Quantifying the effect of nutritional interventions on metabolic resilience using personalized computational models.

The manifestation of metabolic deteriorations that accompany overweight and obesity can differ greatly between individuals, giving rise to a highly heterogeneous population. This inter-individual variation can impede both the provision and assessment of nutritional interventions as multiple aspects of metabolic health should be considered at once. Here, we apply the Mixed Meal Model, a physiology-based computational model, to characterize an individual's metabolic health in silico. A population of 342 personalized models were generated using data for individuals with overweight and obesity from three independent intervention studies, demonstrating a strong relationship between the model-derived metric of insulin resistance (ρ = 0.67, p < 0.05) and the gold-standard hyperinsulinemic-euglycemic clamp. The model is also shown to quantify liver fat accumulation and ß-cell functionality. Moreover, we show that personalized Mixed Meal Models can be used to evaluate the impact of a dietary intervention on multiple aspects of metabolic health at the individual level.

Obesity-induced and weight-loss-induced physiological factors affecting weight regain.

Weight regain after successful weight loss resulting from lifestyle interventions is a major challenge in the management of overweight and obesity. Knowledge of the causal mechanisms for weight regain can help researchers and clinicians to find effective strategies to tackle weight regain and reduce obesity-associated metabolic and cardiovascular complications. This Review summarizes the current understanding of a number of potential physiological mechanisms underlying weight regain after weight loss, including: the role of adipose tissue immune cells; hormonal and neuronal factors affecting hunger, satiety and reward; resting energy expenditure and adaptive thermogenesis; and lipid metabolism (lipolysis and lipid oxidation). We describe and discuss obesity-associated changes in these mechanisms, their persistence during weight loss and weight regain and their association with weight regain. Interventions to prevent or limit weight regain based on these factors, such as diet, exercise, pharmacotherapy and biomedical strategies, and current knowledge on the effectiveness of these interventions are also reviewed.

Plasma Levels of Triglycerides and IL-6 Are Associated With Weight Regain and Fat Mass Expansion.

CONTEXT: Long-term weight loss (WL) maintenance is the biggest challenge for overweight and obesity because of the almost unavoidable phenomenon of partial or even total weight regain (WR) after WL. OBJECTIVE: In the present study we investigated the relations of (the changes of) adipocyte size and other risk biomarkers with WR during the follow-up of the Yoyo dietary intervention. METHODS: In this randomized controlled study, 48 overweight/obese participants underwent a very-low-calorie diet to lose weight, followed by a weight-stable period of 4 weeks and a follow-up period of 9 months. Anthropometric measurements, adipocyte volume of abdominal subcutaneous adipose tissue, and plasma metabolic parameters (free fatty acids [FFAs], triglycerides [TGs], total cholesterol, glucose, insulin, homeostasis model assessment of insulin resistance [HOMA-IR], interleukin 6 [IL-6], angiotensin-converting enzyme [ACE] activity, retinol binding protein 4 [RBP4]) at the beginning and the end of follow-up were analyzed. RESULTS: Our results show that changes of TGs, IL-6, HOMA-IR, and ACE are significantly positively correlated with WR. Multiple linear regression analysis shows that only TG and IL-6 changes remained significantly correlated with WR and increased body fat mass. Moreover, the change in HOMA-IR was tightly correlated with the change in TGs. Surprisingly, change in adipocyte volume during follow-up was not correlated with WR nor with other factors, but positive correlations between adipocyte volume and HOMA-IR were found at the beginning and end of the follow-up. CONCLUSION: These results suggest that TGs and IL-6 are independently linked to WR via separate mechanisms, and that HOMA-IR and adipocyte volume may indirectly link to WR through the change of plasma TGs.

The association of changes in body mass index and metabolic parameters between adults with overweight or obesity and their children in a family-based randomized trial (DiOGenes).

