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Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans.

ABSTRACT: Several clinical guidelines have been proposed to distinguish metabolically healthy obesity (MHO) from other subgroups of obesity but the molecular mechanisms by which MHO individuals remain metabolically healthy despite having a high fat mass are yet to be elucidated. We conducted the first whole blood transcriptomic study designed to identify specific sets of genes that might shed novel insights into the molecular mechanisms that protect or delay the occurrence of obesity-related co-morbidities in MHO. The study included 29 African-American obese individuals, 8 MHO and 21 metabolically abnormal obese (MAO). Unbiased transcriptome-wide network analysis was carried out to identify molecular modules of co-expressed genes that are collectively associated with MHO. Network analysis identified a group of 23 co-expressed genes, including ribosomal protein genes (RPs), which were significantly downregulated in MHO subjects. The three pathways enriched in the group of co-expressed genes are EIF2 signaling, regulation of eIF4 and p70S6K signaling, and mTOR signaling. The expression of ten of the RPs collectively predicted MHO status with an area under the curve of 0.81. Triglycerides/HDL (TG/HDL) ratio, an index of insulin resistance, was the best predictor of the expression of genes in the MHO group. The higher TG/HDL values observed in the MAO subjects may underlie the activation of endoplasmic reticulum (ER) and related-stress pathways that lead to a chronic inflammatory state. In summary, these findings suggest that controlling ER stress and/or ribosomal stress by downregulating RPs or controlling TG/HDL ratio may represent effective strategies to prevent or delay the occurrence of metabolic disorders in obese individuals.

SUBMITTER: Gaye A

PROVIDER: S-EPMC5789085 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans.

Gaye Amadou A Doumatey Ayo P AP Davis Sharon K SK Rotimi Charles N CN Gibbons Gary H GH

NPJ genomic medicine 20180129

Several clinical guidelines have been proposed to distinguish metabolically healthy obesity (MHO) from other subgroups of obesity but the molecular mechanisms by which MHO individuals remain metabolically healthy despite having a high fat mass are yet to be elucidated. We conducted the first whole blood transcriptomic study designed to identify specific sets of genes that might shed novel insights into the molecular mechanisms that protect or delay the occurrence of obesity-related co-morbiditie ...[more]

PMID: 29387454

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Project description:Background: In pediatric age the prevalence of obesity is high. Obese children who do not have other risk factors than excess weight have been defined as "metabolically healthy obese" (MHO). Aim: The aim of this study is to evaluate, in a population of obese children, the prevalence of the MHO and "metabolically unhealthy obese" (MUO) phenotype. Furthermore, we evaluated the distribution of Uric Acid, HOMA index and Waist-Height ratio (W-Hr) in the MHO and MUO sub-groups and the impact of these non-traditional risk factors on the probability to be MUO. Methods: In 1201 obese children and adolescents [54% males, age (±SD) 11.9 (±3.0) years] weight, height, waist circumference, systolic (SBP) and diastolic (DBP) blood pressure, pubertal status, glucose, insulin, HDL cholesterol, triglycerides and Uric Acid serum values were assessed. MUO phenotype was defined as the presence of at least one of the following risk factors: SBP or DBP ≥ 90th percentile, glycaemia ≥ 100 mg/dl, HDL cholesterol <40 mg/dl, triglycerides ≥100 mg/dl (children <10 years) or ≥130 mg/dl (children ≥10 years). A multivariate logistic regression analysis was used to estimate the association between MUO phenotype and non-traditional cardiovascular risk factors. Results: The prevalence of the MUO status was high (61%). MUO subjects were more often male, older and pubertal (p < 0.001). The levels of the three non-traditional risk factors were significantly higher in MUO children compared to MHO children (p < 0.001) and all of them were independent predictors of the fact of being MUO [OR 1.41 (95% CI 1.24-1.69); 1.15 (95% CI 1.06-1.23) and 1.03 (95% CI1.01-1.05) for Uric Acid, HOMA index and W-Hr, respectively]. About 15% of MHO subjects had serum Uric Acid, HOMA index and W-Hr values within the highest quartile of the study population. Conclusion: The prevalence of MUO subjects in a large pediatric population is high and serum Uric Acid, HOMA index and W-Hr values are independent predictors of the probability of being MUO. A non-negligible percentage of subjects MHO has high values of all three non-traditional risk factors.

Project description:BackgroundHigh diet quality is associated with a lower risk of chronic diseases. Metabolomics can be used to identify objective biomarkers of diet quality.ObjectivesWe used metabolomics to identify serum metabolites associated with 4 diet indices and the components within these indices in 2 samples from African Americans and European Americans.MethodsWe studied cross-sectional associations between known metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension Trial (DASH) diet, alternate Mediterranean diet (aMED), and their components using untargeted metabolomics in 2 samples (n1 = 1,806, n2 = 2,056) of the Atherosclerosis Risk in Communities study (aged 45-64 y at baseline). Dietary intakes were assessed using an FFQ. We used multivariable linear regression models to examine associations between diet indices and serum metabolites in each sample, adjusting for participant characteristics. Metabolites significantly associated with diet indices were meta-analyzed across 2 samples. C-statistics were calculated to examine if these candidate biomarkers improved prediction of individuals in the highest compared with lowest quintile of diet scores beyond participant characteristics.ResultsSeventeen unique metabolites (HEI: n = 6; AHEI: n = 5; DASH: n = 14; aMED: n = 2) were significantly associated with higher diet scores after Bonferroni correction in sample 1 and sample 2. Six of 17 significant metabolites [glycerate, N-methylproline, stachydrine, threonate, pyridoxate, 3-(4-hydroxyphenyl)lactate)] were associated with ≥1 dietary pattern. Candidate biomarkers of HEI, AHEI, and DASH distinguished individuals with highest compared with lowest quintile of diet scores beyond participant characteristics in samples 1 and 2 (P value for difference in C-statistics <0.02 for all 3 diet indices). Candidate biomarkers of aMED did not improve C-statistics beyond participant characteristics (P value = 0.930).ConclusionsA considerable overlap of metabolites associated with HEI, AHEI, DASH, and aMED reflects the similar food components and similar metabolic pathways involved in the metabolism of healthy diets in African Americans and European Americans.

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Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans.

Publications

Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans.

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