Network analysis of metabolite GWAS hits: Implication of CPS1 and the urea cycle in weight maintenance

Alice Matone, Marie Pier Scott-Boyer, Jerome Carayol, Parastoo Fazelzadeh, Gregory Lefebvre, Armand Valsesia, Celine Charon, Jacques Vervoort, Arne Astrup, Wim H.M. Saris, Melissa Morine, Jörg Hager

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

Abstract

Background and Scope 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. Methods and 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- II and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tis sue showed that CPS1 expression levels were associated with successful weight mainte nance 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 ana lyzed, 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.

Original languageEnglish
Article numbere150495
JournalPLoS ONE
Volume11
Issue number3
DOIs
Publication statusPublished - 2016

Fingerprint

Carbamyl Phosphate
Genome-Wide Association Study
weight control
Electric network analysis
Metabolites
Urea
urea
Maintenance
phosphates
metabolites
Weights and Measures
Weight Loss
weight loss
Glycine
Genes
glycine (amino acid)
Folic Acid
carbon sinks
folic acid
Aminomethyltransferase

Cite this

Matone, A., Scott-Boyer, M. P., Carayol, J., Fazelzadeh, P., Lefebvre, G., Valsesia, A., ... Hager, J. (2016). Network analysis of metabolite GWAS hits: Implication of CPS1 and the urea cycle in weight maintenance. PLoS ONE, 11(3), [e150495]. https://doi.org/10.1371/journal.pone.0150495
Matone, Alice ; Scott-Boyer, Marie Pier ; Carayol, Jerome ; Fazelzadeh, Parastoo ; Lefebvre, Gregory ; Valsesia, Armand ; Charon, Celine ; Vervoort, Jacques ; Astrup, Arne ; Saris, Wim H.M. ; Morine, Melissa ; Hager, Jörg. / Network analysis of metabolite GWAS hits : Implication of CPS1 and the urea cycle in weight maintenance. In: PLoS ONE. 2016 ; Vol. 11, No. 3.
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title = "Network analysis of metabolite GWAS hits: Implication of CPS1 and the urea cycle in weight maintenance",
abstract = "Background and Scope 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. Methods and 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- II and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tis sue showed that CPS1 expression levels were associated with successful weight mainte nance 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 ana lyzed, 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.",
author = "Alice Matone and Scott-Boyer, {Marie Pier} and Jerome Carayol and Parastoo Fazelzadeh and Gregory Lefebvre and Armand Valsesia and Celine Charon and Jacques Vervoort and Arne Astrup and Saris, {Wim H.M.} and Melissa Morine and J{\"o}rg Hager",
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Matone, A, Scott-Boyer, MP, Carayol, J, Fazelzadeh, P, Lefebvre, G, Valsesia, A, Charon, C, Vervoort, J, Astrup, A, Saris, WHM, Morine, M & Hager, J 2016, 'Network analysis of metabolite GWAS hits: Implication of CPS1 and the urea cycle in weight maintenance' PLoS ONE, vol. 11, no. 3, e150495. https://doi.org/10.1371/journal.pone.0150495

Network analysis of metabolite GWAS hits : Implication of CPS1 and the urea cycle in weight maintenance. / Matone, Alice; Scott-Boyer, Marie Pier; Carayol, Jerome; Fazelzadeh, Parastoo; Lefebvre, Gregory; Valsesia, Armand; Charon, Celine; Vervoort, Jacques; Astrup, Arne; Saris, Wim H.M.; Morine, Melissa; Hager, Jörg.

In: PLoS ONE, Vol. 11, No. 3, e150495, 2016.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Network analysis of metabolite GWAS hits

T2 - Implication of CPS1 and the urea cycle in weight maintenance

AU - Matone, Alice

AU - Scott-Boyer, Marie Pier

AU - Carayol, Jerome

AU - Fazelzadeh, Parastoo

AU - Lefebvre, Gregory

AU - Valsesia, Armand

AU - Charon, Celine

AU - Vervoort, Jacques

AU - Astrup, Arne

AU - Saris, Wim H.M.

AU - Morine, Melissa

AU - Hager, Jörg

PY - 2016

Y1 - 2016

N2 - Background and Scope 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. Methods and 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- II and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tis sue showed that CPS1 expression levels were associated with successful weight mainte nance 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 ana lyzed, 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.

AB - Background and Scope 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. Methods and 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- II and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tis sue showed that CPS1 expression levels were associated with successful weight mainte nance 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 ana lyzed, 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.

U2 - 10.1371/journal.pone.0150495

DO - 10.1371/journal.pone.0150495

M3 - Article

VL - 11

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 3

M1 - e150495

ER -

Matone A, Scott-Boyer MP, Carayol J, Fazelzadeh P, Lefebvre G, Valsesia A et al. Network analysis of metabolite GWAS hits: Implication of CPS1 and the urea cycle in weight maintenance. PLoS ONE. 2016;11(3). e150495. https://doi.org/10.1371/journal.pone.0150495