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Metabolism 101 R. Low, 02/10/14 Need to fix text a la part-1 Definitions Absorptive phase of digestion: Have just eaten a meal Postabsorptive phase of digestion: Several hours after eating a meal Adapted fast: Changes in brain energy use and overall metabolism that extend the ability to fast out to weeks. Begins within a few days. Glycogen Trigylceride Protein Body Energy Stores The “Full Monty” Cell (which does not exist) Amino Acids Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 7 Glucose Amino Acids Glucose Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 NH3 + Urea Ketoacids Fatty Acids Glycolysis Pyruvate Ketoacids Acetyl CoA Krebs Cycle O2 Oxidative Phosphorylation ATP H2O 8 Glucose - Fat Amino Acids Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA Krebs Cycle O2 Oxidative Phosphorylation ATP H2O 9 Glucose - Protein Amino Acids Glucose Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 NH3 + Urea Ketoacids Fatty Acids Glycolysis Pyruvate Ketoacids Acetyl CoA Krebs Cycle O2 Oxidative Phosphorylation ATP H2O 10 Ketoacids Amino Acids Glucose Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 NH3 + Urea Ketoacids Fatty Acids Glycolysis Pyruvate Ketoacids Acetyl CoA Krebs Cycle O2 Oxidative Phosphorylation ATP H2O 11 Brain Glucose Ketoacids Glucose-6-P Glycolysis Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 12 Muscle Amino AcidsLactate Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 13 Adipose Tissue Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 14 Liver Amino Acids Glucose Ketoacids Triglycerides Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 15 Kidney Amino Acids Glucose Ketoacids Triglycerides Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 16 Hormones and Energy Metabolism 17 HOW DOES ONE DO IT? 18 REDUNDANCY -- COMPLEMENTARITY 19 EFFECTS OF INSULIN PRINCIPAL TARGETS: Liver, Adipose, Muscle CARBOHYDRATE: - Increased Glucose Uptake: Muscle and Adipose - Increased Glycogenesis; decreased glycogenolysis - Decreased Gluconeogenesis FAT: - Increased Triglyceride Synthesis for Storage - Decreased Breakdown of Triglyceride Stores PROTEIN: - Increased Synthesis - Decreased Breakdown 20 Major Insulin Actions: Tissue by Tissue Liver: INcreased glycogen deposition DEcreased glycogenolysis INcreased glucose use DEcreased gluconeogenesis Muscle: INcreased Glucose transport / use INcreased Protein synthesis DEcreased protein degradation Adipose: INcreased Triglyceride synthesis / storage DEcreased triglyceride breakdown / release 21 Insulin - Muscle Amino AcidsLactate Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 22 Insulin- Adipose Tissue Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 23 Insulin - Liver Amino Acids Glucose Ketoacids Triglycerides Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 NH3 + Urea Fatty Acids Fatty Acids Glycolysis Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 24 Major Glucagon Actions: Tissue by Tissue Liver: DEcreased glycogen deposition INcreased glycogenolysis DEcreased glucose use INcreased gluconeogenesis INcreased Fatty Acid Oxidation Muscle: Not much Adipose: Not much 25 Glucagon - Muscle Amino AcidsLactate Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 26 Glucagon - Adipose Tissue Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 27 Glucagon - Liver Amino Acids Glucose Ketoacids Triglycerides Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 NH3 + Urea Fatty Acids Fatty Acids Glycolysis Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 28 GROWTH HORMONE AND CARBOHYDRATE Reduced Glucose Uptake by Muscle Reduced intracellular Glucose Processing Gluconeogenesis: do not believe so? - Glycerol from triglyceride breakdown CAME from glucose - Increased utilization of amino acids for protein synthesis means fewer available for true gluconeogensis. Insulin ANTAGONISM: - Carbohydrate and Fat Growth Promoter Fat Mobilizer Glucose Sparer 29 GROWTH HORMONE AND FAT Adipose tissue: Triglyceride Mobilization Reduced fat (triglyceride) Synthesis Central role of fat products in the blood as a regulator of Glucose uptake and utilization They BLOCK Insulin Action: Insulin ANTAGONISM 30 GROWTH HORMONE AND PROTEIN INCREASED SYNTHESIS* DECREASED DEGRADATION Insulin AGONISM *Mostly due to increased numbers of