secondary analysis of the DiOGenes study, we investigated whether physical activity (PA) contributes to diet-induced weight loss and helps to reduce subsequent regain. We also studied the associations of PA with changes in cardiometabolic variables. Adults with overweight were included and followed an 8-week low-calorie diet (LCD). When successful (>8% weight loss), participants were randomized to different ad libitum diet groups and were advised to maintain their weight loss over the 6-month intervention period. Body weight (BW), body composition, cardiometabolic variables and subjectively-assessed PA were measured at baseline, at the end of weight loss and at the end of the intervention. BW was reduced by the LCD (from 99.8 ± 16.7 to 88.4 ± 14.9 kg; P < 0.001). This reduction was maintained during the weight maintenance period (89.2 ± 16.0 kg). Total PA (sum score of the three subscales of the Baecke questionnaire) increased during the weight loss period (from 8.16 ± 0.83 to 8.39 ± 0.78; P < 0.001) and this increase was subsequently maintained (8.42 ± 0.90). We found no evidence that baseline PA predicted weight loss. However, a higher level of baseline PA predicted a larger weight-loss-induced improvement in total cholesterol, triglycerides, glucose and CRP, and in post-prandial insulin sensitivity (Matsuda index). Subsequent weight and fat mass maintenance were predicted by the post-weight loss level of PA and associated with changes in PA during the weight maintenance phase. In conclusion, despite the fact that higher baseline levels of PA did not predict more weight loss during the LCD, nor that an increase in PA during the LCD was associated with more weight loss, higher PA levels were associated with more improvements in several cardiometabolic variables. The positive effect of higher PA on weight loss maintenance seems in contrast to randomized controlled trials that have not been able to confirm a positive effect of exercise training programmes on weight loss maintenance. This analysis supports the notion that higher self-imposed levels of PA may improve the cardiometabolic risk profile during weight loss and help to maintain weight loss afterwards.

Sexual Dimorphism in Body Weight Loss, Improvements in Cardiometabolic Risk Factors and Maintenance of Beneficial Effects 6 Months after a Low-Calorie Diet: Results from the Randomized Controlled DiOGenes Trial.

A low-calorie diet (LCD) is an effective strategy to lose weight and improve cardiometabolic risk factors, however, sexual dimorphism may be present. This study aims to investigate sexual dimorphism in cardiometabolic risk factors following weight loss and after weight maintenance. 782 overweight/obese participants (65% women) of the DiOGenes trial followed an 8-week LCD (~800 kcal/day), with a 6-months follow-up weight maintenance period on ad libitum diets varying in protein content and glycemic index. Men lost more body weight during the LCD period (−12.8 ± 3.9 vs. −10.1 ± 2.8 kg, respectively, p < 0.001), but regained more weight during the follow-up period than women (1.5 ± 5.4 vs. −0.5 ± 5.5 kg, respectively, p < 0.001). Even though beneficial LCD-induced changes in cardiometabolic risk factors were found for both sexes, improvements in HOMA-IR, muscle and hepatic insulin sensitivity, triacylglycerol, HDL−, LDL− and total cholesterol, diastolic blood pressure, cholesterol esters, sphingomyelins and adiponectin were more pronounced in men than women (std. ß range: 0.073–0.144, all q < 0.05), after adjustment for weight change. During follow-up, women demonstrated a lower rebound in HDL-cholesterol, triacylglycerol and diacylglycerol (std. ß range: 0.114–0.164, all q < 0.05), independent of changes in body weight. Overall, we demonstrated sexual dimorphism in LCD-induced changes in body weight and cardiometabolic risk profile, which may be attributed to differences in body fat distribution and metabolic status.

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

BackgroundWeight regain after weight loss is a major problem in the treatment of persons with obesity.MethodsIn 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.ResultsAfter 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.ConclusionsA 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.)

