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Nanjing 3 2013 Lecture "Nutrigenomics part 3"

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From healthy to too much
"The role of Muscle, White Adipose Tissue, Liver for metabolic flexibility"

Veröffentlicht in: Gesundheit & Medizin, Technologie
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Nanjing 3 2013 Lecture "Nutrigenomics part 3"

  1. 1. Lecture 3From healthy to too muchThe role of Muscle, WAT, Liver for metabolic flexibilityMichael MüllerNutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University
  2. 2. Adipocytes at the crossroads of energy homeostasis
  3. 3. Liver functions related to nutrition1. Bile formation2. Gluconeogenesis3. Glycogen-synthesis4. Lipogenesis (new fat, TG)5. VLDL formation6. LDL uptake7. Cholesterol synthesis8. Bile acid synthesis (from cholesterol)
  4. 4. Liver
  5. 5. Hepatocyte
  6. 6. Liver dysfunctions /diseasesrelated to nutrition1. Hepatic steatosis(fatty liver)2. Liver inflammation3. NASH (non-alcoholicsteatohepatitis)4. Fibrosis5. Cirrhosis6. Cancer
  7. 7. Metabolic defects leading to thedevelopment of hepatic steatosis
  8. 8. White (WAT)Brown (BAT)Adipose tissue
  9. 9. Adipose tissue
  10. 10. Adipocyte
  11. 11. WAT Functions related to Nutrition1. Lipolysis2. Lipogenesis (TG)3. Maintaining triglyceride and free fatty acid levels& determining insulin resistance4. Protecting other organs from lipotoxicity
  12. 12. WAT dysfunctions related to nutrition1. Overweight, Obesity, Metabolicsyndrome, Diabetes, CVD, Cancer….2. Abdominal fat has a different metabolicprofile & being more prone to induceinsulin resistance.3. Central obesity is a marker of impairedglucose tolerance & is an independentrisk factor for cardiovascular disease
  13. 13. de Wit NJ, Afman LA, Mensink M, Müller MPhenotyping the effect of diet on non-alcoholicfatty liver disease J Hepatol 2012.
  14. 14. Communication between liver and adiposetissue essential for adequate lipid storage
  15. 15. Healthy (Homeostasis)
  16. 16. Unhealthy (Type 2 Diabetes)
  17. 17. Balance between insulin and glucagonSREBP-1cLXRChREBPGRFOXA2CREBPPARaFed state Fasted stateGlucose FFA
  18. 18. Metabolism & Inflammation
  19. 19. Liver, FAT & NASH/NAFLD Nonalcoholic Fatty Liver Diseases (NAFLD):Liver component of Metabolic Syndrome Different stages in NAFLD progression: Molecular events involved in NASH pathogenesis: Role of PPARa (Endocrinology 2008 & Hepatology 2010) Role Kupffer cells (Hepatology 2010) Role of macrophages in lipid metabolism (JBC 2008; Cell Metabolism 2010)hepatic steatosis steatohepatitis (NASH) & fibrosis cirrhosis
  20. 20. Interaction between WAT and liver tissueessential for NASH/NAFLD in C57Bl/6 miceObjective:– Nonalcoholic fatty liver disease (NAFLD) isstrongly linked to obesity and diabetes,suggesting an important role of adipose tissuein the pathogenesis of NAFLD.– Here we aimed to investigate the interactionbetween adipose tissue and liver in NAFLD,and identify potential early plasma markersthat predict NASH.
  21. 21. Experimental Design• stratificationon body weight• liver• plasma collectionmultiple protein assaysRNA extraction: Affx microarraystissue collectionrun-in diet 20 weeks diet interventionfrozen sections: histological feat.• ep. white adipose tissue10% lowfat diet(palm oil)10 LFD10 HFD45% highfat diet(palm oil)20 LFDRNA extraction: real-time PCRparaffin sections: histological feat.lipid contentquality control &data analysispipelineMousegenome430 2.00 2 4 8 12 16 20 weeks-3
  22. 22. High fat diet-induced obesity05101520250 2 4 8 12 16 20weeks under diet interventionBWgain(g)****** ** *LFLLFHHFLHFH******Liver TG content04080120160200mgTG/gliverALTactivity(UI)ALT plasma activityRatioLW/BW(%)Hepatomegaly**0246810***020406080100* *LFL LFH HFL HFH
