Lecture 3From healthy to too muchThe role of Muscle, WAT, Liver for metabolic flexibilityMichael MüllerNutrition, Metaboli...
Adipocytes at the crossroads of energy homeostasis
Liver functions related to nutrition1. Bile formation2. Gluconeogenesis3. Glycogen-synthesis4. Lipogenesis (new fat, TG)5....
Liver
Hepatocyte
Liver dysfunctions /diseasesrelated to nutrition1. Hepatic steatosis(fatty liver)2. Liver inflammation3. NASH (non-alcohol...
Metabolic defects leading to thedevelopment of hepatic steatosis
White (WAT)Brown (BAT)Adipose tissue
Adipose tissue
Adipocyte
WAT Functions related to Nutrition1. Lipolysis2. Lipogenesis (TG)3. Maintaining triglyceride and free fatty acid levels& d...
WAT dysfunctions related to nutrition1. Overweight, Obesity, Metabolicsyndrome, Diabetes, CVD, Cancer….2. Abdominal fat ha...
de Wit NJ, Afman LA, Mensink M, Müller MPhenotyping the effect of diet on non-alcoholicfatty liver disease J Hepatol 2012.
Communication between liver and adiposetissue essential for adequate lipid storage
Healthy (Homeostasis)
Unhealthy (Type 2 Diabetes)
Balance between insulin and glucagonSREBP-1cLXRChREBPGRFOXA2CREBPPARaFed state Fasted stateGlucose FFA
Metabolism & Inflammation
Liver, FAT & NASH/NAFLD Nonalcoholic Fatty Liver Diseases (NAFLD):Liver component of Metabolic Syndrome Different stages...
Interaction between WAT and liver tissueessential for NASH/NAFLD in C57Bl/6 miceObjective:– Nonalcoholic fatty liver disea...
Experimental Design• stratificationon body weight• liver• plasma collectionmultiple protein assaysRNA extraction: Affx mic...
High fat diet-induced obesity05101520250 2 4 8 12 16 20weeks under diet interventionBWgain(g)****** ** *LFLLFHHFLHFH******...
A subpopulation of mice fed HFD develops NASH
Immunohistochemical staining confirms enhanced liverinflammation and early fibrosis in HFH miceMacrophage CD68CollagenStel...
Upregulation of inflammatory and fibroticgene expression in HFH responder mice
Adipose dysfunction in HFH mice
Change in adipose gene expressionindicate adipose tissue dysfunction
Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice
Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 miceMultivariate analysis of association of proteinplasma...
Conclusions• The data support the existence of a tightrelationship between adipose tissuedysfunction and NASH pathogenesis...
PeripheralbloodProtein turnoverAmino acidmetabolismGlycogenogenesisGlyconeogenesisGlycolysisLipogenesis,oxidationGI-tractM...
Objective Investigating the effect of a high protein diet onhepatic lipid accumulation. Unravel mechanisms which are res...
Design & diets1 week 12 weeksAcute effectof a high fat /high protein dietLong term diet effecton the developmentof liver s...
Body composition and food intakeSchwarz, J. et al., PLoS ONE 2012.
Hepatic steatosis50 µmSchwarz, J. et al., PLoS ONE 2012.
Fasting and postprandial plasma triglyceridesSchwarz, J. et al., PLoS ONE 2012.
Microarray analysis to study geneexpression
Enrichment map for HP vs. NP feedingto identify biological functionsSchwarz, J. et al., PLoS ONE 2012.
Changes in liver amino acid metabolic pathways induced byincreasing dietary proteinSchwarz, J. et al., PLoS ONE 2012.
Skeletal muscle functions & disorders• Force production =>Movement• Heat production• Protein storage• Glucose & lipidhomeo...
Skeletal muscle
Myocyte
Interplay between adipokines andmyokines represent a yin–yang balancePedersen, B. K. & Febbraio, M. A. (2012) Muscles, exe...
Skeletal muscle is a secretory organ
Link of physical activity to protectionagainst premature mortality
The Molecular Basis of Adaptation to Exercise
Transcriptional Regulators of Metabolism and Adaptation in Skeletal Muscle
The timeline of the study (A) and set-upof the endurance exercise bout (B)
Exercise increases heart rate and plasma levelsof FFA, insulin, cortisol and noradrenaline
Exercise mainly causes upregulation of gene expressionin both the exercising and non-exercising leg
Top 20 of most highly induced genes inexercising and non-exercising leg
Induction of transcription factorpathways by exercise
Nutrition, Metabolism & Genomics Group
Wageningen University• Founded in 1918• ~3000 employees• ~7500 students• ~220 PhD graduations per year
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
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Nanjing 3 2013 Lecture "Nutrigenomics part 3"