BACKGROUND: Family-based approaches have been reported to be effective in improving overweight or obesity in children. OBJECTIVES: To investigate the relationship of changes in body mass index and metabolic parameters between adults with overweight or obesity and their children during a weight-maintenance family-based dietary intervention. METHODS: In a multicentre randomized controlled trial, families with at least one parent with overweight or obesity and one healthy child aged between 5 and 18 years, of which the parents completed an 8-week weight-loss phase successfully, were randomized into five different dietary intervention groups to achieve weight maintenance for 6 months. Anthropometric parameters and body composition were measured and blood samples were collected before and after the dietary intervention. Data were analysed using Pearson correlation coefficient analyses and multiple linear regression analysis adjusted for diet group, centre, child's sex and age. RESULTS: A positive association was found between the change in body mass index (BMI) of the mother and change in BMI-for-age Z-score of first and second child (std ß = 0.248, p = 0.000; std ß = 0.326, p = 0.000, respectively). The change in BMI of the father was only significantly associated with the change in BMI-for-age Z-score of first child (std ß = 0.186, p = 0.031). No consistent pattern of associations between parents and children was found for homeostatic model assessment for insulin resistance, fasting glucose and fasting insulin. CONCLUSION: This study supports the inclusion of parents into family-based dietary approaches for weight management of their children regardless of the child's weight status in eight different countries throughout Europe.

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.

Diet Composition, Glucose Homeostasis, and Weight Regain in the YoYo Study.

Based on several randomized clinical trials, it has been suggested that baseline glucose homeostasis interacts with the influence of diet composition on weight loss and weight loss maintenance. In this secondary analysis of the YoYo study, a study investigating predictors of weight loss maintenance, we tested the hypothesis that (self-selected) dietary carbohydrate and/or fibre intake interact with the glucose homeostasis parameters for weight loss maintenance. Sixty-one overweight or obese individuals lost around 10 kg of body weight on an energy-restricted diet and were then followed for 9 months. During this period, participants were advised to maintain their body weight and eat a healthy diet without further recommendations on calorie intake or diet composition. Contrary to our hypothesis, carbohydrate intake showed no positive association with weight regain after weight loss, and no interaction with baseline fasting glucose concentration was found. There was a non-significant negative association between fibre intake and weight regain (B = -0.274, standard error (SE) 0.158, p = 0.090), but again, no interaction with fasting plasma glucose was found. In conclusion, the data from the YoYo study do not support a role for baseline glucose homeostasis in determining the association between self-reported carbohydrate and/or fibre intake and weight regain after weight loss.

Exercise training in the management of overweight and obesity in adults: Synthesis of the evidence and recommendations from the European Association for the Study of Obesity Physical Activity Working Group.

There is a need for updated practice recommendations on exercise in the management of overweight and obesity in adults. We summarize the evidence provided by a series of seven systematic literature reviews performed by a group of experts from across Europe. The following recommendations with highest strength (Grade A) were derived. For loss in body weight, total fat, visceral fat, intra-hepatic fat, and for improvement in blood pressure, an exercise training program based on aerobic exercise at moderate intensity is preferentially advised. Expected weight loss is however on average not more than 2 to 3 kg. For preservation of lean mass during weight loss, an exercise training program based on resistance training at moderate-to-high intensity is advised. For improvement in insulin sensitivity and for increasing cardiorespiratory fitness, any type of exercise training (aerobic, resistance, and combined aerobic or resistance) or high-intensity interval training (after thorough assessment of cardiovascular risk and under supervision) can be advised. For increasing muscular fitness, an exercise training program based preferentially on resistance training alone or combined with aerobic training is advised. Other recommendations deal with the beneficial effects of exercise training programs on energy intake and appetite control, bariatric surgery outcomes, and quality of life and psychological outcomes in management of overweight and obesity.

Effect of exercise training before and after bariatric surgery: A systematic review and meta-analysis.

We aimed to assess the effectiveness of exercise training programs in adults with severe obesity undergoing bariatric surgery. A systematic search of controlled trials published up to October 2019 that assigned participants to either a preoperative or postoperative exercise training group or a nonexercise group was performed. Meta-analyses were conducted using random-effects models. Twenty-two training programs were assessed (18 performed after bariatric surgery). The effect of preoperative exercise training on postsurgery outcomes was reported in only one study. Compared with the control condition without exercise, postoperative exercise training led to higher weight loss (N = 14, mean difference [95% CI] = -1.8 [-3.2; -0.4] kg, P = 0.01), fat loss (N = 9, P = 0.01), increase in VO2 max (N = 8, P < 0.0001), and increase in muscle strength (N = 9, P < 0.0001). No significant effect was found on lean body mass (N = 11). Preliminary evidence suggests a beneficial effect of postoperative exercise training on bone mineral density (N = 3, P < 0.001) and weight maintenance after the end of the intervention (N = 2, P < 0.001) but no significant effect on quality of life (N = 2), habitual physical activity (N = 2), or cardiometabolic outcomes (N < 4). In conclusion, exercise training performed after bariatric surgery improves physical fitness and leads to a small additional weight and fat loss and may prevent bone loss and weight regain after bariatric surgery.

