title: Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance.
abstract: OBJECTIVE
  Weight loss success is dependent on the ability to refrain from regaining the lost weight in time. This feature was shown to be largely variable among individuals, and these differences, with their underlying molecular processes, are diverse and not completely elucidated. Altered plasma metabolites concentration could partly explain weight loss maintenance mechanisms. In the present work, a systems biology approach has been applied to investigate the potential mechanisms involved in weight loss maintenance within the Diogenes weight-loss intervention study.
  
  
  RESULTS
  A genome wide association study identified SNPs associated with plasma glycine levels within the CPS1 (Carbamoyl-Phosphate Synthase 1) gene (rs10206976, p-value = 4.709e-11 and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tissue showed that CPS1 expression levels were associated with successful weight maintenance and with several SNPs within CPS1 (cis-eQTL). In order to contextualize these results, a gene-metabolite interaction network of CPS1 and glycine has been built and analyzed, showing functional enrichment in genes involved in lipid metabolism and one carbon pool by folate pathways.
  
  
  CONCLUSIONS
  CPS1 is the rate-limiting enzyme for the urea cycle, catalyzing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria. Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle. Furthermore, glycine could be linked to metabolic health and insulin sensitivity through the betaine osmolyte. These considerations, and the results from the present study, highlight a possible role of CPS1 and related pathways in weight loss maintenance, suggesting that it might be partly genetically determined in humans.
authors.affiliation: The Microsoft Research-University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Matone
authors.affiliation: The Microsoft Research-University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy.
authors.forename: Marie-Pier
authors.initials: MP
authors.lastname: Scott-Boyer
authors.affiliation: Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
authors.forename: Jerome
authors.initials: J
authors.lastname: Carayol
authors.affiliation: Nutrition, Metabolism & Genomics group, University of Wageningen, Wageningen, Netherlands.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Fazelzadeh
authors.affiliation: Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
authors.forename: Gregory
authors.initials: G
authors.lastname: Lefebvre
authors.affiliation: Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
authors.forename: Armand
authors.initials: A
authors.lastname: Valsesia
authors.affiliation: CEA-Genomics Institute- National Genotyping Center, Evry, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Charon
authors.affiliation: Nutrition, Metabolism & Genomics group, University of Wageningen, Wageningen, Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Vervoort
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Astrup
authors.affiliation: Dept of Human Biology Medical and Health Science Faculty, University of Maastricht, Maastricht, Netherlands.
authors.forename: Wim H M
authors.initials: WH
authors.lastname: Saris
authors.affiliation: The Microsoft Research-University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Morine
authors.affiliation: Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hager
mesh_terms: D000328:Adult; D000641:Ammonia / Q000097:blood; D001622:Betaine / Q000097:blood; D031204:Caloric Restriction; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D002221:Carbamyl Phosphate / Q000097:blood; D002874:Chromosome Mapping; D005260:Female; D015870:Gene Expression; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005998:Glycine / Q000097:blood; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D055442:Metabolome; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000178:diet therapy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014508:Urea / Q000097:blood*; D015431:Weight Loss
chemical_list: D001622:Betaine; D002221:Carbamyl Phosphate; D000641:Ammonia; D014508:Urea; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D005998:Glycine