Metabolite Profiling Identifies Candidate Markers Reflecting the Clinical Adaptations Associated with Roux-en-Y Gastric Bypass Surgery

Background: Roux-en-Y gastric bypass (RYGB) surgery is associated with weight loss, improved insulin sensitivity and glucose homeostasis, and a reduction in co-morbidities such as diabetes and coronary heart disease. To generate further insight into the numerous metabolic adaptations associated with RYGB surgery, we profiled serum metabolites before and after gastric bypass surgery and integrated metabolite changes with clinical data. Methodology and Principal Findings: Serum metabolites were detected by gas and liquid chromatography-coupled mass spectrometry before, and 3 and 6 months after RYGB in morbidly obese female subjects (n = 14; BMI = 46.261.7). Subjects showed decreases in weight-related parameters and improvements in insulin sensitivity post surgery. The abundance of 48 % (83 of 172) of the measured metabolites changed significantly within the first 3 months post RYGB (p,0.05), including sphingosines, unsaturated fatty acids, and branched chain amino acids. Dividing subjects into obese (n = 9) and obese/ diabetic (n = 5) groups identified 8 metabolites that differed consistently at all time points and whose serum levels changed following RYGB: asparagine, lysophosphatidylcholine (C18:2), nervonic (C24:1) acid, p-Cresol sulfate, lactate, lycopene, glucose, and mannose. Changes in the aforementioned metabolites were integrated with clinical data for body mass index (BMI) and estimates for insulin resistance (HOMA-IR). Of these, nervonic acid was significantly and negatively correlated with HOMA-IR (p = 0.001, R = 20.55)

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults

Genetic Association Study of Common Mitochondrial Variants on Body Fat Mass

Mitochondria play a central role in ATP production and energy metabolism. Previous studies suggest that common variants in mtDNA are associated with several common complex diseases, including obesity. To test the hypothesis that common mtDNA variants influence obesity-related phenotypes, including BMI and body fat mass, we genotyped a total of 445 mtSNPs across the whole mitochondrial genome in a large sample of 2,286 unrelated Caucasian subjects. 72 of these 445 mtSNPs passed quality control criteria, and were used for subsequent analyses. We also classified all subjects into nine common European haplogroups. Association analyses were conducted for both BMI and body fat mass with single mtSNPs and mtDNA haplogroups. Two mtSNPs, mt4823 and mt8873 were detected to be significantly associated with body fat mass, with adjusted P values of 4.94×10-3 and 4.58×10-2, respectively. The minor alleles mt4823 C and mt8873 A were associated with reduced fat mass values and the effect size (β) was estimated to be 3.52 and 3.18, respectively. These two mtSNPs also achieved nominally significant levels for association with BMI. For haplogroup analyses, we found that haplogroup X was strongly associated with both BMI (adjusted P = 8.31×10-3) and body fat mass (adjusted P = 5.67×10-4) Subjects classified as haplogroup X had lower BMI and fat mass values, with the β estimated to be 2.86 and 6.03, respectively. Our findings suggest that common variants in mitochondria might play a role in variations of body fat mass. Further molecular and functional studies will be needed to clarify the potential mechanism

LipidXplorer: A Software for Consensual Cross-Platform Lipidomics

LipidXplorer is the open source software that supports the quantitative characterization of complex lipidomes by interpreting large datasets of shotgun mass spectra. LipidXplorer processes spectra acquired on any type of tandem mass spectrometers; it identifies and quantifies molecular species of any ionizable lipid class by considering any known or assumed molecular fragmentation pathway independently of any resource of reference mass spectra. It also supports any shotgun profiling routine, from high throughput top-down screening for molecular diagnostic and biomarker discovery to the targeted absolute quantification of low abundant lipid species. Full documentation on installation and operation of LipidXplorer, including tutorial, collection of spectra interpretation scripts, FAQ and user forum are available through the wiki site at: https://wiki.mpi-cbg.de/wiki/lipidx/index.php/Main_Page

Transcriptional analysis of adipose tissue during development reveals depot-specific responsiveness to maternal dietary supplementation

Brown adipose tissue (BAT) undergoes pronounced changes after birth coincident with the loss of the BAT-specifc uncoupling protein (UCP)1 and rapid fat growth. The extent to which this adaptation may vary between anatomical locations remains unknown, or whether the process is sensitive to maternal dietary supplementation. We, therefore, conducted a data mining based study on the major fat depots (i.e. epicardial, perirenal, sternal (which possess UCP1 at 7 days), subcutaneous and omental) (that do not possess UCP1) of young sheep during the frst month of life. Initially we determined what effect adding 3% canola oil to the maternal diet has on mitochondrial protein abundance in those depots which possessed UCP1. This demonstrated that maternal dietary supplementation delayed the loss of mitochondrial proteins, with the amount of cytochrome C actually being increased. Using machine learning algorithms followed by weighted gene co-expression network analysis, we demonstrated that each depot could be segregated into a unique and concise set of modules containing co-expressed genes involved in adipose function. Finally using lipidomic analysis following the maternal dietary intervention, we confrmed the perirenal depot to be most responsive. These insights point at new research avenues for examining interventions to modulate fat development in early life

Associations between severity of obesity in childhood and adolescence, obesity onset and parental BMI: a longitudinal cohort study

