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Integration of metabolism   Biochemický ústav LF MU (J.D.) 2011                                          1
The first law of thermodynamics:     what does it say to us?U = W + Q = work + heat                         less utiliz...
Transformation of energy in human body              energy input              energy output        chemical energy of nutr...
Energy transformations in the human body are   accompanied with continuous production of heat                1            ...
Two ways of ATP formation in body95 % ATP is produced by oxidative phosphorylation (O2 needed):ADP + Pi + energy of H+grad...
Energy data of nutrients    Nutrient               Energy (kJ/g)             Thermogenesis    Lipids                      ...
Basal metabolism (BM) can be estimated from body mass: 0.1 MJ / kg / day body surface: 4.2 MJ /           m 2   / day Exam...
Basal metabolism depends on some factors•   Gender (in females by 10 % lower)•   Age (with increasing age BM decreases)•  ...
Recommended intake of nutrientsNutrient   Percentage of energy intake/dayStarch              55 - 60 %                    ...
The content of nutrients in foodsSaccharides           Lipids                 ProteinsTable sugar (100 %)   Plant oils (10...
Energy reserves in the adult body (male, 70 kg)    Compound              Tissue                 Mass (g)           Energy ...
Basic facts on metabolism•   ATP is universal source of chemical energy•   ATP is produced in the catabolism of nutrients•...
Metabolic intermediates and their relations                                     TAG   glucose   glukosa           glycerol...
Interconversions between nutrientsInterconversion              CommentarySugars  lipids              very easy and quickl...
Metabolism in resorption phase•   after substantial meal•   all nutrients available in sufficient amounts•   chemical ener...
Saccharides after meal (insulin)                                   eryliver                                            CO2...
Glucose (Glc) in liver after meal•   Glc  glycogen•   Glc  pyruvate  acetyl-CoA  CAC  energy•   Glc  pyruvate  acet...
Glucose in extrahepatic tissues after meal•   Glc is the only fuel for erythrocytes (anaerobic glycolysis)•   Glc is promi...
Lipids and proteins after meal (insulin)                                                               BCAAliver          ...
Lipids after meal•   Exogen. TAG (CM) and endogen. lipids (VLDL) supply mainly    adipose, less other tissues (muscles, my...
Amino acids after meal•   AA are partially metabolized in enterocytes (Gln)•   some AA are utilized in liver (proteosynthe...
Organ functions in absorptive state (insulin)          • increased glucose phosphorylation  Glc-6-P (glukokinase)        ...
Insulin•   After meal, insulin is released from β-cells of pancreas•   2. messenger ??•   decreases blood glucose by four ...
Insulin is anabolic hormone    Stimulates the synthesis of energy stores and cellular utilization of glucose            fa...
Post-resorption phase•   in fasting (first feelings of hunger)•   about 10-12 h after meal (morning before breakfast)•   H...
Saccharides and proteins in fasting (glucagon)                                    eryliver                                ...
Glucose in fasting (glucagon)    blood Glc level is maintained by two processes:•    (1) liver glycogenolysis (phosphoroly...
Most amino acids (14) are glucogenic                Ser, Gly, Thr, Ala, Cys, Trp                Ala, Cys, Gly, Ser, Thr, (...
Lipids in fasting (glucagon)                                               CO2liver                                       ...
Lipids in post-resorption phase•   lipolysis in adipocytes•   hormon sensitive lipase (HSL) is activated by glucagon•   FA...
Glucagon is antagonist of insulin•   2. messenger is cAMP•   stimulates the degradation of energy stores:    glycogen (liv...
Glucagon is antagonist of insulin           (ketogenic hormone)CO2         fatty acids             TAG             glucose...
Ketone bodies       OH                O                            O                                     O                ...
KB as metabolic fuel         succinyl-CoA: acetoacetate-CoA transferase   O                                          O    ...
Organ functions in fasting state (glucagon)          • increased glycogen degradation (glycogenolysis)                    ...
Metabolic turn-over of saccharides in fasting (g/d)                                                   liver               ...
