Abstract:Summary
Childhood obesity has become a global epidemic and carries significant long‐term consequences to physical and mental health. Metabolomics, the global profiling of small molecules or metabolites, may reveal the mechanisms of development of childhood obesity and clarify links between obesity and metabolic disease. A systematic review of metabolomic studies of childhood obesity was conducted, following Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, searching across Scopus, Ovid, Web… Show more
“…Higher levels of tyrosine (an AAA) and leucine (a BCAA) were associated with obesity, SMFQ, and depression symptoms with consistent effects. Both tyrosine and leucine are widely and consistently associated with childhood obesity ( Handakas et al, 2021 ). A recent study in children showed that high tyrosine levels during life are associated with more internalizing behaviors and negative emotions ( Van Vliet et al, 2019 ).…”
Section: Discussionmentioning
confidence: 99%
“…Animal studies showed that gut microbiota play a causal role in the development of features of depression ( Kelly et al, 2016 ) and anxiety ( De Palma et al, 2017 ), supporting further evidence that there is a modulation of neurotransmission that is likely a route of communication along the gut-brain axis. Plasma AAAs, which are directly modulated by the gut microbiota ( Handakas et al, 2021 ) could therefore influence later propensity for mental health disorders through metabolic processes of gut and brain interaction. BCAAs, including leucine, play an important role in the activation of the mammalian target of rapamycin (mTor) pathway–a pathway involved in the control of cell growth and proliferation–and has been associated with a short-term decrease in depressive symptoms ( Baranyi et al, 2016 ).…”
Section: Discussionmentioning
confidence: 99%
“…Although this CpG was identified through the EWAS approach and therefore strongly associated with obesity in this study, it was not among the 483 CpGs identified as putatively associated with body mass in the literature review ( Alfano et al, 2021 ) or the study of ( Wahl et al, 2017 ), suggesting that while it may contribute to poorer mental health among ALSPAC children with obesity, this relationship is unlikely to be generalizable to other populations. To date, few CpGs have been consistently associated with body mass in children ( Vehmeijer et al, 2020 ; Alfano et al, 2021 ), in contrast to adults ( Wahl et al, 2017 ) and indeed metabolites ( Handakas et al, 2021 ). This lack of consistency may be related to the length of time in an obese state, which is shorter for children ( Vehmeijer et al, 2020 ).…”
Section: Discussionmentioning
confidence: 99%
“…For instance, branched-chain amino acids (BCAAs) may influence brain function by modifying large, neutral amino acid transport at the blood–brain barrier, interfering with neurotransmitter synthesis ( Fernstrom, 2005 ) ( Gruenbaum et al, 2019 ). Recent reviews of the effects of obesity on the epigenome and metabolome in children identified consistent increases in both BCAAs and aromatic amino acids (AAAs) ( Handakas et al, 2021 ) and methylation at multiple CpGs (sites of DNA methylation), albeit with less consistency between studies ( Alfano et al, 2021 ).…”
Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies.
“…Higher levels of tyrosine (an AAA) and leucine (a BCAA) were associated with obesity, SMFQ, and depression symptoms with consistent effects. Both tyrosine and leucine are widely and consistently associated with childhood obesity ( Handakas et al, 2021 ). A recent study in children showed that high tyrosine levels during life are associated with more internalizing behaviors and negative emotions ( Van Vliet et al, 2019 ).…”
Section: Discussionmentioning
confidence: 99%
“…Animal studies showed that gut microbiota play a causal role in the development of features of depression ( Kelly et al, 2016 ) and anxiety ( De Palma et al, 2017 ), supporting further evidence that there is a modulation of neurotransmission that is likely a route of communication along the gut-brain axis. Plasma AAAs, which are directly modulated by the gut microbiota ( Handakas et al, 2021 ) could therefore influence later propensity for mental health disorders through metabolic processes of gut and brain interaction. BCAAs, including leucine, play an important role in the activation of the mammalian target of rapamycin (mTor) pathway–a pathway involved in the control of cell growth and proliferation–and has been associated with a short-term decrease in depressive symptoms ( Baranyi et al, 2016 ).…”
Section: Discussionmentioning
confidence: 99%
“…Although this CpG was identified through the EWAS approach and therefore strongly associated with obesity in this study, it was not among the 483 CpGs identified as putatively associated with body mass in the literature review ( Alfano et al, 2021 ) or the study of ( Wahl et al, 2017 ), suggesting that while it may contribute to poorer mental health among ALSPAC children with obesity, this relationship is unlikely to be generalizable to other populations. To date, few CpGs have been consistently associated with body mass in children ( Vehmeijer et al, 2020 ; Alfano et al, 2021 ), in contrast to adults ( Wahl et al, 2017 ) and indeed metabolites ( Handakas et al, 2021 ). This lack of consistency may be related to the length of time in an obese state, which is shorter for children ( Vehmeijer et al, 2020 ).…”
Section: Discussionmentioning
confidence: 99%
“…For instance, branched-chain amino acids (BCAAs) may influence brain function by modifying large, neutral amino acid transport at the blood–brain barrier, interfering with neurotransmitter synthesis ( Fernstrom, 2005 ) ( Gruenbaum et al, 2019 ). Recent reviews of the effects of obesity on the epigenome and metabolome in children identified consistent increases in both BCAAs and aromatic amino acids (AAAs) ( Handakas et al, 2021 ) and methylation at multiple CpGs (sites of DNA methylation), albeit with less consistency between studies ( Alfano et al, 2021 ).…”
Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies.