From healthy to too much "The role of Muscle, White Adipose Tissue, Liver for metabolic flexibility"
Published on: Mar 3, 2016
Published in: Health & Medicine      Technology      
Source: www.slideshare.net


Transcripts - Nanjing 3 2013 Lecture "Nutrigenomics part 3"

  • 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. Adipocytes at the crossroads of energy homeostasis
  • 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. Liver
  • 5. Hepatocyte
  • 6. Liver dysfunctions /diseasesrelated to nutrition1. Hepatic steatosis(fatty liver)2. Liver inflammation3. NASH (non-alcoholicsteatohepatitis)4. Fibrosis5. Cirrhosis6. Cancer
  • 7. Metabolic defects leading to thedevelopment of hepatic steatosis
  • 8. White (WAT)Brown (BAT)Adipose tissue
  • 9. Adipose tissue
  • 10. Adipocyte
  • 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. 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. de Wit NJ, Afman LA, Mensink M, Müller MPhenotyping the effect of diet on non-alcoholicfatty liver disease J Hepatol 2012.
  • 14. Communication between liver and adiposetissue essential for adequate lipid storage
  • 15. Healthy (Homeostasis)
  • 16. Unhealthy (Type 2 Diabetes)
  • 17. Balance between insulin and glucagonSREBP-1cLXRChREBPGRFOXA2CREBPPARaFed state Fasted stateGlucose FFA
  • 18. Metabolism & Inflammation
  • 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. 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. 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. 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. A subpopulation of mice fed HFD develops NASH
  • 24. Immunohistochemical staining confirms enhanced liverinflammation and early fibrosis in HFH miceMacrophage CD68CollagenStellate cell GFAP
  • 25. Upregulation of inflammatory and fibroticgene expression in HFH responder mice
  • 26. Adipose dysfunction in HFH mice
  • 27. Change in adipose gene expressionindicate adipose tissue dysfunction
  • 28. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice
  • 29. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 miceMultivariate analysis of association of proteinplasma concentrations with final livertriglyceride content
  • 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. PeripheralbloodProtein turnoverAmino acidmetabolismGlycogenogenesisGlyconeogenesisGlycolysisLipogenesis,oxidationGI-tractMacronutrientcompositionof the dietLiverGut peptidesNutrientsBacterialderivedcomponentsInfluence of dietary protein on gene expression andmetabolic phenotype in the gut-liver axis
  • 32. Objective Investigating the effect of a high protein diet onhepatic lipid accumulation. Unravel mechanisms which are responsible forthe reduced liver fat.
  • 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. Body composition and food intakeSchwarz, J. et al., PLoS ONE 2012.
  • 35. Hepatic steatosis50 µmSchwarz, J. et al., PLoS ONE 2012.
  • 36. Fasting and postprandial plasma triglyceridesSchwarz, J. et al., PLoS ONE 2012.
  • 37. Microarray analysis to study geneexpression
  • 38. Enrichment map for HP vs. NP feedingto identify biological functionsSchwarz, J. et al., PLoS ONE 2012.
  • 39. Changes in liver amino acid metabolic pathways induced byincreasing dietary proteinSchwarz, J. et al., PLoS ONE 2012.
  • 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. Skeletal muscle
  • 42. Myocyte
  • 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. Skeletal muscle is a secretory organ
  • 45. Link of physical activity to protectionagainst premature mortality
  • 46. The Molecular Basis of Adaptation to Exercise
  • 47. Transcriptional Regulators of Metabolism and Adaptation in Skeletal Muscle
  • 48. The timeline of the study (A) and set-upof the endurance exercise bout (B)
  • 49. Exercise increases heart rate and plasma levelsof FFA, insulin, cortisol and noradrenaline
  • 50. Exercise mainly causes upregulation of gene expressionin both the exercising and non-exercising leg
  • 51. Top 20 of most highly induced genes inexercising and non-exercising leg
  • 52. Induction of transcription factorpathways by exercise
  • 53. Nutrition, Metabolism & Genomics Group
  • 54. Wageningen University• Founded in 1918• ~3000 employees• ~7500 students• ~220 PhD graduations per year

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