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Adipose tissue innate immunity & inflammation - a nutrigenomics perspective of the metabolic syndrome

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Adipose tissue, innate immunity and inflammation – a nutrigenomics perspective of the metabolic syndrome …

Adipose tissue, innate immunity and inflammation – a nutrigenomics perspective of the metabolic syndrome
Lecture in Scheveningen 2 Sept 2011

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  • Inflammation has been associated with many disease phenotypes including steatohepatitis or diabetes. This relationship is in particular when inflammation is chronic or non-resolving. There is an interaction between metabolism and inflammation with positive or negative consequences with respect to organ and systemic health.In my talk I will briefly discuss two unpublished studies, one investigating the important interaction of WAT and liver in particular under conditions of diet-induced obesity. Organ-specific macrophages in WAT and liver play an crucial role in progressing organ-specific inflammatory phenotypes. In the second study we found very interesting interaction between dietary fat and macrophages in mesenteric lymph nodes that are exposed postprandially to very high concentrations of chylomicrons. We used a k.o. mouse for ANGPTL4 and could show that chronic consumption of saturated fat can be deadly.
  • Haematoxylin and eosin staining (D) and oil red O staining (E) of representative liver sections of the 4 subgroups
  • (Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH miceImmunohistochemical staining of macrophage activation in representative liver section of HFL and HFH mice using antibody against the specific macrophagemarker Cd68Collagen staining using fast green FCF/sirius red F3B. Staining of stellate cell activation using antibody against GFAP.
  • - Number of genes up- or down-regulated in the various subgroups in comparison to the LFL mice, as determined by Affymetrix GeneChip analysis. Genes with a p-value below 0.05 were considered significantly regulated. - Heat map showing changes in expression of selected genes involved in lipid metabolism, inflammation and fibrosis in liver. Changes in gene expression of selected genes as determined by real-time quantitative PCR. Mean expression in LFL mice was set at 100%. Error bars reflect standard deviation. Bars with different letters are statistically different (P<0.05 according to Student’s t-test). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
  • Haematoxylin and eosin staining of representative adipose tissue sections. Immunohistochemical staining of macrophages using antibody against Cd68. Collagen staining using fast green FCF/sirius red F3B.
  • Adipose tissue mRNA expression of a selected group of genes was determined by quantitative real-time PCR after 21 weeks of dietary intervention. Mean expression in LFL mice was set at 100%. Error bars reflect standard deviation. * = significantly different from HFL mice according to Student’s t-test (P<0.05). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
  • . A) Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6h fast. White squares: LFL, Light grey squares: LFH, dark grey squares: HFL, black squares: HFH. Error bars reflect standard deviation. * = significantly different from HFL mice according to Student’s t-test (P<0.05). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
  • Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. Significant proteins display an inverse RSD value higher than 2 (bold line indicates the inverse RSD threshold value of 2).RSD = Relative standard deviation.
  • Transcript

