starvation and ketogenesis

• Physiological Conditions Triggering Metabolic Adaptations

  • Fed/Fast Homeostasis
  • Starvation
  • Diabetes Mellitus: Type 1 and Type 2
  • Obesity and Metabolic Syndrome
  • Cachexia (Cancer)
  • Developmental Stages: Pregnancy, lactation
  • Diets: Low carbohydrate (ketogenic) diets
• Homeostasis


  The property of a system that regulates its internal environment to maintain stable conditions such as temperature, pH, or glucose levels
• Mechanisms of Homeostasis


  • Hormonal System: Insulin, glucagon, adrenaline
  • Signal Transduction: cAMP-PKA and posttranslational modifications like phosphorylation
  • Gene Induction: Regulation of gene expression
  • Metabolite Regulation: Control by metabolic intermediates
• Fed State (High Insulin)

  Increased: Glucose uptake, glycogen synthesis, fatty acid synthesis, protein synthesis

  Decreased: Gluconeogenesis
• Fasting State (High Glucagon)

  Increased: Gluconeogenesis, glycogenolysis, fatty acid degradation
• Metabolic Pathways During Starvation

  Glucose Production: Liver glycogen breakdown and gluconeogenesis from amino acids and glycerol

  Fuel Utilization: Liver uses fatty acids, converting excess acetyl-CoA to ketone bodies for export to tissues like the brain
• Adipose Tissue During Starvation

  Triacylglyceride Mobilization:

  Glucagon Activation: Binds to receptors on adipocytes, activating adenylyl cyclase via G protein to produce cAMP

  PKA Activation: Phosphorylates hormone-sensitive lipase and perilipin, leading to the hydrolysis of triacylglycerols to free fatty acids

  Fatty Acid Transport: Fatty acids bind to serum albumin in the blood and are transported to myocytes for oxidation
• Liver During Starvation


  Ketone Body Synthesis:

  Acetoacetyl-CoA Formation: From two acetyl-CoA molecules

  HMG-CoA Synthesis and Lyase: Converts acetoacetyl-CoA to HMG-CoA, then to acetoacetate

  Reduction: Acetoacetate is reduced to D-3-hydroxybutyrate or decarboxylated to acetone

  Ketone Body Utilization:

  Entry into TCA Cycle: Ketone bodies are converted back to acetyl-CoA in tissues like the brain and muscle for energy production
• Enzymes Involved in Ketogenesis

  • Thiolase: Present in liver, brain, and muscle

  HMG-CoA Synthetase and Reductase: Present in the liver

  β-Hydroxybutyrate Dehydrogenase: Present in liver and brain

  β-Ketoacyl-CoA Transferase: Present in brain and muscle
• Key Regulatory Reactions in the Liver During Starvation

  • Gluconeogenesis: Synthesis of glucose from non-carbohydrate sources

  Glycogen Metabolism: Regulation of glycogen breakdown and synthesis
• Major Metabolic Pathways in Muscle and Brain During Starvation


  • Muscle: Utilizes fatty acids and ketone bodies for energy, releases amino acids for gluconeogenesis in the liver

  Brain: Utilizes glucose and ketone bodies, completely oxidizing them to CO2 and water
• Events During Adaptation to Starvation

  Intestine and Portal Vein: Nutrient Absence - Low glucose and amino acids in the blood

  Pancreas: Low Insulin - Reduced release by beta cells, High Glucagon - Increased release by alpha cells

  Adipose Tissue: Fatty Acid Release - From triacylglycerol hydrolysis

  Liver: Glucose Release - From glycogen degradation and gluconeogenesis, Ketone Body Production - Increased synthesis and release

  Muscle: Fatty Acid and Ketone Utilization - Increased oxidation for energy, Amino Acid Release - For gluconeogenesis

  Brain: Glucose and Ketone Utilization - Oxidized to CO2 and water for energy
• Starvation and Ketogenesis


  Trigger: Suppression of carbohydrate intake, leading to increased reliance on lipids and proteins for energy

  Main Pathway: Ketogenesis in mitochondria

  Blood Levels: Changes in glucose, ketone bodies, and fatty acids during starvation
• Regulation of Glycolysis and Krebs Cycle

  Coordination: Regulated by ATP, citrate, and O2 levels

  Epigenetic Regulation: DNA methylation and histone acetylation affecting gene expression and phenotype changes
• Detailed Steps of Ketogenesis

  Initial Steps:

  Fatty Acid Oxidation: Fatty acids are transported to the liver and undergo β-oxidation to form acetyl-CoA

  Acetoacetyl-CoA Formation: Two molecules of acetyl-CoA are condensed by thiolase to form acetoacetyl-CoA

  HMG-CoA Formation:

  HMG-CoA Synthase: Acetoacetyl-CoA is converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by HMG-CoA synthase

  Formation of Ketone Bodies:

  HMG-CoA Lyase: Cleaves HMG-CoA to produce acetoacetate and acetyl-CoA

  1. 3-Hydroxybutyrate Dehydrogenase: Acetoacetate is reduced to D-3-hydroxybutyrate using NADH

  Spontaneous Decarboxylation: Some acetoacetate spontaneously decarboxylates to form acetone

  Transport and Utilization:

  Blood Transport: Ketone bodies are transported in the blood to peripheral tissues

  Conversion to Acetyl-CoA: In target tissues, D-3-hydroxybutyrate is oxidized back to acetoacetate, which is then converted to acetyl-CoA via β-ketoacyl-CoA transferase and thiolase
• Consequences of Starvation and Ketogenesis

  • Ketosis: A state where ketone bodies accumulate in the blood, providing an alternative energy source

  Ketoacidosis: A dangerous condition where high levels of ketone bodies lead to a decrease in blood pH, commonly seen in uncontrolled diabetes
• Starvation leads to metabolic adaptations including increased gluconeogenesis and ketogenesis
• Ketone Bodies are produced in the liver and used by the brain and muscle as alternative fuels
• Glucagon and insulin play key roles in regulating metabolic pathways during starvation