The document discusses the relationship between adipose tissue, innate immunity, inflammation, and the metabolic syndrome from a nutrigenomics perspective. It emphasizes the impact of dietary saturated fat on inflammation and health, outlining the characteristics of metabolic syndrome and proposing new nutritional science approaches. Additionally, the findings suggest a strong link between adipose tissue dysfunction and the progression of nonalcoholic fatty liver disease (NAFLD), highlighting potential early biomarkers for disease prediction.

1. Adipose tissue, innate immunity and inflammation – a nutrigenomics perspective of the metabolic syndromehttp://twitter.com/nutrigenomicsMichael MüllerNetherlands Nutrigenomics Centre& Nutrition, Metabolism and Genomics GroupDivision of Human Nutrition, Wageningen University

2. I will talk aboutOur challenges: What is healthyWhat is Nutrigenomics?The metabolic syndromeThe deadly sinsGood fat / bad fat (tissue)Modern nutritional science & early biomarkersNASH & the role of the adipose tissueDietary saturated fat can induce pro-inflammatory responsesWe have different phenotypes: Personalized healthSaturated fat can be “killing” (in transgenic mice)Summary & recommendations

3. What do we know about the health network?

4. Our scientific challenge: What's healthy?

5. We are what we eat

6. Our “paleolithic” genes + modern dietsPaleolithic eraModern Times1.200.000 Generations between feast en famine2-3 Generations in energy abundance% Energy% Energy100100GrainMilk/-productsIsolated CarbohydratesIsolated Fat/OilAlcoholLow-fat meatChickenEggsFish50MeatChickenFish50FruitVegetables (carrots)NutsHoneyFruitVegetablesBeans00

7. Nutrigenomics Quantification of the nutritional genotype-phenotype LifestyleNutritionEnvironment

8. Adipocytes at the crossroads of energy homeostasis

9. What is the metabolic syndrome? The metabolic syndrome is characterized by a group of metabolic risk factors in one person:Central obesity (excessive fat tissue in and around the abdomen) Atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls) Raised blood pressure (130/85 mm Hg or higher) Insulin resistance or glucose intolerance (the body can’t properly use insulin or blood sugar) Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood) Proinflammatory state (e.g., elevated high-sensitivity C-reactive protein in the blood)

10. The 7 deadly sins (gluttony & sloth)

11. Proposed pathway to the metabolic syndrome

12. Metabobolic homeostasis & syndrome

13. NormalType 2 DiabetesVisceral Fat Distribution:Normal vs Type 2 Diabetes

15. We need a new nutritional science Insulin ± oral agentsOral combinationOral monotherapyDiet & exerciseComplex Disease100Different & similar targets80Pharma60DISEASE STATE (%) 40Nutrition200TIME (months/years)HomeostasisHealthL. Afman & M. Müller J Am DietAssoc. 2006;106:569-576.

16. Late biomarkersof diseaseEarlybiomarkersof diseaseOnset of diseaseBiomarkers of earlydiseasestateSingle marker vsmultimarker profilesDiseasePharmaNutritionEarly biomarkers in human nutrition researchhealthy

17. Organ-specific gene expression signatures of the early phase (metabolic stress) & the late phase of metabolic syndrome 1 2 3 4 10 16 WeeksWAT 1 2 3 4 10 16 WeeksMuscle 1 2 3 4 10 16 WeeksLiver 1 2 3 4 10 16 WeeksIntestineHealthy UnhealthyHealthy UnhealthyHealthy UnhealthyHealthy Unhealthy

19. Metabolism & Inflammation

20. Liver, FAT & NASH/NAFLDNonalcoholic Fatty Liver Diseases (NAFLD):Liver component of Metabolic Syndrome

21. Different stages in NAFLD progression:

22. Molecular events involved in NASH pathogenesis:

23. Role of PPARa (Endocrinology 2008 & Hepatology 2010)

24. Role Kupffer cells (Hepatology 2010)

25. Role of macrophages in lipid metabolism (JBC 2008; Cell Metabolism 2010)hepatic steatosis steatohepatitis (NASH) & fibrosiscirrhosis

26. Study: Interaction between WAT and liver tissue essential for NASH/NAFLD in C57Bl/6 miceObjective: Nonalcoholic fatty liver disease (NAFLD) is strongly linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aimed to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH.

27. Experimental Designtissue collectionrun-in diet20 weeks diet interventionplasma collectionmultiple proteinassaysliver

28. stratification on body weightfrozen sections: histological feat.lipid contentRNA extraction:Affx microarrays10 LFD0248121620 weeks20 LFD-3quality control & data analysis pipeline10 HFDMouse genome 430 2.010% low fat diet (palm oil)45% high fat diet (palm oil)ep. white adipose tissueparaffin sections: histological feat.RNA extraction: real-time PCR

29. High fat diet-induced obesity0248121620HFLLFLHFHLFH2520**15**BW gain (g)*10****50weeks under diet interventionLiver TG contentHepatomegalyALT plasma activity20010100********160880**120660*Ratio LW/BW (%)mg TG/g liverALT activity (UI)80440**40220000LFLLFHHFLHFH

30. A subpopulation of mice fed HFD develops NASH

31. Immunohistochemicalstaining confirms enhanced liver inflammation and early fibrosis in HFH miceMacrophage CD68CollagenStellate cell GFAP

32. Upregulation of inflammatory and fibrotic gene expression in HFH responder mice

33. Adipose dysfunction in HFH mice

34. Change in adipose gene expression indicate adipose tissue dysfunction

35. Plasma proteins as early predictive biomarker for NASH in C57Bl/6 mice

36. Plasma proteins as early predictive biomarker for NASH in C57Bl/6 miceMultivariate analysis of association of protein plasma concentrations with final liver triglyceride content

37. ConclusionsOur data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis.It points to several novel potential predictive biomarkers for NASH. Duval C, Thissen U, Keshtkar S, Accart B, Stienstra R, Boekschoten MV, Roskams T, Kersten S, Müller M. Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice. Diabetes. 2010;59:3181-91.

