Altered Metabolic States

• Integration of metabolism: Thermogenesis

  Generating heat from metabolic processes:

  1. Shivering
  2. Uncoupled respiration - UCP1(Thermogenin), Fatty acyl amino acids
• Brown Adipose Tissue (BAT)

  Modified adipocytes which generate heat by wasting the energy in stored fats. It is important in babies
• Derangement of metabolism: Diabetes

  Mouse model for diabetes: Transgenic mouse that has no adipose tissue, Eats 5x quantity of food/day, Blood glucose and TG 3x normal, Insulin 50-400x normal (and ineffective), Diabetes cured by transplanting in adipose tissue
• Define the anabolic state and describe which hormones, pathways, and organs are involved

  The anabolic state is when the body synthesizes molecules and stores energy. Key hormones include insulin, which promotes pathways like glycogenesis, lipogenesis, and protein synthesis. The main organs involved are the liver, muscle, and adipose tissue
• List the different versions of hexokinase and GLUT in different tissues and their characteristics

  • GLUT1 and GLUT3: Low Km, found in most tissues.
  • GLUT2: High Km, found in liver and pancreatic β-cells.
  • GLUT4: Medium Km, insulin-responsive, found in muscle and adipose tissue.
  • Hexokinase I-III: Low Km, found in most tissues.
  • Hexokinase IV (Glucokinase): High Km, not inhibited by G-6-P, found in liver and pancreatic β-cells.
• Explain how fructose is metabolised in the liver and the consequences of a high fructose diet

  Fructose is metabolized by fructokinase to fructose-1-phosphate, then split into glyceraldehyde and DHAP by aldolase B. This bypasses glycolysis control points, leading to increased lipogenesis. High fructose intake can cause fatty liver and insulin resistance
• Explain how alcohol is metabolised in the liver and the consequences of high alcohol consumption

  Alcohol is converted to acetaldehyde by alcohol dehydrogenase, then to acetate by aldehyde dehydrogenase. High alcohol intake raises NADH, inhibiting gluconeogenesis and fatty acid oxidation, leading to fatty liver, hypoglycemia, metabolic acidosis, and increased triglyceride synthesis
• Explain the metabolic priorities of the catabolic state and which hormones, pathways, and organs are involved

  The catabolic state prioritizes maintaining blood glucose. Key hormones are glucagon, adrenaline, and cortisol. Pathways include glycogenolysis, gluconeogenesis, and lipolysis. The liver, muscle, and adipose tissue are involved. Cortisol promotes protein degradation, while glucagon and adrenaline increase glycogen breakdown and fat mobilization
• Describe the different substrates used by muscles in different types of exercise

  • Short-term intense exercise: Uses ATP, creatine phosphate, and glucose.
  • Long-duration low-intensity exercise: Primarily uses fatty acids and glycogen.
• Explain how the electron transport chain can be utilized in thermogenesis

  In brown adipose tissue, uncoupling protein 1 (UCP1) allows protons to re-enter the mitochondrial matrix without ATP synthesis, dissipating energy as heat. This accelerates the electron transport chain and increases heat production, utilizing stored fat as fuel
• What are the effects of insulin on key metabolic enzymes in the anabolic state?

  Insulin increases the activity of enzymes like glycogen synthase (increases glycogenesis), pyruvate kinase, and acetyl-CoA carboxylase (increases fatty acid synthesis). It decreases the activity of enzymes such as phosphorylase (decreases glycogenolysis) and hormone-sensitive lipase (decreases lipolysis)
• What are the metabolic effects of high fructose consumption on liver metabolism?

  High fructose consumption leads to increased lipogenesis due to the conversion of fructose to fructose-1-phosphate, which bypasses key regulatory steps in glycolysis. This results in the accumulation of fatty acids and triglycerides in the liver, contributing to fatty liver disease and insulin resistance
• How does fructose metabolism differ from glucose metabolism in the liver?

  Fructose is metabolized to fructose-1-phosphate by fructokinase and then split into glyceraldehyde and DHAP by aldolase B, bypassing the PFK-1 regulatory step of glycolysis. This leads to unregulated production of pyruvate and acetyl-CoA, promoting lipogenesis. In contrast, glucose metabolism is tightly regulated by PFK-1
• How does excessive alcohol consumption affect liver metabolism?

