Nutrigenomics: We are what we eat - the impact of nutrition on health and phenotype plasticity

1. Nutrigenomics:
We are what we eat - the impact of nutrition on
health and phenotype plasticity
Michael Müller
Netherlands Nutrigenomics Centre
& Nutrition, Metabolism and Genomics Group
Division of Human Nutrition, Wageningen University

2. Challenge 1:
Successful ageing - Stay healthy as long as possible
100 %
Health/ “Quality of life”
time

3. Challenge 2:
What's healthy?

4. Challenge 3:
Our “paleolithic” genes + modern diets
Paleolithic era Modern Times
1.200.000 Generations 2-3 Generations
between feast en famine in energy abundance
% Energy % Energy
100 100 Grain
Low-fat meat Milk/-products
Chicken Isolated Carbohydrates
Eggs Isolated Fat/Oil
Fish Alcohol
50 50 Meat
Fruit Chicken
Vegetables (carrots) Fish
Nuts
Honey
Fruit
Vegetables
0 0 Beans

5. Challenge 4:
We have a tsunami of health problems

6. Challenge 5:
Complex diseases are to complex for
„mono-target‟ drug therapies

7. We are what we eat

8. We are what we eat
Our foods have large impact on our gene expression & phenotype
• (Micro & Macro) Nutrients
– Mono & PU fatty acids
– Vitamins (e.g. vitamin A & D) , minerals (e.g. Zn)
• Microbiota (from foods)
– Vegetarians / omni- /carnivores => different microbiota
– “Raw” (e.g. “Sushi”) or fermented food consumption => food-
specific microbiota
• Food components (bitter, toxic – or healthy?)
– Secondary plant metabolites (e.g. resveratrol, glucosinolates,
cafestol....)
– MicroRNA (e.g. rice) => “nutrient”?

9. Phenotype plasticity
Phenotypic plasticity is the ability of an organism to
change its phenotype in response to changes in the
environment (e.g. nutrition).

10. 1 Genotype => 5 nutritional phenotypes
155 kg 76 kg

11. Genome plasticity

12. Timely relatively modest interventions in early
life can have a large effect on disease risk later

13. You are what you eat and have eaten:
Received, Recorded, Remembered & Revealed

14. Nutrigenomics
Quantification of the nutritional genotype-phenotype
Phenotype
Metabolome
Lifestyle
Proteome
Nutrition
Environment Transcriptome
Epigenome
Genotype

15. Why Nutrigenomics
• To understand nutrition &  Mechanisms
metabolic health/plasticity
• To comprehensively  Biomarkers
phenotype
• To validate FFQ  Nutritional Science 2.0
• To enable strategies to  Personal Nutrition
optimize personal health
• To provide scientific  Health claim support
evidence for health
claims of “functional”
foods

16. Dietary fat => Triglycerides => Fatty acids
Triglycerides Fatty acids
↕

17. Study of effects of fatty acids
at organ and cellular level
Fatty acids Organs Cells
Diabetes/
obesity
Cardiovascular
disease

18. How is gene regulation by dietary fat mediated ?
PPAR
PPAR /
PPAR
HNF4
RXRs
LXRs
FXR
SREBP1
TLR4
more

19. Understanding Nutrition
How nutrients regulate our genes: via sensing molecular switches
Changed
organ
metabolic
capacity
J Clin Invest. 2004;114:94-103 Am J Clin Nutr. 2007;86(5):1515-23 Am J Clin Nutr. 2009; 90:415-24
J Biol Chem. 2006;28:934-44 PLOS ONE 2008;3(2):e1681 Am J Clin Nutr. 2009;90:1656-64
Endocrinology. 2006;147:1508-16 BMC Genomics 2008; 9:231 Mol Cell Biology 2009;29:6257-67
Physiol Genomics. 2007;30:192-204 BMC Genomics 2008; 9:262 Am J Clin Nutr. 2010;91:208-17
Endocrinology. 2007;148:2753-63 J Biol Chem. 2008;283:22620-7 BMC Genomics 2009
BMC Genomics 2007; 8:267 Arterioscler Thromb Vasc Biol. 2009;29:969-74. Physiol. Genomics 2009
Arterioscler Thromb Vasc Biol. 2007;27:2420-7 Plos One 2009;4(8):e6796 Circulation 2010
HEPATOLOGY 2010;51:511-522 Diabetes 2010
Cell Metabolism 2010
Nature 2011

20. Intestine
LXR
Decreased cholesterol absorption
FXR
Increased bile salt recirculation
PPAR
Improved lipid handling
Regulation of Cholesterol and
Lipid Handling in Metabolic Organ
Systems by Nuclear Receptors

