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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
1
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
2
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
3
Obese vs. lean Difference in metabolite profiles?
Metabolite profiles Classic biomarkers
Maternal peripartum characteristics Child metabolite profile
obesity ● excessive GWG gestational diabetes
HOMA-IR ● leptin, adiponectin triglycerides ● CRP, IL-6
Aim 1
Aim 2
Aim 3
4
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
5
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
6
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
Dif
fere
nce
(9
5%
CI)
in f
acto
r sc
ore
s*
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
8
HOMA-IR
Triglycerides
(mg/dL) Leptin
(ng/mL) Adiponectin
(µg/mL) CRP
(mg/L) IL-6
(pg/mL)
Dif
fere
nce
(9
5%
CI)
in b
iom
arke
r*
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 obesity
Excessive gestational weight gain
Gestational diabetes mellitus
Aim 3: Associations of maternal peripartum characteristics with offspring metabolite patterns
Dif
fere
nce
(9
5%
CI)
in f
acto
r sc
ore
*
BCAA-related pattern
Androgen pattern
+ child BMI
Results
9
10
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.
11
Acknowledgements
13
-1,30
-0,80
-0,30
0,20
0,70
1,20
Pre-pregnancy obesity
Excessive gestational weight gain
Gestational diabetes mellitus
Associations of maternal peripartum characteristics with offspring metabolite patterns, accounting for child BMI
Dif
fere
nce
(9
5%
CI)
in f
acto
r sc
ore
*
*Adjusted for maternal education and child age, sex, race/ethnicity, fast-food intake, and child’s BMI z-score
14
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 on accurate mass, spectral and chromatographic similarity to tier 1 identified compounds.
15
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.
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