Fed state vs. fasting state metabolism

Overview - Feast or Famine

• Fed (Absorptive) State: Post-meal period. Driven by Insulin. Anabolic processes (synthesis & storage) dominate.
  • ↑ Glycogenesis, ↑ Lipogenesis, ↑ Protein synthesis.
• Fasting (Postabsorptive) State: Between meals. Driven by Glucagon & Epinephrine. Catabolic processes (breakdown & release) dominate.
  • ↑ Glycogenolysis, ↑ Gluconeogenesis, ↑ Lipolysis.

⭐ The brain relies on glucose. In prolonged fasting (>2-3 days), it adapts to use ketone bodies for up to 2/3 of its energy needs.

Fed State - Insulin's Power Play

• Trigger: Post-meal ↑ in blood glucose & amino acids.
• Key Player: Insulin, released from pancreatic β-cells.
• Primary Goal: Anabolism - build and store energy.
• Glucose Transport:
  • Insulin drives GLUT4 transporter insertion into muscle and adipose tissue membranes.
  • Liver uptake via GLUT2 is insulin-independent.
• Metabolic Shift: Insulin signaling activates anabolic pathways while inhibiting catabolism.

⭐ Insulin drives potassium into cells by stimulating the Na+/K+-ATPase pump, a mechanism used to treat hyperkalemia but which can cause hypokalemia.

• Key Enzymes Upregulated:
  • Glucokinase, PFK-1
  • Glycogen synthase
  • Acetyl-CoA carboxylase (ACC)

Fasting State - Glucagon's Grand Stand

• Hormonal Shift: ↓ Insulin, ↑ Glucagon. The body's primary goal is to maintain euglycemia, especially for the brain and RBCs.
• Primary Metabolic Pathways:
  • Hepatic Glycogenolysis: First-line response; glycogen stores deplete in ~24 hours.
  • Adipose Lipolysis: Hormone-sensitive lipase (HSL) activation releases free fatty acids (FFAs) and glycerol.
  • Hepatic Gluconeogenesis: Takes over as the primary source of glucose. Key precursors:
    • Lactate (Cori cycle)
    • Alanine (Cahill cycle)
    • Glycerol
• Ketogenesis: The liver converts excess acetyl-CoA from FFA oxidation into ketone bodies to fuel the brain and muscle.

⭐ Alanine is the key gluconeogenic amino acid shuttled from muscle to the liver.

Starvation State - Ketone Kick-In

• Occurs after >3 days of fasting; a crucial metabolic shift to spare vital proteins.
• Primary Fuel Source: Ketone bodies, synthesized in the liver from fatty acid oxidation.
  • Adipose tissue releases fatty acids (via HSL).
  • Liver converts fatty acids → Acetyl-CoA → acetoacetate & $β$-hydroxybutyrate.
• Brain Metabolism: Adapts to derive up to 75% of its energy from ketones, significantly reducing the need for gluconeogenesis.
• RBCs: Still rely exclusively on glucose as they lack mitochondria.
• Hormonal State: Extremely high glucagon, very low insulin.

⭐ The liver synthesizes ketone bodies but cannot use them for energy because it lacks the enzyme thiophorase (Succinyl-CoA:acetoacetate CoA transferase).

High‑Yield Points - ⚡ Biggest Takeaways

• Fed state is anabolic, driven by insulin, promoting glycogen synthesis and lipogenesis.
• Fasting state is catabolic, driven by glucagon and epinephrine, activating glycogenolysis and gluconeogenesis.
• In prolonged fasting, fatty acid oxidation predominates, and ketone bodies become the brain's primary alternative fuel.
• The liver is the primary site of gluconeogenesis to maintain blood glucose for other tissues.
• RBCs lack mitochondria and depend exclusively on anaerobic glycolysis.