Metabolic turn-over of saccharides in fasting/starvation•   liver gluconeogenesis gradually decreases•   muscle proteolysi...
Metabolic turn-over of lipids in fasting (g/d)Early fasting                                   liver                       ...
Metabolic turn-over of lipids in fasting/starvation•   the extent of lipolysis is approximately the same•   the production...
Two main priorities in starvation•   saving glucose (utilization of KB in brain)•   saving proteins (= KB save gluconeogen...
Metabolism in stress - catecholamines•   noradrenaline, adrenaline – released from adrenal medulla•   act through adrenerg...
Metabolism in the fight or flight situation                         adrenalineliver        glycogen                       ...
Glucocorticoids are released in chronic stress•   cortisol prepares the body for adrenaline action•   regulates gene expre...
Fat reserves in adult bodyFeature                 Males                         FemalesTotal body water        60 – 67 %  ...
45
Selected adipokines              produced in adipocytes in proportion to fat mass, acts in hypothalamus asLeptin        th...
Metabolism in obesity•   higher intake of energy than expenditure  increased size (hypertrophy) and    number (hyperplasi...
mass (kg)Body mass index                 BMI                                       [height (m)]2    BMI           Classif...
Criteria of obesity•   BMI, obesity if > 30 (males), > 28.6 (females)•   WHR (waist hip ratio)    normal values: < 0,95 (m...
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  1. 1. Integration of metabolism  Biochemický ústav LF MU (J.D.) 2011 1
  2. 2. The first law of thermodynamics: what does it say to us?U = W + Q = work + heat less utilizable form of energy 2
  3. 3. Transformation of energy in human body energy input energy output chemical energy of nutrients = work + heatenergy of nutrients = BM + phys. activity + reserves + heat any work requires ATP 3
  4. 4. Energy transformations in the human body are accompanied with continuous production of heat 1 2 3 chemical proton NADH+H+ energyof nutrients FADH2 gradient across IMM ATP heat heat heat 41 .. metabolic dehydrogenations with NAD+ and FAD work2 .. respiratory chain (oxidation of reduced cofactors + reduction of O2 to H2O)3 .. oxidative phosphorylation, IMM inner mitochondrial membrane4 .. transformation of chemical energy of ATP into work + some heat.. high energy systems 4
  5. 5. Two ways of ATP formation in body95 % ATP is produced by oxidative phosphorylation (O2 needed):ADP + Pi + energy of H+gradient  ATP5 % ATP is made by substrate-level phosphorylation:ADP + macroergic phosphate-P*  ATP + second product* 1,3-bisphosphoglycerate (glycolysis) phosphoenolpyruvate (glycolysis) succinyl-CoA + Pi  succinyl-phosphate (citrate cycle) 5
  6. 6. Energy data of nutrients Nutrient Energy (kJ/g) Thermogenesis Lipids 38 4% Saccharides 17 6% Proteins 17 30 %Thermogenesis is the heat production 3-5 h after meal.It is expressed in % of the nutrient energy ingested. Thermogenesis is theconsequence of digestion, absorption, and metabolism of nutrient. 6
  7. 7. Basal metabolism (BM) can be estimated from body mass: 0.1 MJ / kg / day body surface: 4.2 MJ / m 2 / day Example: 70 kg  BM = 0.1 × 70 = 7 MJ/day 7
  8. 8. Basal metabolism depends on some factors• Gender (in females by 10 % lower)• Age (with increasing age BM decreases)• Body temperature (increasing temperature by 1 C increases BM by 12 %)• environmental temperature – increased in cold climates• Hormones thyroxine and adrenaline - increase BM• Long starvation – BM decreases 8
