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 C. Lefebvre; Armand Valsesia; Celine Charon; Jacques Vervoort; Arne Astrup; Wim H M Saris; Melissa Morine; Jörg Hager

doi:10.1371/journal.pone.0150495

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 C. Lefebvre, Armand Valsesia, Celine Charon, Jacques Vervoort, Arne Astrup, Wim H M Saris, Melissa Morine, Jörg Hager

Obesity Research

8 Citations (Scopus)

102 Downloads (Pure)

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 language	English
Article number	e0150495
Journal	P L o S One
Volume	11
Issue number	3
Number of pages	16
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0150495
Publication status	Published - Mar 2016

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Matone et al_PLoS One_2016_Vol 11(3)_0150495Final published version, 802 KBLicence: CC BY

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@article{693e0b8acac643a8bdaf7f3e10eab542,

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 Marie-Pier Scott-Boyer and Jerome Carayol and Parastoo Fazelzadeh and Lefebvre, {Gregory C.} 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",

note = "CURIS 2016 NEXS 078",

year = "2016",

month = mar,

doi = "10.1371/journal.pone.0150495",

language = "English",

volume = "11",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

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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 C.

AU - Valsesia, Armand

AU - Charon, Celine

AU - Vervoort, Jacques

AU - Astrup, Arne

AU - Saris, Wim H M

AU - Morine, Melissa

AU - Hager, Jörg

N1 - CURIS 2016 NEXS 078

PY - 2016/3

Y1 - 2016/3

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 - Journal article

C2 - 26938218

SN - 1932-6203

VL - 11

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 3

M1 - e0150495

ER -

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

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