ribosomes, i. e. capacity 31 Growth Hormone - Muscle Amino AcidsLactate Protein Glucose ( Ketoacids Triglycerides Glycogen Fatty Acids Triglycerides ) (Indirect) Glucose-6-P Amino Acids ( ) Glycerol Fatty Acids (Indirect) Glycolysis Pyruvate ( Lactate ( ) = Indirect Ketoacids ) Acetyl CoA (Indirect) TCA Cycle (Indirect) O2 Oxidative Phosphorylation ATP H2O 32 Growth Hormone - Adipose Tissue Glucose ( Triglycerides Fatty Acids Triglycerides ) Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA ( ) = Indirect O2 TCA Cycle Oxidative Phosphorylation ATP H2O 33 Growth Hormone - Liver Amino Acids Glucose Ketoacids Triglycerides Glycogen Triglycerides Fatty Acids (Indirect) Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate (Indirect) Ketoacids Acetyl CoA (Indirect) TCA Cycle O2 Oxidative Phosphorylation ATP H2O 34 Cortisol and Foodstuff Metabolism Increased Appetite: Obesity Insulin Resistance (fatty acids) Carbohydrate: Gluconeogenesis: - Muscle protein breakdown - Increased liver gluconeogenic enzymes - Glycogen deposition - Hyperglycemia Fat: - Increased adipose tissue (appetite) - Selective deposition: trunk / visceral fat Protein: - Profound muscle protein breakdown 35 Cortisol and Metabolism Organ by Organ Muscle Increased Protein Breakdown Adipose Increased Triglyceride deposition – trunk Liver Increased gluconeogenesis Increased glycogen deposition Increased glucose export 36 Cortisol- Muscle Amino Acids Lactate Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 37 Cortisol - Adipose Tissue Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 38 Cortisol - Liver Amino Acids Glucose Ketoacids Triglycerides Glycogen (Indirect) Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 NH3 + Urea (Indirect) Glycolysis Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 39 Epinephrine: Effects on Metabolism KEY PHRASES EMERGENCY / STRESS ENERGY PROVIDER Carbohydrate: - Glycogen Breakdown: Liver and Muscle - Gluconeogenesis: Liver (works with cortisol) Fat: - Increased Lipolysis: Mobilization Protein: - Little or no effect 40 Epinephrine and Metabolism Organ by Organ Muscle Little effect Adipose Increased Triglyceride breakdown / lipolysis Liver Increased glycogenolysis Increased gluconeogenesis Increased glucose export 41 Epinephrine - Muscle Amino Acids Lactate Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides (Indirect) Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Lactate (Indirect) Ketoacids Acetyl CoA (Indirect) TCA Cycle (Indirect) O2 Oxidative Phosphorylation ATP H2O 42 Epinephrine - Adipose Tissue Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 43 Epinephrine - Liver Amino Acids Glycerol Glucose Ketoacids Glycogen (Indirect) Triglycerides (Indirect ) Fatty Acids (Indirect) Glucose-6-P Amino Acids (Indirect ) R + NH2 NH3 + Urea Triglycerides Glycerol Fatty Acids Glycolysis Pyruvate Ketoacids (Indirect ) Acetyl CoA (Indirect) TCA Cycle O2 Oxidative Phosphorylation ATP H2O 44 Daily Living Feeding to Fasting Sources of glucose over time following a Meal 46 Whole Body Substrate Utilization During Fasting 47 Feeding to Adapted Fast Organ Integration – Version 1 Metabolism-101 Cartoons 48 We are talking about adults Not Children* We are talking about Adaptation Not starvation / cachexia *Low: Protein-Energy Malnutrition Coming up next 49 49 Big Picture - Fed Carbs: Refill stores: Glycogen, liver, muscle Burn Remainder (most tissues) Protein: Refill stores (muscle) Burn Remainder Fat: Storage Limited use as ongoing energy source Dominant Ongoing Energy Needs: glucose, amino acids Big Picture – 24 hr Fast Carbs: Some glycogen stores used Gluconeogenesis Protein: Amino acids (muscle) to liver - gluconeogenesis Fat: Mobilization of triglyceride reserves Dominant Ongoing Energy Needs: fatty acids (Exceptions: Nerves, Blood Cells – Glucose) Big Picture – Adapted Fast Carbs: Some glycogen stores used Gluconeogenesis Protein: Amino acids (muscle) to liver - gluconeogenesis Fat: Mobilization of triglyceride reserves Keto Acids as dominant Energy Source, Incl. Brain (exception: liver uses fatty acids) Reduced Gluconeogenesis: Kidney takes over Reduced BMR Big Picture – Hormone Profiles Fed: Insulin Glucagon Growth Hormone Thyroid Hormone 24 hr Fast: Insulin Glucagon Growth Hormone Thyroid Hormone Adapted Fast: Insulin Glucagon Growth Hormone Thyroid