T2 L5- Metabolism in the Fed and Starved States.pptx

Liver & metabolism T2, L5 Metabolism in the fed and starved states Learning outcome: By the end of this lecture, the successful student should be able to: Discuss the roles the major organs play in the handling of nutrients from the diet in the fed state; Explain th...

Liver & metabolism T2, L5 Metabolism in the fed and starved states Learning outcome: By the end of this lecture, the successful student should be able to: Discuss the roles the major organs play in the handling of nutrients from the diet in the fed state; Explain the major metabolic changes that occur within the body on going from the fed state through to the prolonged fasting state; Discuss the importance of fatty acids and ketone bodies in terms of sparing glucose utilisation. [email protected] 1  Metabolism: the feed-fast cycle Human metabolism oscillates between the fed and fasting states The ‘switch’ that determines metabolic changes is the molar ratio of insulin to glucagon in the blood FED state - during meals and for several hours afterwards Characterized by high insulin and low glucagon (a high insulin/glucagon ratio) FASTING state: 6-12 hr after a meal Characterized by low insulin and high glucagon (a low insulin/glucagon ratio) Fasting that lasts in excess of 12 hr is ‘prolonged fasting’ or starvation 2  Changes in metabolism from the absorptive state to the post-absorptive state ABSORPTIVE PHASE POST-ABSORPTIVE PHASE Glycogen Liver cells Glucose Glucose Triglyceride Amino acids Most body cells Amino acids Amino acids Proteins Glycerol Glycerol Fatty acids Triglycerides Fatty acids Triglycerides Glucose Glycogen Glucose Energy source for most Energy source for most cells is GLUCOSE cells are FATTY ACIDS 3  Metabolism in the fed state Food intake stimulates insulin release and insulin inhibits glucagon secretion This affects metabolism in the liver, muscle and adipose tissue Glucose utilization in the brain remains unchanged 4  Metabolism in the fed state - Liver High insulin: glucagon ratio (4) High concentrations of nutrients lead to an increase in the insulin:glucagon ratio High blood glucose means it enters the liver and is converted to glycogen and TGs which are secreted as VLDL. Some enters TCA cycle. Glycerol from peripheral tissues is also converted to triacylglycerols Excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCA cycle for energy or converted to triacylglycerols 5  Metabolism in the fed state – Muscle Glucose enters the muscle via insulin-stimulated Glut 4 transport system - converted to glycogen or metabolised via glycolysis and TCA cycle Fatty acids enter muscle both from the diet via chylomicrons and from the liver via VLDL. These are oxidised via β-oxidation to acetyl CoA to produce ATP to support contraction Amino acids are incorporated into proteins 6  Metabolism in the fed state – Adipose tissue Glucose enters adipose tissue by the insulin- dependent Glut 4 transport system - converted via glycolysis and PDH into acetyl CoA and then to fatty acids and triacylglycerol Fatty acids enter from VLDL and chylomicrons and are converted to triacylglycerol LPL activity increased & HSL activity inhibited by insulin Glycerol released from TGs is returned to liver for re-use 7  Metabolism in the fed state – Brain The brain takes up glucose via Glut 1 & 3 transporters and metabolises it oxidatively by glycolysis and the TCA cycle to produce ATP 8  Metabolism in the early fasting state During fasting, the liver switches from a glucose-utilizing to a glucose-producing organ Decrease in glycogen synthesis and increase in glycogenolysis Gluconeogenesis 9  The early fasting state - Liver As plasma glucose falls no longer enters liver as Glut 2 transporter has low affinity. Liver changes from a user to exporter of glucose Reduced insulin: glucagon ratio activates glycogenolysis and gluconeogenesis (from lactate and alanine) via cAMP Low insulin: glucagon ratio production in response to glucagon (0.8) Lipolysis = mobilisation of fatty acids from TGs Protein in liver and other tissues are broken down to amino acids to fuel gluconeogenesis. Fatty acids from lipolysis used to produce energy via b-oxidation. Citrate and acetyl CoA produced from oxidation of fatty acids activate gluconeogenesis and inhibit glycolysis 10  The early fasting state – Muscle The fall in insulin reduces glucose entry. Glycogenolysis does not occur as there are no glucagon receptors in skeletal muscle