Post on 11-Oct-2020
transcript
INFLUENCE OF EARLY NUTRITION ON METABOLIC PROCESSES
Investigated by targeted LC/MS based metabolomics
Christian Hellmuth
02/04/2014
Note: for non-commercial purposes only
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
TABLE OF CONTENT
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
2
2. EUROPEAN CHILDHOOD OBESITY PROJECT
1. METABOLOMICS
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
METABOLOMICS FUNCTIONAL INSIGHTS IN MOLECULAR CHANGES
02/04/2014 3
Genomics Transcriptomics
Proteomics
Metabolomics
Genotype Phenotype
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
METABOLOMICS ?
Determination of Metabolites
Metabolites
Small molecules (<1000 Dalton)
Substrates, intermediates and products of biological processes
Metabolome
Complete set of metabolites found within a biological sample
Understanding of biochemical changes & differences
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
4
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BENEFITS OF THE NEXT „OMICS“ FIELD
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
5
Dynamic response of living systems to stimuli and genetics1
Information on what is actual happening2
1 Nicholson, Lindon Nature. 2008 Oct 23;455(7216):1054-6 2 Xie, Schirra et al. J Biomed Biotechnol. 2012;2012:805683
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BENEFITS OF THE NEXT „OMICS“ THING
Insights into underlying molecular pathology1
Definition of biomarkers in biofluids1
Is the interplay between functional subunits changed by nutritional
changes?
Can we gain new functional insights?
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
6
1 Heazell, Dune et al. Placenta. 2011 Mar;32 Suppl 2:S119-24
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
HOW TO ANALYSE THE METABOLOME?
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
7
First: THINK
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BEFORE I DETERMINE THE METABOLOME!
What do I want to know?
Background of my clinical trial
Hypothesis for metabolic differences/response
What do I have?
Sample number, material, volume
Sampling conditions
Which of the possible analytical strategies are available?
Targeted vs. untargeted metabolomics
Analytical equipment – GC, LC, MS, NMR
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
8
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
CHOP - EUROPEAN CHILDHOOD OBESITY PROJECT
EARLY PROGRAMMING EFFECTS REFLECTED IN THE METABOLOME CHRISTIAN HELLMUTH, FRANCA KIRCHBERG, PETER RZEHAK, MARTINA WEBER, ANNICK XHONNEUX, NATALIA FERRE, ELVIRA VERDUCI, PIOTR SOCHA AND BERTHOLD KOLETZKO FOR THE EUROPEAN CHILDHOOD OBESITY TRIAL STUDY GROUP
02/04/2014 9
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
EARLY PROGRAMMING
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
10
Conception Birth 6 Month
Maternal nutrition Maternal stress Placental development Placental transfer
Infant nutrition
Later Life
Obesity Diabetes CVD Allergy Cognition Behaviour ….
Environment and Nutrition
Genotype Phenotype
Metabolomics
PROGRAMMING
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
EARLY PROTEIN HYPOTHESIS
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
11
Protein Intake
Insulin, IGF1 levels
Weight gain 0-24 month
Adipogenic activity
Later obesity risk
Metabolomics Insulinogenic amino acids
Metabolomics Changes in fat oxidation - acylcarnitines
Changes in lipid profile - phospholipids
Metabolomics Changes in energetic efficiency
Modified from Koletzko, Grote et al. Am J Clin Nutr. 2009 May;89(5):1502S-1508S
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
EUROPEAN CHILDHOOD OBESITY PROJECT
02/04/2014 12
Intervention groups Observational group
Lower protein formula (LP)
Higher protein formula (HP) Breastfed (BF)
263 265 163
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
Koletzko et al. Am J Clin Nutr. 2009 Jun;89(6):1836-45
BLOOD SAMPLING AT 6 MONTH OF AGE
RANDOMIZATION
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
CHOP – WEIGHT GAIN
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
13
Koletzko, Grote et al. Am J Clin Nutr. 2009 Jun;89(6):1836-45
Data published in Socha, Koletzko et al. Am J Clin Nutr. 2011 Dec;94(6 Suppl):1776S-1784S
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
EARLY PROTEIN HYPOTHESIS
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
14
Higher Protein Intake
Elevated Insulin, IGF1 levels
Increased weight gain 0-24 month
Adipogenic activity
✔
✔
✔
?
?