Hormone Brain - FED Glucose Glucose-6-P FED Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 54 Brain – 24 hr FAST Glucose Glucose-6-P 24 hr FAST Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 55 Brain - ADAPTED FAST Glucose Ketoacids Glucose-6-P ADAPTED FAST Glycolysis Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 56 Muscle - FED Amino Acids Lactate Glucose Ketoacids Triglycerides Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate FED Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 57 Muscle – 24 hr FAST Amino AcidsLactate Glucose Ketoacids Fatty Acids Glycogen Protein Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate 24 hr. FAST Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 58 Muscle - ADAPTED FAST Amino AcidsLactate Glucose Ketoacids Glycerol Glycogen Protein Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Adapted Fast Lactate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 59 Adipose Tissue - FED Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol FED Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 60 Adipose Tissue – 24 hr FAST Glucose Glycerol Fatty Acids Triglycerides Glucose-6-P Glycerol 24 hr. FAST Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 61 Adipose Tissue - ADAPTED FAST Glucose Glycerol Fatty Acids Triglycerides Glucose-6-P ADAPTED FAST Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation ATP H2O 62 Liver - FED Amino Acids Glucose Ketoacids Triglycerides Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 FED Oxidative Phosphorylation ATP H2O 63 Liver- 24 hr FAST Amino Acids Glucose Ketoacids Glycerol Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation FAST-24 hr. ATP H2O 64 Liver – ADAPTED FAST Amino Acids Glucose Ketoacids Glycerol Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation 24 hr FAST ATP H2O 65 Kidney - FED Amino Acids Glucose Ketoacids Triglycerides Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle O2 Oxidative Phosphorylation H2O FED ATP 66 Kidney – 24 hr FAST Amino Acids Glucose Ketoacids Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle 24 hr. FAST O2 Oxidative Phosphorylation ATP H2O 67 Kidney - ADAPTED FAST Amino Acids Glucose Ketoacids Glycerol Glycogen Fatty Acids Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA TCA Cycle Adapted Fast O2 Oxidative Phosphorylation ATP H2O 68 Add Kidney Glycerol replaces Triglycerides-Fast Add Red Bars Add Slide text including hormone profile Feeding to Fast Organ Integration – Version 2 (Based on Devlin) 70 Absorptive – Just Ate Glucose Pyruvate Lactate Glucose 71 Absorptive Phase (Just Ate) Glycogen Glucose Amino Acids ATP ATP VLDL FAT TG CHO Amino Acids FAT Glycogen ATP 72 Postabsorptive Phase (No Food Several Hours) Glycogen Glucose ATP ATP CHO Amino Acids FAT aa Glycogen Lactate / pyruvate Glucose-6-P 73 Adapted Fast Glycogen Glucose Ketoacids ATP ATP CHO Amino Acids FAT aa Glycogen Lactate / pyruvate Glucose-6-P 74 Feeding to Fast Organ Integration – Version 3 (Based on CMB Lectures - Tracy) 75 Absorptive – Just Ate ATP Glucose Glycogen ATP Amino Acids Fats Carbs Fat Amino Acids 76 Post-absorptive – Have not eaten for awhile ATP Glucose Glycogen Amino Acids ATP Pyruvate Lactate Fats Carbs Fat Amino Acids 77 Post-absorptive – Adapted Fast ATP Glucose Glycogen Amino Acids Ketoacids ATP Pyruvate Lactate Fats Carbs Fat Amino Acids 78 Hormones and Daily Living How are all of these things managed? 79 HOW DOES ONE DO IT? 80 Managing Daily Living Order of importance 1st: Insulin 2nd: Insulin 3rd: Insulin 4th: Glucagon 5th: Growth Hormone 81 EFFECTS OF INSULIN PRINCIPAL TARGETS: LIVER, ADIPOSE, MUSCLE Carbohydrate: - Increased Glucose Uptake: Muscle and Adipose - Increased Glycogenesis; decreased glycogenolysis - Decreased Gluconeogenesis Fat: - Increased Triglyceride Synthesis for Storage - Decreased Breakdown of Triglyceride Stores Protein: - Increased Synthesis - Decreased Breakdown 82 Lack of Insulin Muscle Reduced glucose uptake and utilization Mobilization of glycogen Increased muscle protein breakdown Adipose Tissue Reduced triglyceride uptake and storage Increased triglyceride breakdown and release into the blood Liver Increased Glycogenolysis Increased gluconeogenesis THE LIVER IS A GLUCOSE EXPORTER 83 Hormones and Daily Living The End 85 85
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