to cause activation Muscle and other peripheral tissues switch to fatty acid oxidation as a source of energy which inhibits glycolysis and glucose utilisation Proteins are broken down to amino acids and the carbon skeletons can be used for energy or exported to the liver in the form of alanine 11  The early fasting state – Adipose tissue Entry of glucose into adipose tissue via the Glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis is severely inhibited Mobilisation of TGs occurs in response to the reduced insulin:glucagon ratio and activation of the sympathetic NS by release of noradrenaline Some fatty acids are used directly within the tissue to produce energy - remainder are released into the bloodstream to support glucose-independent energy production in muscle and other tissues Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis 12  The early fasting state – Brain Continues to take up glucose because of the high affinity of Glut1 and Glut3 transport system and independence from insulin Glucose continues to be metabolised despite the fact that no glucose is provided in the diet Brain cannot switch to fatty acids as a source of fuel as free fatty acids do not cross the blood brain barrier 13  Metabolism in the starved state Chronic low-insulin, high glucagon state Accompanied by decrease in concentration of thyroid hormones – decreases metabolic rate Free fatty acids become the major energy source Production of ketone bodies as alternative fuel source 14  The starved state - Liver No glucose enters liver and glycogen stores are depleted within 24 hours Plasma glucose dependent on gluconeogenesis from lactate, glycerol & alanine from fat and protein breakdown. The kidney also becomes an important source of gluconeogenesis Urea synthesis stimulated to cope with increasing amino groups entering liver Very low insulin: glucagon ratio Glycogen synthesis and glycolysis are inhibited (0.4) Fatty acids enter the liver and provide energy to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies (acetoacetate and β-hydroxybutyrate). These are not used by the liver but released for oxidation by other tissues (e.g. muscle, brain) 15  The starved state – Muscle Little glucose entry with fall in insulin and switch to fatty acids as the fuel Ketone bodies are taken up by muscle and other peripheral tissues and used as a further source of fuel in heart and muscle conserving glucose Ketone bodies reduce proteolysis and decrease muscle wasting Fatty acid oxidation supplies the energy needed for muscle contraction. 16  The glucose-fatty acid cycle spares glucose during fatty acid oxidation Mobilisation of fatty acids in response Not actually a cycle! to glucagon or adrenaline increases fatty acid oxidation to acetyl CoA in peripheral tissues Excess acetyl CoA converted to citrate in TCA cycle which builds up in cytoplasm and inhibits PFK-1 Build up of G-6-P inhibits hexokinase and prevents glucose phosphorylation Increase in glucose prevents further glucose entry and so conserves glucose 17  The starved state – Adipose tissue Little glucose entry with fall in insulin secretion Body switches to using fatty acids from triacylglycerol to supply all the energetic needs of the major tissues Lipolysis is greatly activated because of the low insulin:glucagon ratio and blood levels of fatty acids rise 10-fold Glycerol exported to the liver to be converted into glucose 18  The starved state – Brain Although fatty acids cannot be used by brain, as the levels of ketone bodies rise in the plasma, these can cross the blood brain barrier and enter the brain as a source of energy sparing use of glucose Ketone bodies cannot completely replace the need for glucose and therefore brain continues to take up glucose and metabolise through glycolysis net glucose synthesis during starvation is essential 19 Ketone body concentration increases during fasting or starvation [KB] plasma of 4mM or above is sufficient to allow use by the CNS Occurs after approx. 