  9. 9. Recommended intake of nutrientsNutrient Percentage of energy intake/dayStarch 55 - 60 % SAFA  5 %Lipids  30 % MUFA  20 % PUFA  5 %Proteins 10 - 15 % 9
  10. 10. The content of nutrients in foodsSaccharides Lipids ProteinsTable sugar (100 %) Plant oils (100 %) Parmesan cheese (40 %)Rice (80 %) Kitchen fat (100 %) Emmental cheese (30 %)Bread roll (60 %) Butter (80 %) Turkey steak (20 %)Bread (50 %) Margarins (60-80 %) Carp (16 %)Potatoes (15 %) Fatty meat (20-40 %) Bread (10 %)Milk (5 %) Milk (3 %) Milk (4 %) 10
  11. 11. Energy reserves in the adult body (male, 70 kg) Compound Tissue Mass (g) Energy (MJ) Glycogen liver 70 1,2 Glycogen muscles 120 2,0 Glucose ECF 20 0,3 Lipids adipose t. 15 000 570 Proteins muscles 6 000 102/3 = 34• the biggest energy store is in adipose tissue• total body fat makes 10-30 % (males , females )• only ⅓ of muscle proteins can be used as fuel• liver glycogen lasts approx. 24 h• muscle glycogen – can be utilized only in muscles (lack of glucose 6-phosphatase) 11
  12. 12. Basic facts on metabolism• ATP is universal source of chemical energy• ATP is produced in the catabolism of nutrients• there are two ways how to produce ATP (see page 5)• body needs the constant level of ATP and glucose• Glucose is prominent metabolic fuel for brain and erythrocytes• glucose is also needed to utilize energy from lipids = for citrate cycle (Glc  pyruvate  oxaloacetate  CAC)• glucose cannot be produced from lipids 12
  13. 13. Metabolic intermediates and their relations TAG glucose glukosa glycerol MK FA irreversible nevratná irreversible nevratná ketogenic AA pyruvát pyruvate acetyl-CoA ketogenní AK mixed AA - CO2 essential glukogenní AKglucogenic AA CC 13
  14. 14. Interconversions between nutrientsInterconversion CommentarySugars  lipids very easy and quickly not possible,Lipids  glucose × pyruvate dehydrogenase reaction is irreversibleAmino acids  glucose most AA are glucogenic pyruvate and CAC intermediate provide carbonGlucose intermediates  AA skeleton for some amino acidsAmino acids  lipids in excess of proteins pyruvate dehydrogenase reaction is irreversible ×Lipids  amino acids ketogenic AA and most mixed AA are essential 14
  15. 15. Metabolism in resorption phase• after substantial meal• all nutrients available in sufficient amounts• chemical energy is stored (glycogen, lipids)• principal hormonal regulation - insulin 15
  16. 16. Saccharides after meal (insulin) eryliver CO2 brain lactate glycogenNADPH Glc high blood Glc muscle glycogenTAG CO2 Gln Glc CO CO2 glycerol-P CO2 2 GIT TAG adipose GLUT 4 insulin dependent transporter 16
  17. 17. Glucose (Glc) in liver after meal• Glc  glycogen• Glc  pyruvate  acetyl-CoA  CAC  energy• Glc  pyruvate  acetyl-CoA  FA  TAG (VLDL)• considerable amount of Glc just passes through liver into blood• small portion of Glc is converted into specialized products (pentoses + NADPH, galactose, glucuronate)• excess of Glc  lipids (VLDL)  blood  adipose tissue  obesity 17
  18. 18. Glucose in extrahepatic tissues after meal• Glc is the only fuel for erythrocytes (anaerobic glycolysis)• Glc is prominent fuel for brain (aerobic glycolysis)• Glc is source of energy in (resting) muscles (aerobic glycolysis) + substrate for muscle glycogen (limited capacity)• Glc is source of energy, glycerol-3-P, and NADPH+H+ (pentose cycle) for TAG synthesis in adipose tissue Glc   glyceraldehyde-3-P + dihydroxyacetone-P glycerol-3-P 18
  19. 19. Lipids and proteins after meal (insulin) BCAAliver Glc proteins blood plasma proteins FA LPL AA TAG FA VLDL muscle NH3 CO2 LPL AA TAG FA + glycerol-P chylomicronsGln LPL FA intestine TAG adipose tissue myocardium 19
