Slide 1Why bother with metabolism?I don’t care if you know metabolismMost energy in is storedAverage energy out = 2300 kcal/dayWhole body metabolism: balance between anabolism & catabolismMolecules of energy storage and utilizationThe difference between anabolism and catabolism is confusingMolecules of anabolismCarbohydrate metabolismLipid metabolism: lipolysis & lipogenesisLipid metabolismGlucose is produced in the LIVER by gluconeogenesisGlucose is produced in the liver by gluconeogenesisLipid transport & storageTissue metabolism is specializedFed state metabolism: Storage rulesFed State Metabolism: Storage RulesFasting metabolism: Glucose mobilizationFasting Metabolism: Usage RulesThe difference glucose storage & useMultiple hormones target the same pathwaysNotesNotes (cont.)Review QuestionsPGY452/552: Endocrine physiology5. Quick overview of whole body metabolismA. Food to energyB. 3 sources of energyIN in 4 organsC. Metabolic pathwaysD. Integration of metabolismWhy bother with metabolism?2HHHHHHHHHHHInputInputHormoneResponseMetabolic control is the major function of the endocrine systemCommon view of metabolismNot relevant to complex organismsDoes not account for Specialized roles of tissuesTimeResponseI don’t care if you know metabolismEmphasizeThe names of the pathwaysSubstrates (start) & productsEach pathway’s role in physiology Anabolic vs catabolicCharacteristic of fed or fasted stateTissue specificity This will allow us to focus on endocrine control3Most energy in is storedCarbohydratesCarbohydratesFatsFatsInvoluntary movementExcessExcessShort-term storage: carbohydratesShort-term storage: carbohydratesShort & long- term storage: fatsShort & long- term storage: fatsEnergy inEnergy outThermogenesisProteinsProteins4Synthetic reactionsMembrane transportSignal transductionDetoxification & degradationVoluntary movementMetabolismMetabolismFOODAverage energy out = 2300 kcal/dayBasel metabolic rate (BMR)Minimum expenditure for normal biochemistry1400 kcal/day → 1 kcal/minVariability in Eout1. Age2. Sex3. Energy intake4. Lean muscle mass5. Genetics → physiology6. Voluntary movement5Average person:70 kg (150 pounds)Major source of variabilityMajor source of variabilityWhole body metabolism: balance between anabolism & catabolism6Energy storageEnergy storageFed state(absorptive)AnabolismFasting state(post-absorptive)CatabolismLarge moleculesSmall moleculesEnergy mobilizatonEnergy mobilizatonLarge moleculesSmall moleculesMolecules of energy storage and utilizationGlycogenProteins Triacylglycerols7Non-esterified fatty acidsGlucoseENERGY=ATPENERGY=ATPAnabolismAnabolismCatabolismCatabolismStorageUsageAmino acidsThe difference between anabolism and catabolism is confusingEasy way to tell for our purposes INSULIN → ANABOLISMWe will get to that next8Molecules of anabolismTriacylglycerols (TAGs; fats)FromDietary fatsAnabolism from glucose60-70% of energy storesLipid dropletsAt ~9 kcal/g that’s 100,000 kcal9Glycogen:Highest metabolic priorityStores short-lived4 kcal/g=1500 kcal totalProteins: ~25% of energy stores“Mobilizable”4 kcal/gOther major rolesGlycogenesis: glucose → g-6-P → glycogenGlycogenolysis: glycogen → g 6-p ‑ → glucoseGlycolysisATP – catabolic → no endocrine controlNonesterified fatty acid synthesis – anabolic → endocrine controlPyruvateGlycolysis6 carbon3 carbonATPATPGlycogenGlucose-6-PhosphateGlucoseGlucose transporterCarbohydrate metabolismAcetyl-CoAATPATPCitrateElectron transport systemO2Citric acid cycle10NEFANEFAPyruvateGlycolysisLipogenesis: glucose (or cytoplasmic acetyl-CoA) → NEFA → TAGLipolysis: TAG → NEFA11Lipid metabolism: lipolysis & lipogenesisAc-CoACitrateCitric acid cycleLPLGlycerolLipidDropletLipoprotein lipase3322115544NEFATAGAcetyl-CoALipid metabolism121. As covered previously, de novo synthesis of NEFA occurs from glucose by way of glycolysis and the citric acid cycle. This is lipogenesis (a stricter definition would only include the cytoplasmic acetyl-CoA to NEFA, but that doesn’t help with the physiology of the process, so I’m not going to make the distinction).2. Lipoproteins called Chylomicrons or VLDL (covered on slide #__) carry triacylglycerol (TAG) in the ECF. The TAG are de-esterified by lipoprotein lipase (LPL) to diacylglycerol (not shown), then to non-esterified fatty acids (NEFA; 3 moles) & 1 mole glycerol per mole TAG. 3. Depending on metabolic state, glycerol can be converted to pyruvate in the 3 carbon phase of glycolysis, or glycolysis can produce the glycerol necessary for TAG synthesis.4. In the cell, NEFA and glycerol are condensed to form TAG which are stored in lipid droplets. Cells to not store TAG directly; it must first be converted to NEFA. This is also part of lipogenesis5. Mobilization of lipid droplet TAG occurs through lipolysis. Most tissues that release lipids do so as NEFA.Amino acidsGlucose is produced in the LIVER by gluconeogenesis13ATPATPElectron transport systemO2OCoAKetone BodiesGluconeogenesisATPATPRequires ENERGY and CARBON atomsRequires ENERGY and CARBON atomsPyruvateNEFACAcT5544332211β oxidation Citric acid cycleNH3NH3Ac-CoAGlucose is produced in the liver by gluconeogenesis141. Gluconeogenesis requires energy. This energy must come from non-esterified fatty acids2. The NEFAs are imported into the mitochondria, acylated, and conjugated with CoA by the carnitine-acylcarnitine transferase complex. The fatty acylated CoA molecule is then oxidized two carbons at a time, providing substrate for the citric acid cycle & resulting in generation of ATP. This process is called β oxidaton of NEFA.3. Carbon atoms to make pyruvate are provided by amino acids. Some amino acids are directly converted to pyruvate, others must be converted in the citric acid cycle.4. Gluconeogenesis is the conversion of pyruvate to glucose-6-phosphate with input of ATP from β oxidation of NEFA.5. Lack of coenzyme A can leave β oxidation incomplete causing a build up of ketone bodies. More specifically, acetone, acetoacetic acid, and β hydroxybutyric acid.Hydrophobic Stored as triglycerides in lipid droplets inside cellsNeed carrier proteins in bloodChylomicrons (FED)Very low density lipoproteins (FED)Albumin (FASTED)15Lipid transport &