Effect of exercise on cardiometabolic health of adults with overweight or obesity: Focus on blood pressure, insulin resistance, and intrahepatic fat-A systematic review and meta-analysis.

This systematic review examined the impact of exercise intervention programs on selected cardiometabolic health indicators in adults with overweight or obesity. Three electronic databases were explored for randomized controlled trials (RCTs) that included adults with overweight or obesity and provided exercise-training interventions. Effects on blood pressure, insulin resistance (homeostasis model of insulin resistance, HOMA-IR), and magnetic resonance measures of intrahepatic fat in exercise versus control groups were analyzed using random effects meta-analyses. Fifty-four articles matched inclusion criteria. Exercise training reduced systolic and diastolic blood pressure (mean difference, MD = -2.95 mmHg [95% CI -4.22, -1.68], p < 0.00001, I2  = 63% and MD = -1.93 mmHg [95% CI -2.73, -1.13], p < 0.00001, I2  = 54%, 60 and 58 study arms, respectively). Systolic and diastolic blood pressure decreased also when considering only subjects with hypertension. Exercise training significantly decreased HOMA-IR (standardized mean difference, SMD = -0.34 [-0.49, -0.18], p < 0.0001, I2 = 48%, 37 study arms), with higher effect size in subgroup of patients with type 2 diabetes (SMD = -0.50 [95% CI: -0.83, -0.17], p = 0.003, I2 = 39%). Intrahepatic fat decreased significantly after exercise interventions (SMD = -0.59 [95% CI: -0.78, -0.41], p < 0.00001, I2  = 0%), with a larger effect size after high-intensity interval training. In conclusion, exercise training is effective in improving cardiometabolic health in adults with overweight or obesity also when living with comorbitidies.

Effect of exercise training interventions on energy intake and appetite control in adults with overweight or obesity: A systematic review and meta-analysis.

This systematic review examined the impact of exercise training interventions on energy intake (EI) and appetite control in adults with overweight/obesity (≥18 years including older adults). Articles were searched up to October 2019. Changes in EI, fasting appetite sensations, and eating behavior traits were examined with random effects meta-analysis, and other outcomes were synthesized qualitatively. Forty-eight articles were included (median [range] BMI = 30.6 [27.0-38.4] kg/m2 ). Study quality was rated as poor, fair, and good in 39, seven, and two studies, respectively. Daily EI was assessed objectively (N = 4), by self-report (N = 22), with a combination of the two (N = 4) or calculated from doubly labeled water (N = 1). In studies rated fair/good, no significant changes in pre-post daily EI were found and a small but negligible (SMD < 0.20) postintervention difference when compared with no-exercise control groups was observed (five study arms; MD = 102 [1, 203] kcal). There were negligible-to-small pre-post increases in fasting hunger and dietary restraint, decrease in disinhibition, and some positive changes in satiety and food reward/preferences. Within the limitations imposed by the quality of the included studies, exercise training (median duration of 12 weeks) leads to a small increase in fasting hunger and a small change in average EI only in studies rated fair/good. Exercise training may also reduce the susceptibility to overconsumption (PROSPERO: CRD42019157823).

Effect of exercise training on weight loss, body composition changes, and weight maintenance in adults with overweight or obesity: An overview of 12 systematic reviews and 149 studies.

This overview of reviews aimed to summarize the effects of exercise training programs on weight loss, changes in body composition, and weight maintenance in adults with overweight or obesity. A systematic search of systematic reviews and meta-analyses (SR-MAs) published between 2010 and December 2019 was performed. Only SR-MAs of controlled trials were included. The mean difference (MD) or standardized MD (SMD) were extracted from SR-MAs. Twelve SR-MAs (149 studies) were included. Exercise led to a significant weight loss (4 SR-MAs, MDs ranging from -1.5 to -3.5 kg), fat loss (4 SR-MAs, MDs ranging from -1.3 to -2.6 kg) and visceral fat loss (3 SR-MAs, SMDs ranging from -0.33 to -0.56). No difference in weight, fat, and visceral loss was found between aerobic and high-intensity interval training as long as energy expenditure was equal. Resistance training reduced lean mass loss during weight loss (1 SR-MA, MD: 0.8 [95%CI: 0.4-1.3] kg). No significant effect of exercise was found on weight maintenance (1 SR-MA). These findings show favorable effects of exercise training on weight loss and body composition changes in adults with overweight or obesity. Visceral fat loss may lead to benefits for cardiometabolic health. More research is needed to identify training modalities that promote weight maintenance.