  20. 20. Lipids after meal• Exogen. TAG (CM) and endogen. lipids (VLDL) supply mainly adipose, less other tissues (muscles, myocard, kidney)• FA are released from TAG by the action of LPL• In adipose, FA are substrates for TAG synthesis• LPL is activated by insulin mainly in adip. t. (not very in muscles) – exog. lipids (CM) are directed to adipose tissue• FA are secondary fuel for muscles (primary = glucose) FA  acetyl-CoA  CAC  CO2 + energy 20
  21. 21. Amino acids after meal• AA are partially metabolized in enterocytes (Gln)• some AA are utilized in liver (proteosynthesis)• AA excess  synthesis of FA and TAG• Val, Leu, Ile (BCAA) are not utilized in liver (lacking aminotransferases), they are directed to muscles and brain 21
  22. 22. Organ functions in absorptive state (insulin) • increased glucose phosphorylation  Glc-6-P (glukokinase) • Glc-6-P  CO2 + energy (metabolic fuel for liver – quite exceptionally !!) • Glc-6-P  glycogen (glucose stores for other tissues)Liver • Glc-6-P   NADPH+H+ (pentose cycle)   FA   TAG  VLDL • AA  hepatic + blood plasma proteins • AA surplus  carbon skeleton + ammonia   urea • increased glucose influx (GLUT4 / insulin) • increased glycolysis  energy + glycerol-3-P (for lipogenesis)Adipose • increased pentose cycle   FA (FA synthesis de novo is not relevant) • influx of FA (CM + VLDL / LPL)  TAG (lipogenesis) • increased glucose influx (GLUT4 / insulin) • glucose  CO2 + energyMuscle • increased glycogen synthesis (for itself only) • uptake of AA (esp. BCAA)  protein synthesis (+ AA oxidation)Brain • glucose  CO2 + energyKidney • glucose / FA / glutamine  CO2 + energy 22
  23. 23. Insulin• After meal, insulin is released from β-cells of pancreas• 2. messenger ??• decreases blood glucose by four processes: A) supports glucose entry into muscles and adipocytes B) stimulates glycogen synthesis (liver, muscles) C) inhibits liver glycogenolysis + gluconeogenesis D) supports glycolysis in liver, muscles, and other tissues• stimulates TAG synthesis (adipocytes, liver) and proteosynthesis (muscles) 23
  24. 24. Insulin is anabolic hormone Stimulates the synthesis of energy stores and cellular utilization of glucose fatty acids TAGCO2 glycolysis glucose glycogen amino acids proteinsInsulin induces the synthesis of key enzymes of glycolysis (glucokinase,phosphofructokinase, pyruvate kinase) a glycogenesis (glycogen synthase) 24
  25. 25. Post-resorption phase• in fasting (first feelings of hunger)• about 10-12 h after meal (morning before breakfast)• Hormonal influence - glucagon 25
  26. 26. Saccharides and proteins in fasting (glucagon) eryliver CO2 brain glycogen lactate (100%)phosphorolysis muscle glycogen Glc Glc in blood CO2 90% gluconeogenesis lactate Ala, Gln proteolysis 10% gluconeogenesis Gln  CO2 kidney GIT metabolic fuel for 26 some tissues
  27. 27. Glucose in fasting (glucagon) blood Glc level is maintained by two processes:• (1) liver glycogenolysis (phosphorolysis) (Glc)n + Pi  (Glc)n-1 + Glc-1-P phosphorylase is activated by glucagon (and adrenaline) Glc-6-P  free glucose• (2) liver gluconeogenesis from alanine, lactate, glycerol .... recycling three C atoms (saving Glc) other glucogenic AA glucagon induces the synthesis of three key enzymes: phosphoenolpyruvate carboxykinase (PEPCK) fructose-1,6-bisphosphatase glucose-6 phosphatase 27
  28. 28. Most amino acids (14) are glucogenic Ser, Gly, Thr, Ala, Cys, Trp Ala, Cys, Gly, Ser, Thr, (Trp) pyruvát pyruvateglucoseglukosa Ile, Leu, Lys, Thr acetyl-CoA acetoacetate acetoacetát Leu, Lys, Phe, Trp, Tyr oxalacetátAsp, Asn oxaloacetate CC 2-oxoglutarát 2-oxoglutarate Arg, Glu, Gln, His, Pro Phe, Tyr fumarát fumarate Asp succinyl-CoA sukcinyl-CoA Ile, Val, Met, Thr 28
