Fasting and postprandial remnant-like particle cholesterol concentrations in obese participants are associated with plasma triglycerides, insulin resistance, and body fat distribution

Elevated plasma concentrations of remnant-like particle cholesterol (RLP-C) are atherogenic. However, factors that determine RLP-C are not fully understood. This study evaluates which factors affect RLP-C in the fasting and postprandial state, using multiple regression analyses in a large cohort of lean and obese participants. All participants (n = 740) underwent a test meal challenge containing 95 energy % (en%) fat (energy content 50% of predicted daily resting metabolic rate). Fasting and postprandial concentrations of circulating metabolites were measured over a 3-h period. Obese participants (n = 613) also participated in a 10-wk weight loss program (-2510 kJ/d), being randomized to either a low-fat or a high-fat diet (20-25 vs. 40-45en% fat). Postprandial RLP-C was associated with fasting RLP-C, waist:hip ratio (WHR), HOMA(IR) (homeostasis model assessment index for insulin resistance) (P < 0.001), and age, independently of BMI and gender [adjusted R(2) (adj. R(2)) = 0.70). These factors were also related to fasting RLP-C (P < 0.010), along with gender and physical activity (adj. R(2) = 0.23). The dietary intervention resulted in significantly lower fasting RLP-C concentrations, independently mediated by weight loss, improvements in HOMA(IR), and the fat content of the prescribed diet. However, after inclusion of plasma triglyceride (TG), HDL-cholesterol, and FFA concentrations in the models, HOMA(IR) and WHR no longer significantly predicted fasting RLP-C, although WHR remained a predictor of postprandial RLP-C (P = 0.002). Plasma TG was strongly associated with both fasting and postprandial RLP-C (P < 0.001). In conclusion, plasma RLP-C concentrations are mainly associated with plasma TG concentrations. Interestingly, the high-fat diet was more effective at decreasing fasting RLP-C concentrations in obese participants than the low-fat diet

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P&lt;10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P&lt;5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health

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 beta = 0.248, p = 0.000; std beta = 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 beta = 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

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 (similar to 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

The triglyceride-glucose index as an adiposity marker and a predictor of fat loss induced by a low-calorie diet

Background This study aimed to investigate the putative role of the triglyceride-glucose index (TyG index) computed as ln[TG (mg/dl) x glucose (mg/dl)/2] and derived proxies as predictors of adiposity and weight loss changes after a low-calorie diet (LCD) intervention. Methods A total of 744 adult participants from the multicentre DIOGenes intervention study were prescribed a LCD (800 kcal/day) during 8 weeks. Body composition and fat content at baseline and after 8 weeks were estimated by DEXA/BIA. A multivariate analysis approach was used to estimate the difference in Delta Weight(1-2) (kg), Delta BMI1-2 (kg/m(2)) or Delta Fat(1-2) (%) between the basal value (point 1) and after 8 weeks following a LCD (point 2), respectively. The TyG index at baseline (TyG(1)), after following the LCD for 8 weeks (TyG(2)) or the TyG index differences between both time points (Delta TyG(1-2)) were analysed as predictors of weight and fat changes. Results TyG(1) was associated with Delta Weight(1-2) (kg) and Delta BMI1-2 (kg/m(2)), with beta = 0.812 (p = .017) and beta = 0.265 (p = .018), respectively. Also, TyG(2) values were inversely related to Delta Fat(1-2) (%), beta = -1.473 (p = .015). Moreover, Delta TyG(1-2) was associated with Delta Weight(1-2) (kg) and Delta Fat(1-2) (%), beta = 0.689 (p = .045) and beta = 1.764 (p = .002), respectively. Furthermore, an association between TyG(2) and resistance to fat loss was found (p = .015). Conclusion TyG(1) index is a good predictor of weight loss induced by LCD. Moreover, TyG(2) was closely related to resistance to fat loss, while Delta TyG(1-2) values were positively associated with body fat changes. Therefore, TyG index and derived estimations could be used as markers of individualized responses to energy restriction and a surrogate of body composition outcomes in clinical/epidemiological settings in obesity conditions

The association between vitamin D receptor polymorphisms and tissue-specific insulin resistance in human obesity

Background/objectives To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort. Methods We included 553 adult obese individuals (mean BMI 34.8 kg/m(2)), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression. Results None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 +/- 0.4 vs. AA 5.6 +/- 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 +/- 13.4 vs. AA: 547.9 +/- 24.7 mu mol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters). Conclusions The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort

Plasma lipid profiling of tissue-specific insulin resistance in human obesity

Obesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid profiles in overweight/obese individuals who show muscle-IR and/or liver-IR.). Muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI) were derived from a 5-point oral glucose tolerance test. The 140 plasma lipids were quantified by liquid chromatography-mass spectrometry. Linear mixed models were used to evaluate associations between MISI, HIRI and plasma lipids.MISI was comparable between sexes while HIRI and triacylglycerol (TAG) levels were lower in women than in men. MISI was associated with higher lysophosphatidylcholine (LPC) levels (standardized (std)β = 0.126; FDR-p = 0.032). Sex interactions were observed for associations between HIRI, TAG and diacylglycerol (DAG) lipid classes. In women, but not in men, HIRI was associated with higher levels of TAG (44 out of 55 species) and both DAG species (stdβ: 0.139-0.313; FDR-p < 0.05), a lower odd-chain/even-chain TAG ratio (stdβ = -0.182; FDR-p = 0.005) and a lower very-long-chain/long-chain TAG ratio (stdβ = -0.156; FDR-p = 0.037).In overweight/obese individuals, muscle insulin sensitivity is associated with higher plasma LPC concentrations. Women have less hepatic IR and lower TAG than men. Nevertheless, hepatic IR is associated with higher plasma TAG and DAG concentrations and a lower abundance of odd-chain and very-long-chain TAG in women, but not in men. This suggests a more pronounced worsening of plasma lipid profile in women with the progression of hepatic IR.BACKGROUND/OBJECTIVESSUBJECTS/METHODSRESULTSCONCLUSIONSFWN – Publicaties zonder aanstelling Universiteit Leide