39. Human nutrigenomics study Dietary fat and inflammation in adipose tissue Change in diet composition?Van Dijk et al. AJCN 2009de Luca, C and Olefsky JM, Nature Medicine 12, 41 - 42 (2006)

40. Design of the SFA vs MUFA-rich intervention studyT=10 wksT=0 wksT=2 wksRun-inSFA-rich diet (n=20)SFA-rich diet (n=10)MUFA-rich diet (n=10)After intervention Clamp

41. Adipose tissue biopsy

42. Blood samplingBaseline Clamp

43. Adipose tissue biopsy

44. Blood samplingVan Dijk et al. AJCN 2009

45. ‘Obese-linked’ pro-inflammatory gene expression profile by SFAsMUFA dietSFA dietThe SFA-rich diet:Induces a pro-inflammatory obese-linked gene expression profileDecreases expression and plasma level of the anti-inflammatory cytokine adiponectin“Personal Transcriptomes”Van Dijk et al. AJCN 2009

46. Humanstudy:Plasma Protein Profiling Reveals Protein Clusters Related to BMI and Insulin Levels in Middle-Aged Overweight SubjectsAIMAssociate plasma protein profiles with BMIIdentifypotential marker profile of earlydisease state. PLoS One. 2010 Dec 23;5(12):e14422

47. MeasurementsRulesBasedMedicine (Austin, USA)Multiplex immunoassayIn total 124 proteinsmeasuredInvolved in diseases, inflammation, endothelialfunction and metabolism. PLoS One. 2010 Dec 23;5(12):e14422

48. We are different: improved phenotyping necessary to reveal phenotype clusters. PLoS One. 2010 Dec 23;5(12):e14422

49. ConclusionWe identified clusters of plasma proteins associated with BMI and insulin in a healthy population. These clusters included earlier identified biomarkers for obesity-related disease as well as potential new biomarkers. These plasma protein clusters could have potential applications for improved phenotypic characterization of volunteers in nutritional intervention studies or as biomarkers in the early detection in obesity-linked disease development and progression.van DijkSJ, Feskens EJM, Heidema AG, Bos MB, van de Rest O, Geleijnse JM, de Groot CPGM, Müller M, Afman LA. Plasma Protein Profiling Reveals Protein Clusters Related to BMI and Insulin Levels in Middle-Aged Overweight Subjects. PLoS One. 2010 Dec 23;5(12):e14422

50. ChylomicronCE/TGAngptl4LPLCE/TGFFAChylomicron remnant

51. Angptl4-\- mice on HFD become very illLichtenstein et al. Cell Metab. 2010

52. Inflammatory response independent of microbiotaLichtenstein et al. Cell Metab. 2010

53. No effect of medium chain or PUFA TGsLichtenstein et al. Cell Metab. 2010

54. Massive enlargement of mesenteric lymph nodes in Angptl4-/- mice fed HFD

55. Angptl4 inhibits lipolysis and subsequent foam cell formation

56. ConclusionA high saturated fat diet causes massive inflammation in Angptl4-/- mice originating in mesenteric lymph nodes.

57. MLN-resident macrophages are protected from the pro-inflammatory effect of saturated fatty acids via expression of Angptl4, which is strongly induced by chyle and fatty acids and which via inhibition of LPL prevents lipolysis of chylomicron-TG.

58. In the absence of this protective mechanism, feeding a diet rich in saturated fat rapidly leads to enhanced lipid uptake into MLN-resident macrophages, triggering foam cell formation and a massive inflammatory response.Lichtenstein et al. Cell Metab. 2010

59. Is bariatric surgery the only solution?

60. Pharma is not the (only) solution:Eat foods rich in challenging food bioactivesDrugsABCPPARgPPARbPPARaReceptorC3C2C1Fatty acidsFC6C5C4Multiple targets

61. SummaryYou are what you eat => during life all events will leave their (epigenetic) traces on our genome, some are irreversible => ageingDisease phenotypes such as obesity, metabolic syndrome, diabetes are largely related to our “gluttony / sloth” lifestyles and modern convenient (“fast”) foods => unhealthy ageing.NASH is the liver phenotype of the metabolic syndrome and appears early in the progression towards diabetes or CVD. There is a tight relationship between adipose tissue dysfunction and NASH pathogenesis.Chronic overconsumption of saturated fat or lipogenic precursors (starch, sugars) induces non-resolving low-grade pro-inflammatory state largely caused by the innate immune system.=> choose the right lifestyle & food pattern (diverse & anti-inflammatory), eat less & exercise more (at least for 30 minutes/day).

62. 2 Meals a day, work as long as possible & embrace challengeWalter Breuning (1896 - 2011)

63. Sander KerstenLinda SandersonNatasha GeorgiadiMark BouwensLydia AfmanGuido HooiveldMeike BungerPhilip de GrootMark BoekschotenNicole de WitMohammad Ohid UllahChristian TrautweinFolkert KuipersBen van Ommen + many more