“…In addition, as bisphenol A is poorly soluble in water, the presence in blood can result from high levels in drinking water [92]. Finally, it should be pointed out that a number of different factors need to be considered when undertaking metabolomic studies, including diet [110] and comorbidities [111][112][113][114][115][116][117][118][119]. In this regard, obesity [111,112], chronic obstructive pulmonary disease [113][114][115], kidney disease [116], diabetes [117,118], and cardiovascular disease [94] have all been reported to have a major impact on the metabolome that can confound metabolomic studies in cancer, and thus, their influence cannot be underestimated.…”
Section: Effect Of Underlying Diseases or Non-related Metabolitesmentioning
The five-year survival rate of lung cancer patients is very low, mainly because most newly diagnosed patients present with locally advanced or metastatic disease. Therefore, early diagnosis is key to the successful treatment and management of lung cancer. Unfortunately, early detection methods of lung cancer are not ideal. In this brief review, we described early detection methods such as chest X-rays followed by bronchoscopy, sputum analysis followed by cytological analysis, and low-dose computed tomography (LDCT). In addition, we discussed the potential of metabolomic fingerprinting, compared to that of other biomarkers, including molecular targets, as a low-cost, high-throughput blood-based test that is both feasible and affordable for early-stage lung cancer screening of at-risk populations. Accordingly, we proposed a paradigm shift to metabolomics as an alternative to molecular and proteomic-based markers in lung cancer screening, which will enable blood-based routine testing and be accessible to those patients at the highest risk for lung cancer.
Diet plays an essential role in health and disease. Therefore, its determination is an important component of many investigations. The aim of the study was to evaluate the effect of a nutritional intervention on the urinary metabolome in children aged 6–12 years. Also, it was intended to identify biomarkers of diet quality and dietary intake. A 2‐month, randomized, controlled, parallel trial was conducted in Spanish children. The analyses focused on the ALINFA group, which followed a full‐fixed meal plan including healthy products, ready‐to‐eat meals, and healthy recipes. Diet quality was assessed by the KIDMED index and dietary intake by a food frequency questionnaire. Untargeted metabolomic analysis on urine samples was carried out, and multivariate analyses were performed for pattern recognition and characteristic metabolite identification. PLS‐DA and Volcano plot analyses were performed to identify the discriminating metabolites of this group. 12 putative metabolites were found to be the most relevant to this intervention. Most of them were products derived from protein and amino acid metabolism (N‐Ribosylhistidine, indolacrylic acid, and peptides) and lipid metabolism (3‐oxo‐2‐pentylcyclopentane‐1‐hexanoic acid methyl, Suberoyl‐L‐carnitine, and 7‐Dehydrodichapetalin E). All these metabolites decreased after the intervention, which was mainly associated with a decrease in the consumption of fatty meat and total fat, especially saturated fat. In turn, N‐Ribosylhistidine and Suberoyl‐L‐carnitine were negatively associated with diet quality, as well as able to predict the change in KIDMED index. In conclusion, the changes observed in urinary metabolome demonstrate the effectiveness of the ALINFA nutritional intervention.
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