Metabolic adaptations in starvation

Hormonal Milieu - The Hunger Hormones

• Primary Metabolic Switch: The defining change is the ↓ Insulin : Glucagon ratio.
• Key Hormonal Shifts:
  • ↓ Insulin: Due to low blood glucose.
  • ↑ Glucagon: Secreted by pancreatic α-cells.
  • ↑ Epinephrine: Released from adrenal medulla.
  • ↑ Cortisol: Secreted to promote gluconeogenesis and lipolysis.

⭐ The Insulin:Glucagon ratio, not the absolute level of either hormone alone, is the most critical factor governing the metabolic transition from the fed to the fasting state.

Hepatic Glycogenolysis - Glycogen's Last Stand

• Timeframe: Primary glucose source for the first 12-24 hours of fasting.
• Process: Liver glycogenolysis bridges the gap until gluconeogenesis fully activates.
  • Key Enzyme: Glycogen phosphorylase (activated by ↑ glucagon & epinephrine).
• Liver vs. Muscle Glycogen:
  • Liver: Has Glucose-6-phosphatase ($G6Pase$) to release free glucose into blood for brain/RBCs.
  • Muscle: Lacks $G6Pase$; glycogen provides fuel for muscle contraction only. 📌 Muscle is "selfish."

⭐ The liver's expression of Glucose-6-phosphatase is the key distinction allowing it to buffer blood glucose, a function muscle cannot perform.

Gluconeogenesis - Desperate Glucose Measures

Active from ~24 hours to ~3-5 days. The liver, and later kidneys, must synthesize new glucose as glycogen depletes to fuel the brain and RBCs.

• Primary Substrates:
  • Alanine: From muscle protein breakdown (Glucose-Alanine Cycle).
  • Lactate: From RBCs & muscle (Cori Cycle).
  • Glycerol: From triglyceride breakdown in adipose tissue.
• Key Regulation:
  • PEPCK (Phosphoenolpyruvate carboxykinase) is the key regulatory enzyme; its synthesis is induced by glucagon and cortisol. ↑

⭐ Even-chain fatty acids cannot yield net glucose because they produce only Acetyl-CoA, and the pyruvate dehydrogenase complex reaction is irreversible. Odd-chain fatty acids are an exception, yielding propionyl-CoA.

Ketosis & Sparing - The Ketone Switch

• Timeline: Kicks in after >3-5 days of starvation, marking the shift to prolonged fasting metabolism.
• Central Process: Liver shifts from gluconeogenesis to robust ketogenesis.
  • Massive fatty acid oxidation from adipose tissue generates excess acetyl-CoA.
  • The liver converts this acetyl-CoA into ketone bodies: acetoacetate and β-hydroxybutyrate.
• Primary Goal: Protein Sparing
  • Reduces the need for gluconeogenesis from amino acid skeletons, thus preserving vital muscle tissue.
• Fuel Source Adaptation:
  • Brain: Adapts to derive up to ~70% of its energy from ketone bodies.
  • RBCs: Lack mitochondria and always depend exclusively on glucose.

⭐ High-Yield Fact: The liver can produce ketone bodies but cannot use them for energy because it lacks the enzyme thiophorase (Succinyl-CoA-Acetoacetate CoA Transferase). This enzyme is present in extrahepatic tissues like the brain, allowing them to convert ketones back to acetyl-CoA.

• In early starvation, hepatic glycogenolysis is the primary source of glucose, depleting within ~24 hours.
• The body then shifts to gluconeogenesis, using substrates like lactate, alanine, and glycerol.
• Fatty acid oxidation becomes the main energy source for most tissues.
• The liver produces ketone bodies, which the brain starts using after 2-3 days to spare glucose.
• Muscle protein catabolism decreases significantly to preserve lean body mass.