INFLUENCE OF EARLY NUTRITION ON METABOLIC PROCESSES

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1 Note: for non-commercial purposes only INFLUENCE OF EARLY NUTRITION ON METABOLIC PROCESSES Investigated by targeted LC/MS based metabolomics Christian Hellmuth

2 TABLE OF CONTENT 1. METABOLOMICS 2. EUROPEAN CHILDHOOD OBESITY PROJECT 2

3 METABOLOMICS FUNCTIONAL INSIGHTS IN MOLECULAR CHANGES Genotype Genomics Transcriptomics Proteomics Metabolomics Phenotype 3

4 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 4

5 BENEFITS OF THE NEXT OMICS FIELD Dynamic response of living systems to stimuli and genetics 1 Information on what is actual happening 2 1 Nicholson, Lindon Nature Oct 23;455(7216): Xie, Schirra et al. J Biomed Biotechnol. 2012;2012:

6 BENEFITS OF THE NEXT OMICS THING Insights into underlying molecular pathology 1 Definition of biomarkers in biofluids 1 Is the interplay between functional subunits changed by nutritional changes? Can we gain new functional insights? 1 Heazell, Dune et al. Placenta Mar;32 Suppl 2:S

7 HOW TO ANALYSE THE METABOLOME? First: THINK 7

8 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 8

CHOP - EUROPEAN CHILDHOOD OBESITY PROJECT EARLY PROGRAMMING EFFECTS REFLECTED IN THE METABOLOME CHRISTIAN HELLMUTH, FRANCA KIRCHBERG, PETER RZEHAK,

9 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 9

10 EARLY PROGRAMMING Metabolomics Genotype Conception Birth 6 Month Phenotype Later Life Maternal nutrition Maternal stress Placental development Placental transfer Infant nutrition Obesity Diabetes CVD Allergy Cognition Behaviour. Environment and Nutrition PROGRAMMING 10

EARLY PROTEIN HYPOTHESIS Protein Intake Metabolomics Insulinogenic amino acids Insulin, IGF1 levels Metabolomics Weight gain 0-24 month Changes in energetic efficiency Adipogenic activity

11 EARLY PROTEIN HYPOTHESIS Protein Intake Metabolomics Insulinogenic amino acids Insulin, IGF1 levels Metabolomics Weight gain 0-24 month Changes in energetic efficiency Adipogenic activity Metabolomics Changes in fat oxidation - acylcarnitines Changes in lipid profile - phospholipids Later obesity risk Modified from Koletzko, Grote et al. Am J Clin Nutr May;89(5):1502S-1508S 11

12 EUROPEAN CHILDHOOD OBESITY PROJECT Intervention groups Observational group RANDOMIZATION Lower protein formula (LP) Higher protein formula (HP) Breastfed (BF) BLOOD SAMPLING AT 6 MONTH OF AGE Koletzko et al. Am J Clin Nutr Jun;89(6):

13 CHOP WEIGHT GAIN Koletzko, Grote et al. Am J Clin Nutr Jun;89(6): Data published in Socha, Koletzko et al. Am J Clin Nutr Dec;94(6 Suppl):1776S-1784S 13

14 EARLY PROTEIN HYPOTHESIS Higher Protein Intake? Elevated Insulin, IGF1 levels? Increased weight gain 0-24 month Adipogenic activity 14 Modified from Koletzko, Grote et al. Am J Clin Nutr May;89(5):1502S-1508S

15 EUROPEAN CHILDHOOD OBESITY PROJECT Amino acids determined by LC-MS/MS 1 Polar lipids and glucose analysis by FIA-MS/MS 2 21 Amino acids (AA) 41 Acylcarnitines (Carn.a) 14 Sphingomyelins (SM) 76 Phosphatidylcholins (PC) 15 Lysosphosphatidylcholins (LPC) 15 1 Harder, Peissner et al. J Chromatogr B Mar 1;879(7-8): Absolute IDQ p 150 kit

16 CHOP HP VS. LP Branched-chain amino acids 16

17 BRANCHED-CHAIN AMINO ACIDS (BCAA) Leucine, Isoleucine, Valine Elevated in HP group Dietary BCAA escape first-pass liver metabolism Oxidized in skeletal muscle 17