Effect of different types of regular exercise on physical fitness in adults with overweight or obesity: Systematic review and meta-analyses.

This systematic review examined the effect of exercise training interventions on physical fitness in adults with overweight or obesity and compared the effectiveness of different types of exercise training. Four electronic databases were searched. Articles were included if they described randomized controlled trials of exercise training interventions and their effect on maximal oxygen consumption or muscle strength in adults with overweight or obesity. Changes in outcome parameters were analyzed using random effects meta-analyses for different training types (aerobic, resistance, combined aerobic plus resistance, and high-intensity interval training). Eighty-eight articles satisfied the inclusion criteria of which 66 (3964 participants) could be included in the meta-analyses. All training types increased VO2max (mean difference 3.82 ml/min/kg (95% CI 3.17, 4.48), P < 0.00001; I2 = 48%). In direct comparisons, resistance training was less effective in improving VO2max than aerobic training, HIIT was slightly more effective than aerobic training, and no difference between aerobic and combined aerobic plus resistance training was found. For muscle strength benefits, incorporation of resistance exercise in the training program is indicated. Exercise training increases VO2max and muscle strength in adults with overweight or obesity. Differences between training types should be weighed with other needs and preferences when health professionals advise on exercise training to improve physical fitness.

Dietary carbohydrates and weight loss maintenance.

PURPOSE OF REVIEW: Aim of the present review is to provide an overview of the effect of manipulating dietary carbohydrates (content, type) after a period of weight loss on weight loss maintenance and its potential underlying mechanisms. RECENT FINDINGS: Few recent studies directly tested whether lower carbohydrate/glycaemic load or higher fibre diets help to limit weight regain after weight loss and they did not provide evidence supporting a role of a reduction of the carbohydrate or an increase of the fibre content of the diet in the prevention of weight regain after weight loss. Some evidence is emerging that personal characteristics (gut microbiota, glycaemia) may interact with diet composition. but randomized clinical trials are needed to substantiate these claims. SUMMARY: There is currently no convincing evidence that lowering dietary carbohydrates has a clinically relevant effect on weight regain after weight loss, unless there is an increase in protein intake at the same time. Further randomized trials are needed to investigate potential interactions with personal characteristics while improving strategies for long-term adherence.

Passive exposure to heat improves glucose metabolism in overweight humans.

AIM: Heat exposure has been indicated to positively affect glucose metabolism. An involvement of heat shock protein 72 (HSP72) in the enhancement of insulin sensitivity upon heat exposure has been previously suggested. Here, we performed an intervention study exploring the effect of passive heat acclimation (PHA) on glucose metabolism and intracellular (a) HSP72 concentrations in overweight humans. METHODS: Eleven non-diabetic overweight (BMI 27-35 kg/m2 ) participants underwent 10 consecutive days of PHA (4-6 h/day, 34.4 ± 0.2°C, 22.8 ± 2.7%RH). Before and after PHA, whole-body insulin sensitivity was assessed using a one-step hyperinsulinaemic-euglycaemic clamp, skeletal muscle biopsies were taken to measure intracellular iHSP72, energy expenditure and substrate oxidation were measured using indirect calorimetry and blood samples were drawn to assess markers of metabolic health. Thermophysiological adaptations were measured during a temperature ramp protocol before and after PHA. RESULTS: Despite a lack of change in iHSP72, 10 days of PHA reduced basal (9.7 ± 1.4 pre- vs 8.4 ± 2.1 µmol · kg-1 · min-1 post-PHA, P = .038) and insulin-stimulated (2.1 ± 0.9 pre- vs 1.5 ± 0.8 µmol · kg-1 · min-1 post-PHA, P = .005) endogenous glucose production (EGP) and increased insulin suppression of EGP (78.5 ± 9.7% pre- vs 83.0 ± 7.9% post-PHA, P = .028). Consistently, fasting plasma glucose (6.0 ± 0.5 pre- vs 5.8 ± 0.4 mmol/L post-PHA, P = .013) and insulin concentrations (97 ± 55 pre- vs 84 ± 49 pmol/L post-PHA, P = .026) decreased significantly. Moreover, fat oxidation increased, and free fatty acids as well as cholesterol concentrations and mean arterial pressure decreased after PHA. CONCLUSION: Our results show that PHA for 10 days improves glucose metabolism and enhances fat metabolism, without changes in iHSP72. Further exploration of the therapeutic role of heat in cardio-metabolic disorders should be considered.

Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation.

Obesity is a global epidemic, contributing significantly to chronic non-communicable diseases, such as type 2 diabetes mellitus, cardiovascular diseases and metabolic syndrome. Metabolic flexibility, the ability of organisms to switch between metabolic substrates, is found to be impaired in obesity, possibly contributing to the development of chronic illnesses. Several studies have shown the improvement of metabolic flexibility after weight loss. In this study, we have mapped the cellular metabolism of the adipose tissue from a weight loss study to stratify the cellular metabolic processes and metabolic flexibility during weight loss. We have found that for a majority of the individuals, cellular metabolism was downregulated during weight loss, with gene expression of all major cellular metabolic processes (such as glycolysis, fatty acid ß-oxidation etc.) being lowered during weight loss and weight maintenance. Parallel to this, the gene expression of immune system related processes involving interferons and interleukins increased. Previously, studies have indicated both negative and positive effects of post-weight loss inflammation in the adipose tissue with regards to weight loss or obesity and its co-morbidities; however, mechanistic links need to be constructed in order to determine the effects further. Our study contributes towards this goal by mapping the changes in gene expression across the weight loss study and indicates possible cross-talk between cellular metabolism and inflammation.

Associations between the proportion of fat-free mass loss during weight loss, changes in appetite, and subsequent weight change: results from a randomized 2-stage dietary intervention trial.

BACKGROUND: Dynamic changes in body composition which occur during weight loss may have an influential role on subsequent energy balance behaviors and weight. OBJECTIVES: The aim of this article is to consider the effect of proportionate changes in body composition during weight loss on subsequent changes in appetite and weight outcomes at 26 wk in individuals engaged in a weight loss maintenance intervention. METHODS: A subgroup of the Diet, Obesity, and Genes (DiOGenes) study (n = 209) was recruited from 3 European countries. Participants underwent an 8-wk low-calorie diet (LCD) resulting in ≥8% body weight loss, during which changes in body composition (by DXA) and appetite (by visual analog scale appetite perceptions in response to a fixed test meal) were measured. Participants were randomly assigned into 5 weight loss maintenance diets based on protein and glycemic index content and followed up for 26 wk. We investigated associations between proportionate fat-free mass (FFM) loss (%FFML) during weight loss and 1) weight outcomes at 26 wk and 2) changes in appetite perceptions. RESULTS: During the LCD, participants lost a mean ± SD of 11.2 ± 3.5 kg, of which 30.4% was FFM. After adjustment, there was a tendency for %FFML to predict weight regain in the whole group (ß: 0.041; 95% CI: -0.001, 0.08; P = 0.055), which was significant in men (ß: 0.09; 95% CI: 0.02, 0.15; P = 0.009) but not women (ß: 0.01; 95% CI: -0.04, 0.07; P = 0.69). Associations between %FFML and change in appetite perceptions during weight loss were inconsistent. The strongest observations were in men for hunger (r = 0.69, P = 0.002) and desire to eat (r = 0.61, P = 0.009), with some tendencies in the whole group and no associations in women. CONCLUSIONS: Our results suggest that composition of weight loss may have functional importance for energy balance regulation, with greater losses of FFM potentially being associated with increased weight regain and appetite. This trial was registered at clinicaltrials.gov as NCT00390637.

The Effect of Vitamin D Supplementation on Insulin Sensitivity: A Systematic Review and Meta-analysis.

BACKGROUND: Vitamin D has been suggested to affect peripheral insulin sensitivity. Evidence regarding the effect of vitamin D supplementation on insulin sensitivity is still conflicting. PURPOSE: This meta-analysis aimed to assess the effect of vitamin D supplementation on insulin sensitivity in humans with or at risk for insulin resistance. DATA SOURCES AND STUDY SELECTION: PubMed, Web of Science, Embase, CINAHL, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) from 1980 until 31 December 2018 reporting treatment effects of vitamin D supplementation on insulin sensitivity. DATA EXTRACTION: The main outcome of interest was the change in insulin sensitivity, derived from the gold standard hyperinsulinemic-euglycemic clamp or the Matsuda index derived from the oral glucose tolerance test and insulin sensitivity index from intravenous glucose tolerance test. We extracted data on the standardized mean difference between the vitamin D treatment and placebo groups in change from baseline insulin sensitivity. DATA SYNTHESIS: Eighteen RCTs were included in this meta-analysis comparing vitamin D supplementation (n = 612) with placebo (n = 608). Vitamin D supplementation had no effect on insulin sensitivity (standardized mean difference -0.01, 95% CI -0.12, 0.10; P = 0.87, I 2 = 0%). Visual inspection of funnel plot symmetry did not suggest potential publication bias. LIMITATIONS: The number of individuals who participated in the included studies was relatively small, possibly due to the invasive character of the measurement (e.g., clamp). CONCLUSIONS: This meta-analysis provides no evidence that vitamin D supplementation has a beneficial effect on peripheral insulin sensitivity in people with or at risk for insulin resistance.

Adipose tissue contribution to plasma fibroblast growth factor 21 and fibroblast activation protein in obesity.

Fibroblast growth factor 21 (FGF21) is an important regulator of energy metabolism. FGF21 is inactivated by fibroblast activation protein (FAP). We investigated whether FGF21 and/or FAP are secreted from human white adipose tissue of individuals with obesity by measuring total FGF21, active FGF21, and FAP concentrations in arterialized blood and venous blood draining the subcutaneous abdominal adipose tissue (scAT). Measurements were performed under fasting conditions and after a high fat meal before and after diet-induced weight loss in 16 adults with BMI 27-35 kg/m2. FGF21 was not released from scAT, neither before nor after weight loss in agreement with an undetectable gene expression of FGF21 in this tissue. Although scAT showed significant gene expression of FAP, no release of FAP from the tissue could be detected. The high fat meal increased postprandial circulating FGF21 but not FAP. Circulating levels of FAP but not FGF21 were significantly reduced after weight loss. On the other hand, FAP expression in scAT was increased. In conclusion, release from scAT does not appear to contribute to circulating concentrations of FGF21 and FAP and their responses to ingestion of a high fat meal or weight loss, respectively, in individuals with obesity.

A computational model of postprandial adipose tissue lipid metabolism derived using human arteriovenous stable isotope tracer data.

Given the association of disturbances in non-esterified fatty acid (NEFA) metabolism with the development of Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, computational models of glucose-insulin dynamics have been extended to account for the interplay with NEFA. In this study, we use arteriovenous measurement across the subcutaneous adipose tissue during a mixed meal challenge test to evaluate the performance and underlying assumptions of three existing models of adipose tissue metabolism and construct a new, refined model of adipose tissue metabolism. Our model introduces new terms, explicitly accounting for the conversion of glucose to glyceraldehye-3-phosphate, the postprandial influx of glycerol into the adipose tissue, and several physiologically relevant delays in insulin signalling in order to better describe the measured adipose tissues fluxes. We then applied our refined model to human adipose tissue flux data collected before and after a diet intervention as part of the Yoyo study, to quantify the effects of caloric restriction on postprandial adipose tissue metabolism. Significant increases were observed in the model parameters describing the rate of uptake and release of both glycerol and NEFA. Additionally, decreases in the model's delay in insulin signalling parameters indicates there is an improvement in adipose tissue insulin sensitivity following caloric restriction.

Adipocyte abundances of CES1, CRYAB, ENO1 and GANAB are modified in-vitro by glucose restriction and are associated with cellular remodelling during weight regain.

Long-term weight loss maintenance is a problem of overweight and obesity. Changes of gene expression during weight loss (WL) by calorie restriction (CR) are linked to the risk of weight regain (WR). However, detailed information on genes/proteins involved in the mechanism is still lacking. Therefore, we developed an in-vitro model system for glucose restriction (GR) and refeeding (RF) to uncover proteome differences between GR with RF vs normal feeding, of which we explored the relation with WR after WL. Human Simpson-Golabi-Behmel Syndrome cells were subjected to changing levels of glucose to mimic the condition of CR and RF. Proteome profiling was performed by liquid chromatography tandem mass spectrometry. This in-vitro model revealed 44 proteins differentially expressed after GR and RF versus feeding including proteins of the focal adhesions. Four proteins showed a persistent up- or down-regulation: liver carboxylesterase (CES1), mitochondrial superoxide dismutase [Mn] (SOD2), alpha-crystallin B-chain (CRYAB), alpha-enolase (ENO1). In-vivo weight loss-induced RNA expression changes linked CES1, CRYAB and ENO1 to WR. Moreover, of these 44 proteins, CES1 and glucosidase II alpha subunit (GANAB) during follow up correlated with WR. Correlation clustering of in-vivo protein expression data indicated an interaction of these proteins with structural components of the focal adhesions and cytoplasmic filaments in the adipocytes.