  Excessive alcohol consumption increases NADH levels, inhibiting gluconeogenesis and fatty acid oxidation, leading to hypoglycemia and fatty liver. Acetaldehyde, a toxic intermediate, can cause liver damage. The increase in NADH also inhibits the TCA cycle and promotes lactic acidosis
• What are the metabolic priorities during starvation?

  During starvation, the primary metabolic priority is to maintain blood glucose levels for the brain and red blood cells. The body increases gluconeogenesis from amino acids, glycerol, and lactate, and shifts to ketone body production to reduce muscle protein breakdown. Hormones like glucagon, adrenaline, and cortisol play key roles
• What is the role of cortisol in the catabolic state?

  In the catabolic state, cortisol promotes protein catabolism to provide amino acids for gluconeogenesis. It also increases the activity of enzymes involved in gluconeogenesis and lipolysis, and reduces the activity of glycogen synthase, thus enhancing glucose production and fat mobilization
• How does brown adipose tissue contribute to thermogenesis?

  Brown adipose tissue contains a high number of mitochondria with uncoupling protein 1 (UCP1), which allows protons to leak back into the mitochondrial matrix, dissipating energy as heat instead of producing ATP. This process helps generate heat and is particularly important in newborns and in response to cold
• What is the role of UCP1 in thermogenesis?

  UCP1 (uncoupling protein 1) in brown adipose tissue uncouples the electron transport chain from ATP synthesis by allowing protons to re-enter the mitochondrial matrix without generating ATP, thus releasing energy as heat. This process increases heat production and accelerates the electron transport chain
• What is the Warburg effect in cancer metabolism?

  The Warburg effect refers to the preference of cancer cells to produce energy through aerobic glycolysis rather than oxidative phosphorylation, leading to high lactate production even in the presence of oxygen. This adaptation supports rapid cell growth and proliferation
• What are some unique fuel preferences of different tissues?

  • Heart: Prefers ketone bodies.
  • Erythrocytes: Use glycolysis exclusively, generating lactate.
  • Kidneys: Use lactate for ATP production.
  • Intestines and Immune Cells: Prefer glutamine.
  • Spermatozoa: Use fructose as the only fuel source.
• What is the role of hormone-sensitive lipase (HSL) in metabolism, and how is it regulated?

  HSL hydrolyzes stored triglycerides into free fatty acids and glycerol. It is activated by adrenaline and glucagon through phosphorylation and inhibited by insulin
• What is the role of cortisol in protein metabolism during the catabolic state?

  Cortisol promotes the breakdown of proteins into amino acids, which are then used for gluconeogenesis in the liver. It increases the activity of enzymes involved in amino acid catabolism and gluconeogenesis
• What is the role of creatine phosphate in muscle energy metabolism?

  Creatine phosphate serves as a rapid source of high-energy phosphate to regenerate ATP from ADP during short bursts of intense exercise, catalyzed by the enzyme creatine kinase
• What metabolic adaptations occur in the body during prolonged starvation?

  During prolonged starvation, the body shifts to using ketone bodies as the primary fuel source for the brain, reduces gluconeogenesis to spare muscle protein, and increases lipolysis to provide fatty acids and glycerol for energy
• What is the function of uncoupling proteins (UCPs) in mitochondria?

  UCPs dissipate the proton gradient across the mitochondrial membrane, releasing energy as heat instead of capturing it as ATP. This process helps in thermoregulation and is significant in brown adipose tissue
• How does insulin affect adipose tissue metabolism?

  Insulin promotes glucose uptake in adipose tissue by increasing GLUT4 translocation to the cell membrane. It also enhances lipogenesis by increasing the activity of enzymes like glycerol-3-phosphate acyltransferase and inhibits lipolysis by decreasing hormone-sensitive lipase activity
• What are the metabolic effects of insulin resistance?

  Insulin resistance leads to impaired glucose uptake in muscle and adipose tissue, increased hepatic gluconeogenesis, elevated blood glucose levels, and dyslipidemia. This condition often precedes type 2 diabetes and is associated with metabolic syndrome