18 FIRST PASS METABOLISM Skeletal muscle Dietary protein BCAA Oxidation Amino acids 20 % BCAA Amino acid metabolism Amino acids > 50% BCAA GIT Portal vein Liver Systemic circulation Wahren J, Felig P, Hagenfeldt L. J Clin Invest Apr;57(4):

19 BRANCHED-CHAIN AMINO ACIDS (BCAA) Leucine, Isoleucine, Valine Elevated in HP group Dietary BCAA escape first-pass liver metabolism Oxidized in skeletal muscle 19

BCAA OXIDATION Valine Val Leucine Leu Isoleucine Ile α-ketoglutarate 5.0.oxo 6.0.oxo 6.0.oxo Glutamate NAD + Glu 4.0 5.0 5.0 NADH/H + 4.1 5.1 5.1 4.0.OH 6.1.DC 5.0.OH NAD + 4.

20 BCAA OXIDATION Valine Val Leucine Leu Isoleucine Ile α-ketoglutarate 5.0.oxo 6.0.oxo 6.0.oxo Glutamate NAD + Glu NADH/H OH 6.1.DC 5.0.OH NAD oxo 6.0.OH.DC NAD oxo NADH/H NADH/H Non-hepatic Shimomura Y, Murakami T, Harris RA et al. J Nutr Jun;134(6 Suppl):1583S-1587S 20

21 CHOP LP VS. HP Branched-chain amino acids Short-chain acylcarnitines 21

22 BCAA OXIDATION Non-hepatic Valine Val Leucine Leu Isoleucine Ile 5.0.oxo 6.0.oxo 6.0.oxo BCKD Rate limiting OH DC OH Brosnan, Brosnan J Nutr Jan;136(1 Suppl):207S-11S 4.0.oxo OH.DC NAD + NADH/H oxo

23 LEUCINE OXIDATION Physiological level - linear stimulation of degradation pathway Regulation of BCAA level Excess BCAA BCAA exceed degradation pathway 23

BCAA EFFECTS Hydrophobic substrates for proteins 1 Stimulation of insulin secretion 2 Inhibition of glucagon secretion 2 Reducing protein breakdown 2 Enhancing protein synthesis (mtor) 3 Signal for

24 BCAA EFFECTS Hydrophobic substrates for proteins 1 Stimulation of insulin secretion 2 Inhibition of glucagon secretion 2 Reducing protein breakdown 2 Enhancing protein synthesis (mtor) 3 Signal for dietary protein intake Brain-uptake of glutamate 1 1 Brosnan, Brosnan J Nutr Jan;136(1 Suppl):207S-11S 2 Nair, Short J Nutr Jun;135(6 Suppl):1547S-52S. 3 Anthony, Kimball et al. J Nutr Oct;130(10):

25 IMPACT OF BCAA ON FAT METABOLISM Leucine slows-down beta-oxidation 1,2 Leucine decreases lipolysis 2 Leucine increases lipogenesis 2 Leucine, Isoleucin and Valin deprivation reduce fat mass 3 1 Goichon, Coeffier et al. J Proteomics Jan 14;78: Cheng, Guo et al. Diabetes Jan;59(1): Du, Guo et al. Amino Acids Aug;43(2):

26 BETA-OXIDATION Even-chain acylcarnitines 26

27 EARLY PROTEIN HYPOTHESIS Protein Intake Elevation of insulinogenic amino acids (BCAA) Insulin, IGF1 levels Reduction of beta-oxidation substrates(long-chain acylcarnitines) Weight gain 0-24 month Adipogenic activity 27 Modified from Koletzko, Grote et al. Am J Clin Nutr May;89(5):1502S-1508S

28 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 28

29 THANK YOU FOR YOUR ATTENTION 29

Dr. von Hauner Children s Hospital, Ludwig-Maximilians-University of Munich

Dr. von Hauner Children s Hospital, Ludwig-Maximilians-University of Munich Effects of early nutrition on the infant metabolome Christian Hellmuth 1, Olaf Uhl 1, Franca F. Kirchberg 1, Veit Grote 1, Martina Weber 1, Peter Rzehak 1, Clotilde Carlier 2, Natalia Ferre 3, Elvira Verduci