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

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

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Obesity Prevention Program Department of Population Medicine Harvard Medical School & Harvard Pilgrim Health Care Institute Boston, MA, USA wei.perng@gmail.com

Note: for non-commercial purposes only

Background

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The role of metabolomics

↑Insulin resistance ↑Inflammation ↑Leptin, ↓Adiponectin ↑HDL, ↓LDL, ↑TG Classic biomarkers of risk Obesity Disturbed metabolite profiles

• Type 2 DM
• CVD
• MetS

Disease

? ?

Research aims

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Obese vs. lean Difference in metabolite profiles? Metabolite profiles Classic biomarkers Maternal peripartum characteristics Child metabolite profile

• besity ● excessive GWG

gestational diabetes HOMA-IR ● leptin, adiponectin triglycerides ● CRP, IL-6

Aim 1 Aim 2 Aim 3

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2128 live singleton births 262 mother-child pairs

Viva

A Study of Health for the Next Generation

P

R O J E C T

648 eligible

Mid-childhood

Criteria:

• Fasting blood from child
• Maternal characteristics

Target sample size: 300

• Include: all child obesity & GDM
• Criteria: adequate serum volume

Study population

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Mean ± SD or % (N) Child

Child's age (years) 8.0 ± 0.9 Female 50% (131) Obesity (BMI ≥95th 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/m2) 22.5% (59) Excessive gestational weight gain 58.8% (154) Gestational diabetes 8.4% (22)

Characteristics of 262 Project Viva mother-child pairs

Study population

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345 metabolites

Serum (n = 262)

Step 1:

Untargeted metabolomic profiling

Step 2:

Principal components analysis (PCA)

Step 3:

Compare factor scores VS.

Obese (BMI≥95th %ile) Lean (BMI<85th %ile)

n = 84 n = 150

18 factors Step 4:

Multivariable linear regression

Metabolite factors scores Classic biomarkers Maternal peripartum characteristics Metabolite factor scores

Methods

• 1,5
• 1,0
• 0,5

0,0 0,5 1,0 1,5 2,0

Difference (95% CI) in factor scores*

F18 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 *Estimates are adjusted for child’s sex, age, and race/ethnicity; 95% CIs reflect Bonferroni’s correction. 7

Factor 4: Branched-chain amino acids (BCAA)

• Valine
• Leucine
• Phenylalanine
• Isoleucine
• Proprionylcarnitine (C3)
• 2-methylbutyrylcarnitine (C5)
• Isovalerylcarnitine
• Isobutyrylcarnitine
• Tryptophan
• 3-methyl-2-oxovalerate
• Kynurenine
• Tyrosine
• Gamma-glutamylleucine
• 4-methyl-2-oxopentanoate

Factor 9: Androgen hormones

• 4-androsten-3beta,17beta-diol disulfate 1
• DHEA-S
• Epiandrosterone sulfate
• Androsterone sulfate
• 4-androsten-3beta,17beta-diol disulfate 2
• Pregn steroid monosulfate
• Pregnen-diol disulfate
• Pregnenolone sulfate
• Andro steroid monosulfate 2

Aim 1: Comparison of factor scores between obese & lean children

Results

• 0,20
• 0,10

0,00 0,10 0,20 0,30 0,40 0,50

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HOMA-IR Triglycerides (mg/dL) Leptin (ng/mL) Adiponectin (µg/mL) CRP (mg/L) IL-6 (pg/mL)

Difference (95% CI) in biomarker*

Aim 2: Associations of BCAA & androgen metabolite patterns with cardiometabolic risk biomarkers

*Adjusted for maternal education and child age, sex, race/ethnicity, and fast-food intake. All biomarkers are ln-transformed.

BCAA-related pattern Androgen pattern

Results

*Adjusted for maternal education and child age, sex, race/ethnicity, and fast-food intake.

• 1,30
• 0,80
• 0,30

0,20 0,70 1,20 Pre-pregnancy

• besity

Excessive gestational weight gain Gestational diabetes mellitus

Aim 3: Associations of maternal peripartum characteristics with offspring metabolite patterns

Difference (95% CI) in factor score*

BCAA-related pattern Androgen pattern + child BMI

Results

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Childhood obesity ↑ BCAA ↑ Androgen hormones ↑ BCAA ↑ Androgen hormones Worse cardiometabolic profile Maternal obesity ↑ BCAA in offspring

Conclusions

Aim 1 Aim 2 Aim 3

• Dr. Emily Oken
• Funding/Support: 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.

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Acknowledgements

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Questions?

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• 1,30
• 0,80
• 0,30

0,20 0,70 1,20

Pre-pregnancy

• besity

Excessive gestational weight gain Gestational diabetes mellitus

Associations of maternal peripartum characteristics with offspring metabolite patterns, accounting for child BMI

Difference (95% CI) in factor score*

*Adjusted for maternal education and child age, sex, race/ethnicity, fast-food intake, and child’s BMI z-score

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Factor 4: Plasma metabolite concentrations of obese versus lean children

Metabolite concentration z-score Pb Obese Lean Factor BMI ≥95th %ile BMI <85th %ile 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

• n accurate mass, spectral and chromatographic similarity to tier 1 identified compounds.

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Factor 9: Plasma metabolite concentrations of obese versus lean children

Metabolite concentration z-score Pb Obese Lean Factor BMI ≥95th %ile BMI <85th %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.