Metabolomic profiles of childhood obesity Wei Perng, Matthew W. - PowerPoint PPT Presentation

Note: for non-commercial purposes only Metabolomic profiles of childhood obesity Wei Perng, Matthew W. Gillman, Abby F. Fleisch, Ryan D. Michalek, Steven Watkins, Elvira Isganaitis, Mary-Elizabeth Patti, and Emily Oken Obesity Prevention Program Department of Population Medicine Harvard Medical School & Harvard Pilgrim Health Care Institute Boston, MA, USA wei.perng@gmail.com 1

Background The role of metabolomics Disturbed Classic biomarkers of risk metabolite profiles Disease ? ↑ Insulin resistance • Type 2 DM ? ↑ Inflammation Obesity • CVD ↑ Leptin, ↓ Adiponectin • MetS ↑ HDL, ↓ LDL, ↑ TG 2

Research aims Aim 1 Obese vs. lean Difference in metabolite profiles? Aim 2 Classic biomarkers Metabolite profiles HOMA-IR ● leptin, adiponectin triglycerides ● CRP, IL-6 Aim 3 Maternal peripartum Child metabolite profile characteristics obesity ● excessive GWG gestational diabetes 3

Study population P R O J E C T A Study of Health for Viva the Next Generation 2128 live singleton births Criteria: • Fasting blood from child • Maternal characteristics Mid-childhood 648 eligible Target sample size: 300 • Include: all child obesity & GDM • Criteria: adequate serum volume 262 mother-child pairs 4

Study population Characteristics of 262 Project Viva mother-child pairs Mean ± SD or % (N) Child Child's age (years) 8.0 ± 0.9 Female 50% (131) Obesity (BMI ≥95 th percentile) 32.1% (84) Race/ethnicity White 56.3% (147) African American 24.1% (63) Hispanic 6.9 %(18) Mother Mother's age at enrollment (years) 32.0 ± 5.8 Pre-pregnancy obesity (BMI >30 kg/m 2 ) 22.5% (59) Excessive gestational weight gain 58.8% (154) Gestational diabetes 8.4% (22) 5

Methods Step 2: Principal components Serum analysis (PCA) ( n = 262) Step 1: Untargeted 345 metabolites metabolomic profiling 18 factors Step 3: Compare factor scores Obese (BMI≥95 th %ile) Lean (BMI<85 th %ile) Step 4: Multivariable linear regression VS. Metabolite factors Classic biomarkers scores Maternal peripartum Metabolite factor n = 84 n = 150 characteristics scores 6

Results Aim 1: Comparison of factor scores between obese & lean children 2,0 Factor 4: Branched-chain Factor 9: Androgen hormones • 4-androsten-3beta,17beta-diol disulfate 1 amino acids (BCAA) 1,5 • DHEA-S • Valine Difference (95% CI) in factor scores* • Epiandrosterone sulfate • Leucine • Androsterone sulfate • Phenylalanine 1,0 • 4-androsten-3beta,17beta-diol disulfate 2 • Isoleucine • Pregn steroid monosulfate • Proprionylcarnitine (C3) • Pregnen-diol disulfate 0,5 • 2-methylbutyrylcarnitine (C5) • Pregnenolone sulfate • Isovalerylcarnitine • Andro steroid monosulfate 2 • Isobutyrylcarnitine 0,0 • Tryptophan • 3-methyl-2-oxovalerate • Kynurenine -0,5 • Tyrosine • Gamma-glutamylleucine • 4-methyl-2-oxopentanoate -1,0 -1,5 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 F18 *Estimates are adjusted for child’s sex, age, and race/ethnicity; 95% CIs reflect Bonferroni’s correction. 7

Results Aim 2: Associations of BCAA & androgen metabolite patterns with cardiometabolic risk biomarkers BCAA-related pattern 0,50 Difference (95% CI) in biomarker* Androgen pattern 0,40 0,30 0,20 0,10 0,00 -0,10 HOMA-IR Triglycerides Leptin Adiponectin CRP IL-6 -0,20 (mg/dL) (ng/mL) (µg/mL) (mg/L) (pg/mL) *Adjusted for maternal education and child age, sex, race/ethnicity, and fast-food intake. All biomarkers are ln-transformed. 8

Results Aim 3: Associations of maternal peripartum characteristics with offspring metabolite patterns BCAA-related pattern 1,20 Difference (95% CI) in factor score* Androgen pattern 0,70 0,20 + child -0,30 BMI -0,80 Pre-pregnancy Excessive gestational Gestational diabetes -1,30 obesity weight gain mellitus *Adjusted for maternal education and child age, sex, race/ethnicity, and fast-food intake. 9