    • 1. Adipose tissue, innate immunity and inflammation – a nutrigenomics perspective of the metabolic syndrome
      http://twitter.com/nutrigenomics
      Michael MüllerNetherlands Nutrigenomics Centre
      & Nutrition, Metabolism and Genomics GroupDivision of Human Nutrition, Wageningen University
    • 2. I will talk about
      Our challenges: What is healthy
      What is Nutrigenomics?
      The metabolic syndrome
      The deadly sins
      Good fat / bad fat (tissue)
      Modern nutritional science & early biomarkers
      NASH & the role of the adipose tissue
      Dietary saturated fat can induce pro-inflammatory responses
      We have different phenotypes: Personalized health
      Saturated 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 diets
      Paleolithic era
      Modern Times
      1.200.000 Generations between feast en famine
      2-3 Generations in energy abundance
      % Energy
      % Energy
      100
      100
      Grain
      Milk/-products
      Isolated Carbohydrates
      Isolated Fat/OilAlcohol
      Low-fat meatChicken
      Eggs
      Fish
      50
      Meat
      Chicken
      Fish
      50
      Fruit
      Vegetables (carrots)
      Nuts
      Honey
      Fruit
      Vegetables
      Beans
      0
      0
    • 7. Nutrigenomics Quantification of the nutritional genotype-phenotype
      Lifestyle
      Nutrition
      Environment
    • 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. Normal
      Type 2 Diabetes
      Visceral Fat Distribution:Normal vs Type 2 Diabetes
    • 14.
    • 15. We need a new nutritional science
      Insulin ± oral agents
      Oral combination
      Oral monotherapy
      Diet & exercise
      Complex Disease
      100
      Different & similar targets
      80
      Pharma
      60
      DISEASE STATE (%)
      40
      Nutrition
      20
      0
      TIME (months/years)
      HomeostasisHealth
      L. Afman & M. Müller J Am DietAssoc. 2006;106:569-576.
    • 16. Late biomarkersof disease
      Earlybiomarkersof disease
      Onset of disease
      Biomarkers of earlydiseasestate
      Single marker vsmultimarker profiles
      Disease
      Pharma
      Nutrition
      Early biomarkers in human nutrition research
      healthy
    • 17. Organ-specific gene expression signatures of the early phase (metabolic stress) & the late phase of metabolic syndrome
      1 2 3 4 10 16
      Weeks
      WAT
      1 2 3 4 10 16
      Weeks
      Muscle
      1 2 3 4 10 16
      Weeks
      Liver
      1 2 3 4 10 16
      Weeks
      Intestine
      Healthy Unhealthy
      Healthy Unhealthy
      Healthy Unhealthy
      Healthy Unhealthy
    • 18.
    • 19. Metabolism & Inflammation
    • 20. Liver, FAT & NASH/NAFLD
      • Nonalcoholic 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 mice
      Objective:
      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 Design
      tissue collection
      run-in diet
      20 weeks diet intervention
      • plasma collection
      multiple proteinassays
      • liver
      • 28. stratification on body weight
      frozen sections: histological feat.
      lipid content
      RNA extraction:Affx microarrays
      10 LFD
      0
      2
      4
      8
      12
      16
      20 weeks
      20 LFD
      -3
      quality control & data analysis pipeline
      10 HFD
      Mouse genome
      430 2.0
      10% low
      fat diet
      (palm oil)
      45% high fat diet (palm oil)
      • ep. white adipose tissue
      paraffin sections: histological feat.
      RNA extraction: real-time PCR
    • 29. High fat diet-induced obesity
      0
      2
      4
      8
      12
      16
      20
      HFL
      LFL
      HFH
      LFH
      25
      20
      *
      *
      15
      **
      BW gain (g)
      *
      10
      *
      *
      *
      *
      5
      0
      weeks under diet intervention
      Liver TG content
      Hepatomegaly
      ALT plasma activity
      200
      10
      100
      ***
      ***
      **
      160
      8
      80
      **
      120
      6
      60
      *
      Ratio LW/BW (%)
      mg TG/g liver
      ALT activity (UI)
      80
      4
      40
      *
      *
      40
      2
      20
      0
      0
      0
      LFL
      LFH
      HFL
      HFH
    • 30. A subpopulation of mice fed HFD develops NASH
    • 31. Immunohistochemicalstaining confirms enhanced liver inflammation and early fibrosis in HFH mice
      Macrophage CD68
      Collagen
      Stellate 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 mice
      Multivariate analysis of association of protein plasma concentrations with final liver triglyceride content
    • 37. Conclusions
      Our 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.
    • 38.
    • 39. Human nutrigenomics study Dietary fat and inflammation in adipose tissue
      Change in diet composition
      ?
      Van Dijk et al. AJCN 2009
      de Luca, C and Olefsky JM, Nature Medicine 12, 41 - 42 (2006)
    • 40. Design of the SFA vs MUFA-rich intervention study
      T=10 wks
      T=0 wks
      T=2 wks
      Run-in
      SFA-rich diet
      (n=20)
      SFA-rich diet (n=10)
      MUFA-rich diet (n=10)
      After intervention
      • Clamp
      • 41. Adipose tissue biopsy
      • 42. Blood sampling
      Baseline
      • Clamp
      • 43. Adipose tissue biopsy
      • 44. Blood sampling
      Van Dijk et al. AJCN 2009
    • 45. ‘Obese-linked’ pro-inflammatory gene expression profile by SFAs
      MUFA diet
      SFA diet
      The SFA-rich diet:
      Induces a pro-inflammatory obese-linked gene expression profile
      Decreases 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 Subjects
      AIM
      Associate plasma protein profiles with BMI
      Identifypotential marker profile of earlydisease state
      . PLoS One. 2010 Dec 23;5(12):e14422
    • 47. Measurements
      RulesBasedMedicine (Austin, USA)
      Multiplex immunoassay
      In total 124 proteinsmeasured
      Involved 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. Conclusion
      We 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. Chylomicron
      CE/TG
      Angptl4
      LPL
      CE/TG
      FFA
      Chylomicron remnant
    • 51. Angptl4-- mice on HFD become very ill
      Lichtenstein et al. Cell Metab. 2010
    • 52. Inflammatory response independent of microbiota
      Lichtenstein et al. Cell Metab. 2010
    • 53. No effect of medium chain or PUFA TGs
      Lichtenstein 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. Conclusion
      • A 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 bioactives
      Drugs
      A
      B
      C
      PPARg
      PPARb
      PPARa
      Receptor
      C3
      C2
      C1
      Fatty acids
      F
      C6
      C5
      C4
      Multiple targets
    • 61. Summary
      You are what you eat => during life all events will leave their (epigenetic) traces on our genome, some are irreversible => ageing
      Disease 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 challenge
      Walter Breuning (1896 - 2011)
    • 63. Sander KerstenLinda SandersonNatasha Georgiadi
      Mark BouwensLydia Afman
      Guido Hooiveld
      Meike Bunger
      Philip de Groot
      Mark Boekschoten
      Nicole de Wit
      Mohammad Ohid Ullah
      Christian Trautwein
      Folkert Kuipers
      Ben van Ommen + many more