  29. 29. Lipids in fasting (glucagon) CO2liver brain muscleketone bodies KB in blood CO2 Acetyl-CoA FA FA-albumin CO2 FA + glycerol HSL kidney Gln  CO2 TAG myocardiumGIT adipocyte 29
  30. 30. Lipids in post-resorption phase• lipolysis in adipocytes• hormon sensitive lipase (HSL) is activated by glucagon• FA transported in ECF in complex with albumin• FA are fuel for liver, muscles, heart and other tissues• ketone bodies utilized in muscles, partially in CNS 30
  31. 31. Glucagon is antagonist of insulin• 2. messenger is cAMP• stimulates the degradation of energy stores: glycogen (liver), TAG (adipocyte), proteins (liver)• supports gluconeogenesis from lactate and AA• inhibits synthesis of glycogen, TAG, and proteins• acts on liver and adipocytes (not muscles) 31
  32. 32. Glucagon is antagonist of insulin (ketogenic hormone)CO2 fatty acids TAG glucose glycogen ketone bodies amino acids 32
  33. 33. Ketone bodies OH O O O - 2H OH3C CH CH2 C H3C C CH2 C H3C C CH3 - CO OH + 2H O H 2-hydroxymáselná kyselina β-hydroxybutyrate acetoacetate acetoctová kyselina acetone aceton anion anion non–electrolyte Cl- Na+ HCO3- OA K+ 33
  34. 34. KB as metabolic fuel succinyl-CoA: acetoacetate-CoA transferase O O OH3C C CH2 COOH H3C C CH2 C acetoacetyl-CoA acetoacetát acetoacetate SCoA succinyl-CoA sukcinyl-CoA sukcinát succinate S CoA H O CAC CC 2 H3C C Energie energy SCoA 34
  35. 35. Organ functions in fasting state (glucagon) • increased glycogen degradation (glycogenolysis) glucose 6-phosphataseLiver • gluconeogenesis (from Ala, AA, lactate/pyruvate, glycerol) • increased FA oxidation  acetyl-CoA   KB  export of KB • increased lipolysis (HSL / glucagon, adrenaline)  FA + glycerolAdipose • increased release of FA into blood • FA (from adipose) + KB (from liver)  CO2 + energyMuscle • in longer fasting only FA are oxidized • proteolysis  AA (esp. Ala, Gln – for liver gluconeogenesis) / cortisol • glucose  CO2 + energyBrain • KB  CO2 + energy (in longer fasting) • glucose / FA / KB / glutamine  CO2 + energyKidney • gluconeogenesis (for itself and other) • compensate ketoacidosis: Gln/Glu  NH3 + H+  NH4+ (release into urine) 35
  36. 36. Metabolic turn-over of saccharides in fasting (g/d) liver CNSEarly fasting 144 glycogen Proteins  AA 75 Glc gluconeogenesis 180 Ery glycerol 36 16 lactate 36Prolonged starvation liver CNS 44Proteins  AA 20 Glc gluconeogenesis 80 Ery glycerol 36 15 lactate 50 36
  37. 37. Metabolic turn-over of saccharides in fasting/starvation• liver gluconeogenesis gradually decreases• muscle proteolysis gradually decreases• substrates for gluconeogenesis remain the same (lactate, amino acids, glycerol)• CNS utilization of glucose decreases• erythrocytes consume constantly the same amount of Glc (36 g/d) – it can make up to 45 % from Glc production 37
  38. 38. Metabolic turn-over of lipids in fasting (g/d)Early fasting liver gluconeogenesis glycerol KB FA 60 40 adip. t. TAG 160 FA FA muscles, myocard, kidney 160 120 liverProlonged starvation CNS 47 gluconeogenesis glycerol KB FA 57 38 x adip. t. TAG 150 FA FA muscles, myocard, kidney 150 112 38 10 urine
  39. 39. Metabolic turn-over of lipids in fasting/starvation• the extent of lipolysis is approximately the same• the production of KB is approximately the same  acidosis• muscles stop utilizing ketone bodies• the brain gradually adapts for KB 39
  40. 40. Two main priorities in starvation• saving glucose (utilization of KB in brain)• saving proteins (= KB save gluconeogenesis from AA) 40