Conclusions Aim 1 ↑ BCAA Childhood obesity ↑ Androgen hormones Aim 2 ↑ BCAA Worse cardiometabolic profile ↑ Androgen hormones Aim 3 ↑ BCAA in offspring Maternal obesity 10

Acknowledgements  Dr. Emily Oken  Funding/Suppor t : This study was funded by the US NIH (K24 HD069408, R37 HD 034568, P30 DK092924).  Sheryl L. Rifas-Shiman for data management and preparation.  The mothers and children of Project Viva.  Past and present Project Viva staff. 11

Questions? 12

Associations of maternal peripartum characteristics with offspring metabolite patterns, accounting for child BMI Difference (95% CI) in factor score* 1,20 0,70 0,20 -0,30 -0,80 -1,30 Pre-pregnancy Excessive gestational Gestational diabetes obesity weight gain mellitus *Adjusted for maternal education and child age, sex, race/ethnicity, fast- food intake, and child’s BMI z -score 13

Factor 4: Plasma metabolite concentrations of obese versus lean children Metabolite concentration z-score Obese Lean P b BMI ≥95 th %ile BMI <85 th %ile Factor loading n = 84 n = 150 Factor 4: mean ± SD = 0.00 ± 1.52 Valine 0.83 1.17 ± 0.30 -0.54 ±0.27 <0.0001 Leucine 0.76 1.38 ± 0.32 -0.37 ±0.29 <0.0001 Phenylalanine 0.72 1.23 ± 0.33 -0.27 ± 0.29 <0.0001 Isoleucine 0.71 1.18 ± 0.31 -0.37 ±0.27 <0.0001 Proprionylcarnitine (C3) 0.66 0.95 ± 0.29 -0.44 ±0.25 <0.0001 2-methylbutyrylcarnitine (C5) 0.63 0.80 ± 0.29 -0.03 ±0.26 0.0002 Isovalerylcarnitine 0.60 1.34 ± 0.30 -0.33 ±0.26 <0.0001 Isobutyrylcarnitine 0.56 1.19 ± 0.35 0.33 ± 0.31 0.001 Tryptophan 0.54 1.07 ± 0.33 0.21 ± 0.29 0.0007 3-methyl-2-oxovalerate 0.52 0.92 ± 0.30 -0.11 ± 0.26 <0.0001 Kynurenine 0.52 0.56 ± 0.32 -0.19 ± 0.28 0.002 Tyrosine 0.51 1.54 ± 0.28 0.04 ± 0.25 <0.0001 Gamma-glutamylleucine 0.51 0.53 ± 0.32 -0.23 ± 0.28 0.002 4-methyl-2-oxopentanoate 0.51 0.73 ± 0.30 -0.23 ± 0.26 <0.0001 a Estimates represent mean ± SE and are adjusted for child's sex, age, and race/ethnicity. b From a t-test. * Indicates tier 2 identification in which no commercially available authentic standards could be found, however annotated based on accurate mass, spectral and chromatographic similarity to tier 1 identified compounds. 14

Factor 9: Plasma metabolite concentrations of obese versus lean children Metabolite concentration z-score Obese Lean P b Factor BMI ≥95 th %ile BMI <85 th %ile loading n = 84 n = 150 Factor 9: mean ± SD: 0.00 ± 1.62 4-androsten-3beta,17beta-diol disulfate 1* 0.86 0.61 ± 0.31 -0.49 ± 0.27 <0.0001 Dehydroepiandrosterone sulfate (DHEA-S) 0.84 0.45 ± 0.27 -0.41 ± 0.23 <0.0001 Epiandrosterone sulfate 0.79 0.14 ± 0.32 -0.70 ± 0.29 0.0007 Androsterone sulfate 0.79 0.30 ± 0.29 -0.38 ± 0.26 0.002 4-androsten-3beta,17beta-diol disulfate 2* 0.78 0.48 ± 0.35 -0.74 ± 0.31 <0.0001 Pregn steroid monosulfate* 0.76 0.70 ± 0.30 -0.22 ± 0.26 <0.0001 Pregnen-diol disulfate* 0.70 0.30 ± 0.30 -0.14 ± 0.26 0.05 Pregnenolone sulfate 0.65 0.71 ± 0.33 -0.09 ± 0.29 0.002 Andro steroid monosulfate 2* 0.61 0.41 ± 0.29 -0.46 ± 0.26 <0.0001 a Estimates represent mean ± SE and are adjusted for child's sex, age, and race/ethnicity. b From the Wald chi-squared test. * Indicates tier 2 identification in which no commercially available authentic standards could be found, however annotated based on accurate mass, spectral and chromatographic similarity to tier 1 identified compounds. 15