1994-P: Task-Oriented Connectivity Analysis of Disease-Dependent Effects of Diet

Previous results have demonstrated that short-term dieting attenuates neuronal inhibitory control on appetite measured with blood-oxygen-level-dependent (BOLD) responses to a food cue task. Because recent studies have suggested that functional connectivity measured during the task is strongly predictive of disease states, we sought to investigate the effect of weight loss on brain functional connectivity during the picture viewing task. Sixteen healthy obese (10F/6M, age 44.4±8 years, BMI 32.7±2) and 9 type 2 diabetes (T2DM) obese subjects (5F/4M, age 48±9, BMI 33.9±2) underwent functional MRI (fMRI) before and after an 8-week low-calorie diet. Brain connectivity (BOLD) was recorded while subjects viewed preselected images (high-calorie food, low-calorie food, and non-food). Participants lost 2.9±2.8 kg (p&amp;lt;0.05) weight after the diet. Using intrinsic connectivity distribution (ICD) analysis, there was a significant diet effect (p&amp;lt; 0.01) in the inferior pons, hypothalamus, and inferior medial hippocampus across all subjects. Diet by group interaction in ICD (p &amp;lt;0.001) was observed in the inferior anterior amygdala, inferior medial hippocampus, and hypothalamus, brain regions involved in the modulation of emotion and glucose metabolism. These results highlight the adaptive nature of neuronal control on diet and provide novel evidence for a variable nature of inhibitory neuronal adaptions in metabolic diseases. Disclosure C. Watt: None. T.K. Stanley: None. C. Lacadie: None. K.W.Y. Lam: None. M. Savoye: None. R. Sinha: None. T. Constable: None. D. Seo: None. J.J. Hwang: Research Support; Self; General Electric. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitches. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK045735, K23 DK098286-02, R01DK020495); National Institutes of Health (UL1TR001863)

275-LB: Connectome Predictive Modeling May Identify Brain Connectivity Signatures to Help Predict Who Will Benefit from Low-Calorie Diet

While studies have investigated changes in brain connectivity following diet and weight loss, it has not yet been explored whether baseline brain connectivity can be used to predict weight loss during diet or to identify individual subjects for which a particular diet may be effective. The following study uses Connectome-based predictive modeling (CPM), a data-driven analysis approach for producing predictive models of individual brain-behavior relationships from brain connectivity data using cross-validation, to help identify individual participants who will lose weight after an 8-week low calorie diet. 16 Healthy OB subjects (10F/6M, age 44.4±8 years, BMI 32.7±2) and 9 T2DM subjects (5F/4M, age 48±9, BMI 33.9±2) underwent functional MRI (fMRI) during a hyperglycemic-euglycemic clamp. Blood-oxygen-level-dependent (BOLD) brain activity was assessed while subjects viewed food (high-calorie, low-calorie) pictures and non-food images. The study was repeated after 8 weeks of a reduced calorie diet. CPM was applied to BOLD activity during hyperglycemia and euglycemia. Analyses show that models built on individual subject brain connectivity matrices averaged between hyperglycemia and euglycemia before an 8-week low calorie diet are able to predict 50.2% and 53.4% of the variance in BMI and weight loss (kg), respectively (p&amp;lt;0.05). While models built on brain connectivity matrices during euglycemia (similar to the post-prandial state), but not hyperglycemia predicted 42.2% of the variance in BMI change (p=0.017). These results suggest the possibility that individual brain connectivity signatures may be used to identify subjects for whom a low calorie diet might be an effective weight loss strategy, while also revealing the relevant functional connections associated with weight loss success. Disclosure D. Groskreutz: None. W. Lam: None. C. Lacadie: None. A. Elshafie: None. J.J. Hwang: None. D. Seo: None. M. Savoye: None. R. Sinha: None. T. Constable: None. R. Sherwin: Other Relationship; Self; ICON plc., IQVIA, MannKind Corporation. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc. Funding National Institutes of Health

Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study

BackgroundAngiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis.MethodsDiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention.ResultsChanges in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p = 0.02) and insulin (p = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss (p = 0.004) and between ANGPTL3 and CK-18 (baseline p = 1.03 × 10−7, during weight loss p = 1.47 × 10−13). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4-APOA5-ZNF259-BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss (p = 0.007).ConclusionWe clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans-acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes.