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.

Adipose tissue oxygenation is associated with insulin sensitivity independently of adiposity in obese men and women.

Adipose tissue (AT) dysfunction contributes to the pathophysiology of insulin resistance and type 2 diabetes. Previous studies have shown that altered AT oxygenation affects adipocyte functionality, but it remains to be elucidated whether altered AT oxygenation is more strongly related to obesity or insulin sensitivity. In the present study, we tested the hypothesis that AT oxygenation is associated with insulin sensitivity rather than adiposity in humans. Thirty-five lean and obese individuals (21 men and 14 women, aged 40-65 years) with either normal or impaired glucose metabolism participated in a cross-sectional single-centre study. We measured abdominal subcutaneous AT oxygenation, body composition and insulin sensitivity. AT oxygenation was higher in obese insulin resistant as compared to obese insulin sensitive (IS) individuals with similar age, body mass index and body fat percentage, both in men and women. No significant differences in AT oxygenation were found between obese IS and lean IS men. Moreover, AT oxygenation was positively associated with insulin resistance (r = 0.465; P = .005), even after adjustment for age, sex and body fat percentage (standardized ß = 0.479; P = .005). In conclusion, abdominal subcutaneous AT oxygenation is associated with insulin sensitivity both in men and women, independently of adiposity. AT oxygenation may therefore be a promising target to improve insulin sensitivity.

Estimating real cell size distribution from cross-section microscopy imaging.

MOTIVATION: Microscopy imaging is an essential tool for medical diagnosis and molecular biology. It is particularly useful for extracting information about disease states, tissue heterogeneity and cell specific parameters such as cell type or cell size from biological specimens. However, the information obtained from the images is likely to be subjected to sampling and observational bias with respect to the underlying cell size/type distributions. RESULTS: We present an algorithm, Estimate Tissue Cell Size/Type Distribution (EstiTiCS), for the adjustment of the underestimation of the number of small cells and the size of measured cells while accounting for the section thickness independent of the tissue type. We introduce the sources of bias under different tissue distributions and their effect on the measured values with simulation experiments. Furthermore, we demonstrate our method on histological sections of paraffin-embedded adipose tissue sample images from 57 people from a dietary intervention study. This data consists of measured cell size and its distribution over the dietary intervention period at four time points. Adjusting for the bias with EstiTiCS results in a closer fit to the true/expected adipocyte size distribution with earlier studies. Therefore, we conclude that our method is suitable as the final step in estimating the tissue wide cell type/size distribution from microscopy imaging pipeline. AVAILABILITY AND IMPLEMENTATION: Source code and its documentation are available at https://github.com/michaelLenz/EstiTiCS The whole pipeline of our method is implemented in R and makes use of the 'nloptr' package. Adipose tissue data used for this study are available on request. CONTACT: Michael.Lenz@Maastrichtuniversity.nl, Gokhan.Ertaylan@Maastrichtuniversity.nl.

The cilium: a cellular antenna with an influence on obesity risk.

Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro- and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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.

Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial.

BACKGROUND: Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. METHODS: A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DISCUSSION: Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup. TRIAL REGISTRATION: EudraCT number 2020-000579-19 . Registered on 29 March 2021.

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.

Combined Analysis of Stress- and ECM-Related Genes in Their Effect on Weight Regain.

OBJECTIVE: During weight loss, the volume of adipocytes decreases, leading to stress because of the misfit between the cell contents and the surrounding extracellular matrix (ECM). This stress can be resolved by remodeling the ECM or the restorage of triglycerides within the adipocytes. The objective of this study was to investigate the existence of a connection between stress-related and ECM-related genes that is associated with weight regain. METHODS: Thirty-one participants with overweight or obesity followed a 5-week very-low-calorie diet (500 kcal/d) with a subsequent 4-week weight-stable diet (WS), and then an uncontrolled 9-month follow-up. Adipose tissue biopsies were collected for microarray analysis. A correlation and interaction analysis was performed with the weight regain percentage (WR%) ([weight after follow-up - weight after WS] ÷ weight after WS × 100%) by using two gene sets that were previously defined as "stress-related" (n = 107) and "ECM-related" genes (n = 277). RESULTS: During WS, a coexpression network of 8 stress-related genes and 15 ECM-related genes correlating with WR% could be constructed, with links to multiple biological processes. Interaction analysis between stress- and ECM-related genes revealed that several gene combinations were highly related to weight regain. CONCLUSIONS: Our findings underscore the importance of the connection between stress- and ECM-related genes in the risk for weight regain.

Effect of diet-induced weight loss on angiopoietin-like protein 4 and adipose tissue lipid metabolism in overweight and obese humans.

Angiopoietin-like protein 4 (ANGPTL4) plays a role in lipid partitioning by inhibiting lipoprotein lipase (LPL)-dependent plasma clearance of triacylglycerol in adipose tissue. We investigated the effects of diet-induced weight loss on plasma ANGPTL4 concentrations in relation to in vivo adipose tissue LPL activity and lipolysis and adipose tissue ANGPTL4 release in overweight/obese participants. Sixteen individuals (BMI: 28-35 kg/m2 ; 10 women) were randomized to a dietary intervention composed of either a low-calorie diet (1250 kcal/day) for 12 weeks (n = 9) or a very low-calorie diet (500 kcal/day) for 5 weeks, followed by a 4-week weight stable period. Before and after the intervention, we measured arteriovenous concentration differences in combination with adipose tissue blood flow before and after intake of a high-fat mixed meal with [U-13 C]-palmitate to assess in vivo adipose tissue LPL activity and lipolysis. The intervention significantly reduced body weight (-8.6 ± 0.6 kg, P < 0.001). Plasma ANGPTL4 concentrations were unaffected. Significant postprandial adipose tissue ANGPTL4 release into the circulation was observed (P < 0.01). No association was observed between plasma ANGPTL4 and in vivo LPL activity. After intervention, fasting and postprandial plasma ANGPTL4 concentrations were positively associated with adipose tissue nonesterified FA (NEFA) and glycerol release, reflecting in vivo adipose tissue lipolysis (fasting NEFA: P = 0.039 and postprandial NEFA: P = 0.003). In conclusion, plasma ANGPTL4 is unaffected by weight loss and is secreted from human adipose tissue after a high-fat meal in overweight/obese participants. Plasma ANGPTL4 concentrations were not related to in vivo adipose tissue LPL activity, but were positively associated with in vivo adipose tissue lipolysis after weight loss.

Adipose tissue autophagy related gene expression is associated with glucometabolic status in human obesity.

Adipose tissue autophagy (AT) is associated with human obesity and increased metabolic risk. Recent findings establish a role for autophagy in lipid metabolism. Here, we compared the expression of autophagy-related and lipolysis genes in human abdominal subcutaneous AT (SCAT) in overweight/obese subjects (n = 17) with or without impaired glucose tolerance in comparison with lean normal glucose tolerant individuals (n = 9), and investigated the association between AT autophagy and lipolysis. Human multipotent adipose-derived stem cells (hMADS) were used to investigate the effect of pharmacological HSL inhibition on changes in the autophagic flux. The expression of autophagy-related genes (ATG) 5, 7 and 12 in SCAT was significantly higher (p = 0.043, p = 0.015, p = 0.004, respectively) in overweight/obese compared to lean men, while expression of the classical lipases HSL (p = 0.092) and ATGL (p = 0.084) tended to be lower. ATG12 mRNA was positively correlated with BMI (r = 0.407, p = 0.039). ATG7 mRNA correlated positively with waist/hip ratio (WHR) (r = 0.420, p = 0.041), 2 h glucose concentration (r = 0.488, p = 0.011) and insulin (r = 0.419, p = 0.033). Multiple linear regressions revealed that ATG7 gene expression was positively related to 2 h glucose, independent of BMI, WHR and insulin. Gene expression interaction analysis showed that ATG7 mRNA negatively correlated with HSL (p<0.01) and ATGL mRNA expression (p<0.01). In line, treatment of differentiated hMADS with an HSL inhibitor increased LC3 accumulation, a marker of increased autophagic flux. Collectively, the present study demonstrated that a low expression of classical lipases in abdominal SCAT is accompanied by an increased expression of ATGs in overweight/obese subjects, which seems to be mainly related to glucose tolerance.

Profiling Cellular Processes in Adipose Tissue during Weight Loss Using Time Series Gene Expression.

Obesity is a global epidemic identified as a major risk factor for multiple chronic diseases and, consequently, diet-induced weight loss is used to counter obesity. The adipose tissue is the primary tissue affected in diet-induced weight loss, yet the underlying molecular mechanisms and changes are not completely deciphered. In this study, we present a network biology analysis workflow which enables the profiling of the cellular processes affected by weight loss in the subcutaneous adipose tissue. Time series gene expression data from a dietary intervention dataset with two diets was analysed. Differentially expressed genes were used to generate co-expression networks using a method that capitalises on the repeat measurements in the data and finds correlations between gene expression changes over time. Using the network analysis tool Cytoscape, an overlap network of conserved components in the co-expression networks was constructed, clustered on topology to find densely correlated genes, and analysed using Gene Ontology enrichment analysis. We found five clusters involved in key metabolic processes, but also adipose tissue development and tissue remodelling processes were enriched. In conclusion, we present a flexible network biology workflow for finding important processes and relevant genes associated with weight loss, using a time series co-expression network approach that is robust towards the high inter-individual variation in humans.

A role for leukocyte integrins and extracellular matrix remodeling of adipose tissue in the risk of weight regain after weight loss.

Background: Weight loss (WL) is often followed by weight regain after an energy-restricted dietary intervention (DI). When people are following a diet, the volume of an adipocyte decreases by loss of triglycerides, which creates stress between the cell contents and the surrounding extracellular matrix (ECM). Previously, we observed that genetic variations in ECM genes are associated with an increased risk of weight regain.Objective: We investigated the relation between the expression of ECM genes during WL and a period of weight stabilization (WS) and the risk of weight regain.Design: In this randomized controlled trial, 61 healthy overweight or obese participants followed either a 5-wk very-low-calorie diet (VLCD; 500 kcal/d) or a 12-wk low-calorie diet (1250 kcal/d) (WL period) with a subsequent 4-wk WS period and a 9-mo follow-up. The WL and WS periods combined were considered the DI. Abdominal subcutaneous adipose tissue biopsy samples were collected for microarray analysis. Gene expression changes for a broad set of ECM-related genes were correlated with the weight-regain percentage (WR%).Results: A total of 26 of the 277 genes were significantly correlated with WR% during WL, WS, or the DI periods. Most correlations were observed in the VLCD group during the WS period. Four genes code for leukocyte-specific receptors. These and other genes belong to a group of 26 genes, among which the expression changes were highly correlated (r ≥ 0.7, P ≤ 0.001). This group could be divided into 3 subclusters linking to 2 biological processes-leukocyte integrin gene activity and ECM remodeling-and a link to insulin sensitivity was also apparent.Conclusions: Our present findings indicate the importance of adipose tissue leukocytes for the risk of weight regain. ECM modification also seems to be involved, and we observed a link to insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT01559415.

Dietary weight loss-induced changes in RBP4, FFA, and ACE predict weight regain in people with overweight and obesity.

Adipokines and other biomarkers were previously identified with roles in energy expenditure, appetite, satiety, and adiposity. Therefore, we investigated whether dietary weight loss-induced changes in adipokines and other biomarkers known to play a role in weight regulation or energy expenditure could predict weight regain in people with overweight and obesity. In this randomized controlled trial 26 males and 30 females (BMI: 28-35 kg/m2) followed either a low-calorie diet (LCD; 1250 kcal/day) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal/day) for 5 weeks followed by a weight stable period of 4 weeks (dietary intervention (DI) period) and a 9-month follow-up period. Blood samples were taken before and after each period to measure FFA, TAG, total cholesterol, insulin, glucose, angiotensin-converting enzyme (ACE) activity, IL-6, RBP4, apelin, leptin, adiponectin, vaspin, and nesfatin-1 concentrations. Weight loss was similar between groups (LCD: -8.2 ± 0.5 kg; VLCD: -8.9 ± 0.4 kg, P = 0.30). Only changes in ACE activity, FFA and RBP4 concentrations during DI were correlated with weight regain in the whole group (r = -0.299, P = 0.030, r = -0.274, P = 0.047, and r = 0.357, P = 0.008, respectively). Together they explained 28% (r = 0.532) of weight regain variation. Dietary weight loss-induced changes in ACE activity, FFA and RBP4 independently contribute to weight regain prediction.

Dietary Intake after Weight Loss and the Risk of Weight Regain: Macronutrient Composition and Inflammatory Properties of the Diet.

Weight regain after successful weight loss is a big problem in obesity management. This study aimed to investigate whether weight regain after a weight loss period is correlated with the macronutrient composition and/or the inflammatory index of the diet during that period. Sixty one overweight and obese adults participated in this experimental study. Subjects lost approximately 10% of their initial weight by means of very low-calorie diet for five weeks, or a low calorie diet for 12 weeks. After that, subjects in both groups followed a strict weight maintenance diet based on individual needs for four weeks, which was followed by a nine-month weight maintenance period without dietary counseling. Anthropometrics and dietary intake data were recorded before weight loss (baseline) and during the weight maintenance period. On average, participants regained approximately half of their lost weight. We found no evidence that macronutrient composition during the weight maintenance period was associated with weight regain. The dietary inflammatory index (r = 0.304, p = 0.032) was positively correlated with weight regain and remained significant after correction for physical activity (r = 0.287, p = 0.045). Our data suggest that the inflammatory properties of diet play a role in weight regain after weight loss in overweight and obese adults.

Adipose Tissue Meal-Derived Fatty Acid Uptake Before and After Diet-Induced Weight Loss in Adults with Overweight and Obesity.

OBJECTIVE: This study investigated whether diet-induced weight loss alters indices of in vivo postprandial fat uptake in adipose tissue (AT) and whether these changes are associated with weight regain in adults with overweight and obesity. METHODS: In this randomized controlled trial, 16 (6 male) individuals (BMI: 28-35 kg/m2 ) were randomized to either a low-calorie diet (1,250 kcal/d) for 12 weeks or a very-low-calorie diet (500 kcal/d) for 5 weeks (weight loss [WL] period) followed by a 4-week weight-stable (WS) period (together, the dietary intervention [DI] period) and a 9-month follow-up period. Arteriovenous difference measurements combined with stable isotope labeling ([U-13 C] palmitate) of a mixed meal were used to determine postprandial fatty acid uptake in AT. RESULTS: Body weight was significantly reduced during the WL period (-8.2 ± 0.6 kg, P < 0.001), remained stable during the WS period (0.4 ± 0.3 kg, P = 0.150), and increased during follow-up (3.5 ± 0.8 kg, P = 0.001). Meal-derived in vivo fatty acid uptake dynamics across AT and expression of genes important for fatty acid uptake, storage, and release were not significantly changed during the DI period. CONCLUSIONS: Subcutaneous AT does not appear prone to enhanced meal-derived fatty acid uptake after weight loss, nor were fatty acid uptake dynamics detected as related to weight regain.

The effect of rate of weight loss on long-term weight regain in adults with overweight and obesity.

OBJECTIVE: To investigate the effect of rate of weight loss, with similar total weight loss, on weight regain in individuals with overweight and obesity. METHODS: Fifty-seven participants (BMI: 28-35 kg/m(2) ) underwent a dietary intervention (DI). They were randomized to a low-calorie diet (LCD; 1250 kcal/day) for 12 weeks (slow weight loss) or a very-low-calorie diet (VLCD; 500 kcal/day) for 5 weeks (rapid weight loss) (weight loss (WL) period) followed by a 4-week weight-stable (WS) period and 9 months follow-up. Body weight and body composition (BodPod) were determined at study start and after each period. RESULTS: Weight change was similar in both groups after WL (LCD: -8.2 kg and VLCD: -9.0 kg, P = 0.24). Weight regain after follow-up was not significantly different between groups (LCD: 4.2 kg and VLCD: 4.5 kg, P = 0.73). Percentage fat-free mass loss (%FFML) was higher in the VLCD-group compared to the LCD-group after DI (8.8% and 1.3%, respectively, P = 0.034) and was associated with weight regain during follow-up in the whole group (r = 0.325, P = 0.018). CONCLUSIONS: The present study showed that, with similar total weight loss, rate of weight loss did not affect weight regain. However, %FFML after DI was associated with weight regain.

Variation in extracellular matrix genes is associated with weight regain after weight loss in a sex-specific manner.

The extracellular matrix (ECM) of adipocytes is important for body weight regulation. Here, we investigated whether genetic variation in ECM-related genes is associated with weight regain among participants of the European DiOGenes study. Overweight and obese subjects (n = 469, 310 females, 159 males) were on an 8-week low-calorie diet with a 6-month follow-up. Body weight was measured before and after the diet, and after follow-up. Weight maintenance scores (WMS, regained weight as percentage of lost weight) were calculated based on the weight data. Genotype data were retrieved for 2903 SNPs corresponding to 124 ECM-related genes. Regression analyses provided us with six significant SNPs associated with the WMS in males: 3 SNPs in the POSTN gene and a SNP in the LAMB1, COL23A1, and FBLN5 genes. For females, 1 SNP was found in the FN1 gene. The risk of weight regain was increased by: the C/C genotype for POSTN in a co-dominant model (OR 8.25, 95 % CI 2.85-23.88) and the T/C-C/C genotype in a dominant model (OR 4.88, 95 % CI 2.35-10.16); the A/A genotype for LAMB1 both in a co-dominant model (OR 18.43, 95 % CI 2.35-144.63) and in a recessive model (OR 16.36, 95 % CI 2.14-124.9); the G/A genotype for COL23A1 in a co-dominant model (OR 3.94, 95 % CI 1.28-12.10), or the A-allele in a dominant model (OR 2.86, 95 % CI 1.10-7.49); the A/A genotype for FBLN5 in a co-dominant model (OR 13.00, 95 % CI 1.61-104.81); and the A/A genotype for FN1 in a recessive model (OR 2.81, 95 % CI 1.40-5.63). Concluding, variants of ECM genes are associated with weight regain after weight loss in a sex-specific manner.

Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions.

BACKGROUND: Consumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI). OBJECTIVE: We determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures. DESIGN: The subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption. RESULTS: Consumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups. CONCLUSION: The results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853.