  41. 41. Metabolism in stress - catecholamines• noradrenaline, adrenaline – released from adrenal medulla• act through adrenergic receptors• β-receptors: cAMP (muscles, adipocytes)• α1-receptors: DAG + IP3 / Ca2+ (liver)• very quick action (seconds)• catecholamines stimulate mainly:• glycogenolysis in liver ( increase of blood Glc)• glycogenolysis and glycolysis in muscles• lipolysis in adipose tissues• energy supply for muscles – they must quickly respond to stress situation (fight, flight) 41
  42. 42. Metabolism in the fight or flight situation adrenalineliver glycogen Glc muscles glycogen adipocyte ATP Glc TAG FA 42
  43. 43. Glucocorticoids are released in chronic stress• cortisol prepares the body for adrenaline action• regulates gene expression – slow effect – hour to days• stimulates the synthesis of HSL in adipocytes – at the moment of stress there is enough enzyme available to perform lipolysis• support muscle proteolysis – substrates for gluconeogenesis• induces synthesis of PEPCK (gluconeogenesis) and glycogen synthase 43
  44. 44. Fat reserves in adult bodyFeature Males FemalesTotal body water 60 – 67 % 50 - 55 %Total body fat 10 – 20 % 20 – 30 % waist, abdomen hips, thighsMain fat distribution android type, apple-shaped gynoid type, pear-shapedSubcutaneous and visceral fat80 – 90 % fat is stored in subcutaneous depots10 – 20 % is visceral (omental, mesenteric) fat – close to portal vein, free FA andproinflammatory cytokines from visceral fat go directly to liver – increasedsynthesis of VLDL – increased health risk (obesity and other diseases) 44
  45. 45. 45
  46. 46. Selected adipokines produced in adipocytes in proportion to fat mass, acts in hypothalamus asLeptin the signal of satiation, in obesity - decreased hypothalamus response to leptin produced in adipocytes, improves tissue sensitivity to insulin,Adiponectin in obesity and DM II – decreased production of adiponectin produced by macrophages, decreases tissue sensitivity to insulin,Resistin in obesity – increased levelVisfatin produced by visceral fat tissue, improves tissue sensitivity to insulin macrophage chemoattractant protein, produced in adipocytes and otherMCP cells, attracts macrophages into hypertrophic adipocytes tumor necrosis factor, produced by macrophages, pro-inflammatoryTNF-α effects, decreases tissue sensitivity to insulin, stimulates lipolysis (paracrine effect) 46
  47. 47. Metabolism in obesity• higher intake of energy than expenditure  increased size (hypertrophy) and number (hyperplasia) of (pre)adipocytes, mainly in abdominal region• after certain adipocyte size – lipolysis  elevated plasma FA• adiponectin production decreases• hypothalamus becomes less sensitive to leptin• increased production of MCP + TNF-α  pro-inflammatory effects  insulin resistance  atherosclerosis  metabolic syndrome• hypertrophic adipocytes have insufficient oxygen supply, lose ability to store fat, just opposite – release FA• TAG are stored in other organs: muscles, heart, pancreas, liver (steatosis) with many pathological consequencies 47
  48. 48. mass (kg)Body mass index BMI  [height (m)]2 BMI Classification < 18,5 underweight 18,5 - 24,9 normal weight 25,0 - 29,9 overweight 30,0 – 34,9 obesity class I 35,0 – 39,9 obesity class II > 40 obesity class III (extreme) 48
  49. 49. Criteria of obesity• BMI, obesity if > 30 (males), > 28.6 (females)• WHR (waist hip ratio) normal values: < 0,95 (males), < 0,85 (females)• waist circumference, normal values: < 94 cm (males), < 84 cm (females)• other instrumental methods: bioelectrical impedance analysis 49
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