Modified from Koletzko, Grote et al. Am J Clin Nutr. 2009 May;89(5):1502S-1508S
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
EUROPEAN CHILDHOOD OBESITY PROJECT
Amino acids determined by LC-MS/MS1
Polar lipids and glucose analysis by FIA-MS/MS2
21 Amino acids (AA)
41 Acylcarnitines (Carn.a)
14 Sphingomyelins (SM)
76 Phosphatidylcholins (PC)
15 Lysosphosphatidylcholins (LPC)
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
15
1 Harder, Peissner et al. J Chromatogr B. 2011 Mar 1;879(7-8):495-504. 2 Absolute IDQ p 150 kit
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
CHOP – HP VS. LP
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
16
Branched-chain amino acids
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BRANCHED-CHAIN AMINO ACIDS (BCAA)
Leucine, Isoleucine, Valine
Elevated in HP group
Dietary BCAA escape first-pass liver metabolism
Oxidized in skeletal muscle
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
17
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
FIRST PASS METABOLISM
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
18
Dietary protein
GIT Portal vein Liver
Amino acids 20 % BCAA
Amino acid metabolism
Systemic circulation
BCAA Oxidation
Amino acids > 50% BCAA
Skeletal muscle
Wahren J, Felig P, Hagenfeldt L. J Clin Invest. 1976 Apr;57(4):987-99.
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BRANCHED-CHAIN AMINO ACIDS (BCAA)
Leucine, Isoleucine, Valine
Elevated in HP group
Dietary BCAA escape first-pass liver metabolism
Oxidized in skeletal muscle
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
19
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BCAA OXIDATION
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
20
Non-hepatic
4.1
Valine
5.0.oxo
Val
4.0
4.0.OH
4.0.oxo
3.0
5.1
Leucine
6.0.oxo
Leu
5.0
6.1.DC
6.0.OH.DC
5.1
Isoleucine
6.0.oxo
Ile
5.0
5.0.OH
5.0.oxo
3.0 2.0
Glutamate
α-Ketoglutarate
Glu
NAD+
NADH/H+
NAD+
NADH/H+ NAD+
NADH/H+
Shimomura Y, Murakami T, Harris RA et al. J Nutr. 2004 Jun;134(6 Suppl):1583S-1587S
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
CHOP – LP VS. HP
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
21
Branched-chain amino acids
Short-chain acylcarnitines
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BCAA OXIDATION
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
22
Non-hepatic
4.1
Valine
5.0.oxo
Val
4.0
4.0.OH
4.0.oxo
3.0
5.1
Leucine
6.0.oxo
Leu
5.0
6.1.DC
6.0.OH.DC
5.1
Isoleucine
6.0.oxo
Ile
5.0
5.0.OH
5.0.oxo
3.0 2.0
NAD+
NADH/H+
BCKD Rate limiting
Brosnan, Brosnan J Nutr. 2006 Jan;136(1 Suppl):207S-11S
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
LEUCINE OXIDATION
Physiological level - linear stimulation
of degradation pathway
Regulation of BCAA level
Excess BCAA BCAA exceed
degradation pathway
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
23
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BCAA EFFECTS
Hydrophobic substrates for proteins1
Stimulation of insulin secretion2
Inhibition of glucagon secretion2
Reducing protein breakdown2
Enhancing protein synthesis (mTOR)3
Brain-uptake of glutamate1
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
24
Signal for dietary protein intake
1 Brosnan, Brosnan J Nutr. 2006 Jan;136(1 Suppl):207S-11S 2 Nair, Short J Nutr. 2005 Jun;135(6 Suppl):1547S-52S. 3 Anthony, Kimball et al. J Nutr. 2000 Oct;130(10):2413-9.
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
IMPACT OF BCAA ON FAT METABOLISM
Leucine slows-down beta-oxidation1,2
Leucine decreases lipolysis2
Leucine increases lipogenesis2
Leucine, Isoleucin and Valin deprivation reduce fat mass3
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
25
1 Goichon, Coeffier et al. J Proteomics. 2013 Jan 14;78:535-44. 2 Cheng, Guo et al. Diabetes. 2010 Jan;59(1):17-25. 3 Du, Guo et al. Amino Acids. 2012 Aug;43(2):725-34.
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BETA-OXIDATION
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
26
Even-chain acylcarnitines
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
EARLY PROTEIN HYPOTHESIS
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
27
Protein Intake
Insulin, IGF1 levels
Weight gain 0-24 month
Adipogenic activity
✔
✔
✔
Modified from Koletzko, Grote et al. Am J Clin Nutr. 2009 May;89(5):1502S-1508S
Elevation of insulinogenic amino acids (BCAA)
Reduction of beta-oxidation substrates(long-chain acylcarnitines)
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
TAKE HOME MESSAGE
Metabolomics provides insights into pathways and metabolic changes
Higher Protein intake results especially in elevated BCAA levels
Excess BCAA levels overcome BCAA degradation
BCAA may effect beta-oxidation and fat storage
Reduced long-chain acylcarnitines reflect reduced beta-oxidation
02/04/2014
Influence of Early Nutrition on Metabolic processes – Christian Hellmuth
28
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
DIVISION OF METABOLIC AND NUTRITIONAL MEDICINE
DR. VON HAUNER CHILDREN’S HOSPITAL
THANK YOU FOR YOUR ATTENTION
02/04/2014 29
www.project-earlynutrition.eu