  23. 23. A subpopulation of mice fed HFD develops NASH
  24. 24. Immunohistochemical staining confirms enhanced liverinflammation and early fibrosis in HFH miceMacrophage CD68CollagenStellate cell GFAP
  25. 25. Upregulation of inflammatory and fibroticgene expression in HFH responder mice
  26. 26. Adipose dysfunction in HFH mice
  27. 27. Change in adipose gene expressionindicate adipose tissue dysfunction
  28. 28. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice
  29. 29. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 miceMultivariate analysis of association of proteinplasma concentrations with final livertriglyceride content
  30. 30. Conclusions• The data support the existence of a tightrelationship between adipose tissuedysfunction and NASH pathogenesis.• It points to several novel potentialpredictive biomarkers for NASH.
  31. 31. PeripheralbloodProtein turnoverAmino acidmetabolismGlycogenogenesisGlyconeogenesisGlycolysisLipogenesis,oxidationGI-tractMacronutrientcompositionof the dietLiverGut peptidesNutrientsBacterialderivedcomponentsInfluence of dietary protein on gene expression andmetabolic phenotype in the gut-liver axis
  32. 32. Objective Investigating the effect of a high protein diet onhepatic lipid accumulation. Unravel mechanisms which are responsible forthe reduced liver fat.
  33. 33. Design & diets1 week 12 weeksAcute effectof a high fat /high protein dietLong term diet effecton the developmentof liver steatosis2 weeksRun-in:control dietExperimental diets Carbohydrate (en%) Fat (en%) Protein (en%)Two low fat diet – normal or high proteinLF-NP 75 10 15LF-HP 40 10 50Two high fat diet – normal or high proteinHF-NP 50 35 15HF-HP 15 35 50
  34. 34. Body composition and food intakeSchwarz, J. et al., PLoS ONE 2012.
  35. 35. Hepatic steatosis50 µmSchwarz, J. et al., PLoS ONE 2012.
  36. 36. Fasting and postprandial plasma triglyceridesSchwarz, J. et al., PLoS ONE 2012.
  37. 37. Microarray analysis to study geneexpression
  38. 38. Enrichment map for HP vs. NP feedingto identify biological functionsSchwarz, J. et al., PLoS ONE 2012.
  39. 39. Changes in liver amino acid metabolic pathways induced byincreasing dietary proteinSchwarz, J. et al., PLoS ONE 2012.
  40. 40. Skeletal muscle functions & disorders• Force production =>Movement• Heat production• Protein storage• Glucose & lipidhomeostasis• Myopathies (muscularweakness)• Atrophy• Sarcopenia of aging• Ectopic fat disposition• Insulin resistance
  41. 41. Skeletal muscle
  42. 42. Myocyte
  43. 43. Interplay between adipokines andmyokines represent a yin–yang balancePedersen, B. K. & Febbraio, M. A. (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organNat. Rev. Endocrinol. doi:10.1038/nrendo.2012.49
  44. 44. Skeletal muscle is a secretory organ
  45. 45. Link of physical activity to protectionagainst premature mortality
  46. 46. The Molecular Basis of Adaptation to Exercise
  47. 47. Transcriptional Regulators of Metabolism and Adaptation in Skeletal Muscle
  48. 48. The timeline of the study (A) and set-upof the endurance exercise bout (B)
  49. 49. Exercise increases heart rate and plasma levelsof FFA, insulin, cortisol and noradrenaline
  50. 50. Exercise mainly causes upregulation of gene expressionin both the exercising and non-exercising leg
  51. 51. Top 20 of most highly induced genes inexercising and non-exercising leg
  52. 52. Induction of transcription factorpathways by exercise
  53. 53. Nutrition, Metabolism & Genomics Group
  54. 54. Wageningen University• Founded in 1918• ~3000 employees• ~7500 students• ~220 PhD graduations per year