3 days of starvation Evans et al., 2017. J Physiol 595.9, 2857-2871 Glucose utilization in various metabolic states Fed state: glucose provided by diet Fasted state: most glucose provided by the breakdown of liver glycogen, increasing amounts by gluconeogenesis Starved state: most glucose comes from gluconeogenesis, the breakdown of protein and fats provide amino acids and glycerol as substrates 21  Metabolic Liver Muscle Adipose tissue Brain state Fed I:G ratio: I:G ratio: I:G ratio: I:G ratio: ATP: ATP: ATP: ATP: Main activity: Main activity: Main activity: Main activity: Early fasting I:G ratio: I:G ratio: I:G ratio: I:G ratio: ATP: ATP: ATP: ATP: Main activity: Main activity: Main activity: Main activity: Starved I:G ratio: I:G ratio: I:G ratio: I:G ratio: ATP: ATP: ATP: ATP: Main activity: Main activity: Main activity: Main activity: I:G ratio – Insulin:glucagon ratio in the blood ATP – the main metabolic fuel used to generate ATP for the tissue Main activity – main metabolic activity of the tissue  Hormonal control of glycogenolysis and glycogen synthesis Enzymes involved in glycogenolysis / glycogen synthesis are subject to allosteric control (see Lecture 4) Enzymes involved in glycogenolysis / glycogen synthesis are also subject to hormonal control by glucagon, adrenaline, cortisol and insulin Hormonal control is mediated by changes in phosphorylation 23  Hormonal control of glycogenolysis and gluconeogenesis Hormone Source Initiator Effect on glycogenolysis/ gluconeogenesis Glucagon pancreatic α-cells hypoglycaemia rapid activation Adrenaline adrenal medulla stress, rapid activation hypoglycaemia Cortisol adrenal cortex stress chronic activation Insulin pancreatic β-cells hyperglycaemia inactivation 24  Hormonal regulation of glycogen mobilisation (covalent modification) Insulin released in response to increases in blood glucose promoting glucose oxidation, glycogen synthesis and TG synthesis Glucagon and adrenaline (epinephrine) released in response to low blood glucose, thus releasing glucose from glycogen in the liver to increase blood glucose Adrenaline is also part of the “fight or flight” response; levels rise greatly during exercise when glycogen breakdown is required to support muscle contraction 25  Reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation Glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibit synthesis by activating cAMP PK with ultimate phosphorylation of phosphorylase and glycogen synthase Mimicked by increasing Ca2+ during contraction Insulin activates protein phosphatase to reverse these effects 26  Reciprocal regulation of phosphorylase and glycogen synthase by glucagon and adrenalin Glucagon and adrenaline increase cAMP production and activate cAMP PK. cAMP PK phosphorylates glycogen synthase switching it OFF. Does not phosphorylate phosphorylase but another kinase, phosphorylase kinase leading to activation. Phosphorylase kinase can also phosphorylate glycogen synthase ensuring it is inactive 27  Reciprocal regulation of phosphorylase and glycogen synthase Phosphorylase kinase exists in an a and b form. The phosphorylated form is the active a form. Phosphorylase kinase phosphorylates phosphorylase switching it ON, allowing glycogen degradation at the same time that it inhibits glycogen synthesis. Phosphorylase kinase can also be activated allosterically by Ca2+ ions linking muscle contraction with glycogen breakdown ensuring adequate ATP 28  Regulation of phosphorylase and glycogen synthase by insulin Insulin activates protein phosphatase -1 which removes the phosphates from phosphorylase, glycogen synthase and phosphorylase kinase This switches OFF glycogen breakdown and switches ON glycogen synthesis 29  Glycogen metabolism in liver & muscle Glucagon stimulates glycogenolysis: In liver - 2nd messenger is cAMP Adrenaline stimulates glycogenolysis: in muscle & liver via b-adrenergic receptors – 2nd messenger is cAMP in liver via a1-adrenergic receptors – second messenger is Ca2+ 30 Insulin stimulates glycogen synthesis in both tissues  Regulation of glycogen metabolism For glycogen to function efficiently as a fuel, there must be coordinated regulation of the enzymes _____________ and __________ ________activity to prevent futile cycling of intermediates. Regulation occurs via both _________ regulation and _________ _____________ ____________ of these enzymes During exercise glycogen breakdown is ____________ to provide energy for muscle contraction while glycogen synthesis is ____________. Adrenaline _________ breakdown and ____________ synthesis of glycogen in skeletal muscle to prepare the body for physical work In liver glycogen breakdown is ____________ by adrenaline and glucagon, whereas glycogen synthesis is ____________ in order to elevate blood glucose Insulin ______________ glycogen synthesis in response to _________ and ____ ______ glucose, whereas it simultaneously ___________ glycogen breakdown in both liver and muscle. 31