Objective: To explore the relationship between severity of obesity at age 7 and age 15, age at onset of obesity, and parental body mass index (BMI) in obese children and adolescents. Design: Longitudinal cohort study.Subjects:Obese children (n231) and their parents (n462) from the Swedish National Childhood Obesity Centre. Methods: Multivariate regression analyses were applied with severity of obesity (BMI standard deviation score (BMI SDS)) and onset of obesity as dependent variables. The effect of parental BMI was evaluated and in the final models adjusted for gender, parental education, age at onset of obesity, severity of obesity at age 7 and obesity treatment. Results: For severity of obesity at age 7, a positive correlation with maternal BMI was indicated (P<0.05). Severity of obesity at this age also showed a strong negative correlation with the age at onset of obesity. Severity of obesity at age 15 was significantly correlated with both maternal and paternal BMI (P≥0.01). In addition, BMI SDS at age 15 differed by gender (higher for boys) and was positively correlated with severity of obesity at age 7 and negatively correlated with treatment. Also, a negative correlation was indicated at this age for parental education. No correlation with age at onset was found at age 15. For age at onset of obesity there was no relevant correlation with parental BMI. Children within the highest tertile of the BMI SDS range were more likely to have two obese parents. Conclusion: The impact of parental BMI on the severity of obesity in children is strengthened as the child grows into adolescence, whereas the age at onset is probably of less importance than previously thought. The influence of parental relative weight primarily affects the severity of childhood obesity and not the timing. © 2011 Macmillan Publishers Limited All rights reserved.link_to_subscribed_fulltex

Short-term fatty acid intervention elicits differential gene expression responses in adipose tissue from lean and overweight men

The goal of this study was to investigate the effect of a short-term nutritional intervention on gene expression in adipose tissue from lean and overweight subjects. Gene expression profiles were measured after consumption of an intervention spread (increased levels of polyunsaturated fatty acids, conjugated linoleic acid and medium chain triglycerides) and a control spread (40 g of fat daily) for 9 days. Adipose tissue gene expression profiles of lean and overweight subjects were distinctly different, mainly with respect to defense response and metabolism. The intervention resulted in lower expression of genes related to energy metabolism in lean subjects, whereas expression of inflammatory genes was down-regulated and expression of lipid metabolism genes was up-regulated in the majority of overweight subjects. Individual responses in overweight subjects were variable and these correlated better to waist–hip ratio and fat percentage than BMI

Plasma sphingosine-1-phosphate is elevated in obesity

Background: Dysfunctional lipid metabolism is a hallmark of obesity and insulin resistance and a risk factor for various cardiovascular and metabolic complications. In addition to the well known increase in plasma triglycerides and free fatty acids, recent work in humans and rodents has shown that obesity is associated with elevations in the bioactive class of sphingolipids known as ceramides. However, in obesity little is known about the plasma concentrations of sphinogsine-1-phosphate (S1P), the breakdown product of ceramide, which is an important signaling molecule in mammalian biology. Therefore, the purpose of this study was to examine the impact of obesity on circulating S1P concentration and its relationship with markers of glucose metabolism and insulin sensitivity. Methodology/Principal Findings: Plasma S1P levels were determined in high-fat diet (HFD)-induced and genetically obese (ob/ob) mice along with obese humans. Circulating S1P was elevated in both obese mouse models and in obese humans compared with lean healthy controls. Furthermore, in humans, plasma S1P positively correlated with total body fat percentage, body mass index (BMI), waist circumference, fasting insulin, HOMA-IR, HbA1c (%), total and LDL cholesterol. In addition, fasting increased plasma S1P levels in lean healthy mice. Conclusion: We show that elevations in plasma S1P are a feature of both human and rodent obesity and correlate with metabolic abnormalities such as adiposity and insulin resistance

Relationship between perceived body weight and body mass index based on self- reported height and weight among university students: a cross-sectional study in seven European countries

Mikolajczyk RT, Maxwell AE, El Ansari W, Stock C, Petkeviciene J, Guillen-Grima F. Relationship between perceived body weight and body mass index based on self- reported height and weight among university students: a cross-sectional study in seven European countries. BMC Public Health. 2010;10(1): 40.Background Despite low rates of obesity, many university students perceive themselves as overweight, especially women. This is of concern, because inappropriate weight perceptions can lead to unhealthy behaviours including eating disorders. Methods We used the database from the Cross National Student Health Survey (CNSHS), consisting of 5,900 records of university students from Bulgaria, Denmark, Germany, Lithuania, Poland, Spain and Turkey to analyse differences in perceived weight status based on the question: "Do you consider yourself much too thin, a little too thin, just right, a little too fat or much too fat?". The association between perceived weight and body mass index (BMI) calculated from self-reported weight and height was assessed with generalized non-parametric regression in R library gam. Results Although the majority of students reported a normal BMI (72-84% of males, 65-83% of females), only 32% to 68% of students considered their weight "just right". Around 20% of females with BMI of 20 kg/m2 considered themselves "a little too fat" or "too fat", and the percentages increased to 60% for a BMI of 22.5 kg/m2. Male students rarely felt "a little too fat" or "too fat" below BMI of 22.5 kg/m2, but most felt too thin with a BMI of 20 kg/m2. Conclusions Weight ideals are rather uniform across the European countries, with female students being more likely to perceive themselves as "too fat" at a normal BMI, while male students being more likely to perceive themselves as "too thin". Programs to prevent unhealthy behaviours to achieve ill-advised weight ideals may benefit students