21. Comparison PPAR target pathways
intestine / liver

22. Concept of lipid sensing
Nutrient sensing:
Analogy with control panel

23. Saturated fatty acid Poly unsaturated fatty acid

24. Angptl4 is highly induced by fatty acids
in numerous cell types and tissues
Angptl4

25. Induction Angptl4 to prevent lipotoxicity

26. Differential regulation between saturated
and unsaturated fatty acids
Angptl4 CHOP
60 5.0
50 4.0
Fold change
Fold change
40
3.0
30
2.0
20
10 1.0
0 0.0

27. Differential regulation between saturated
and unsaturated fatty acids
Protective Toxic
60 5.0
50 4.0
Fold change
Fold change
40
3.0
30
2.0
20
10 1.0
0 0.0

28. Nutrigenomics & molecular nutrition allows
us to define the mechanistic framework
Blood
triglycerides

29. 29

30. Changes in the SFA, MUFA and MED groups in the expression of
genes involved in oxidative phosphorylation, mitochondrial
dysfunction, and ubiquinone biosynthesis
30

31. You are what you eat
Influence of dietary protein on the metabolic phenotype
in the gut-liver axis
Protein turnover
Gut Amino acid
Macronutrient peptides metabolism
composition Nutrients Glycogenogenesis
of the diet
Bacterial Glyconeogenesis
derived
Glycolysis
components
Lipogenesis,
oxidation
GI-tract Peripheral
Liver blood

32. Objectives
• Investigating the effect of a high protein diet on hepatic
lipid accumulation.
• Unravel mechanisms which are responsible for the
reduced liver fat.

33. Design & diets
2 weeks 1 week 12 weeks
Run-in: Acute effect Long term diet effect
control diet of a high fat / on the development
high protein diet of liver steatosis
Experimental diets Carbohydrate (en%) Fat (en%) Protein (en%)
Two low fat diet – normal or high protein
LF-NP 75 10 15
LF-HP 40 10 50
Two high fat diet – normal or high protein
HF-NP 50 35 15
HF-HP 15 35 50

34. Body composition and food intake
Schwarz, J. et al., PLoS ONE 2012.

35. Less liver fat / hepatic steatosis
50 µm
Schwarz, J. et al., PLoS ONE 2012.

36. Enrichment map for HP vs. NP feeding
to identify biological functions
Schwarz, J. et al., PLoS ONE 2012.

37. Schematic fate of dietary
amino acid utilisation in the liver
Schwarz, J. et al., PLoS ONE 2012.

38. Conclusion
• Prevention of NAFLD by HP diet by enhanced lipid
secretion and less efficient use of ingested energy.
• High protein diet modulates lipid handling in the mouse
small intestine.
• Microbiota and host response in the colon after
adaptation to a high protein diet.

39. Research
questions
Genomics
Databasing
MADMAX DB / DIETome DB
DB mining
PBMCs DB / NutriPheno DB
Microbiome DB
Secretome DB
Quantitative
Improved
Modeling
Systems Biology study design
Nutrigenomics Platform
NNC
High Standardization Omics-based
Omics-based Comprehensive Phenotyping
Phenotyping Phenotyping
Data capturing, basing, mining
MRI Nutritional Science 2.0 MRI
Imaging Imaging
Metabolic Metabolic
Challenge Controlled Challenge
nutritional
intervention

40. Metabolic flexibility
Optimal health: the ability of an organism to keep
metabolic balance in response to a wide range of
stressors.
Metabolic flexibility (=phenotypic flexibility): the
individual`s capacity to adapt in time and location to
changes in dietary conditions to keep metabolic balance.
Metabolic flexibility is thus a very important indicator of
individual health status, as it reflects the (dys)functioning
of metabolic organs, such as liver, muscle, adipose
tissue and gut.

41. Very personal conclusions
How to keep our metabolic flexibility/health
• Identify chronic (non-resolving) stress using
systems “perturbation” tests & deep genomics-
based phenotyping
• Solve it!
– Less Inflammation
– Less Metabolic Stress (less sat. fat, highly processed
/ lipogenic foods)
– More Exercise (muscle & other organs) with a
“challenging” lifestyle & food pattern
– Eat less from time to time
41

42. 2 Meals a day, work as long as possible &
embrace challenges
Walter Breuning (1896 - 2011)

43. Sander Kersten
Linda Sanderson
Natasha Georgiadi
Mark Bouwens
Lydia Afman
Guido Hooiveld
Wilma Steegenga
Philip de Groot
Mark Boekschoten
Nicole de Wit
Mohammad Ohid Ullah
Christian Trautwein
Folkert Kuipers
Ben van Ommen
Hannelore Daniel
Bart Staels
Edith Feskens
…..