Fasting State Metabolism

Hormonal Orchestra - Fasting's Conductors

• Primary Goal: Maintain blood glucose; mobilize stored fuel.
• ↓ Insulin/Glucagon Ratio: The critical switch activating fasting pathways.
• Key Hormones & Actions:
  • Glucagon (from pancreatic α-cells): Master regulator.
    • ↑ Hepatic Glycogenolysis (early fasting)
    • ↑ Hepatic Gluconeogenesis (primary source later)
    • ↑ Adipose Lipolysis (provides FFAs, glycerol)
    • ↑ Hepatic Ketogenesis (alternative fuel)
  • Epinephrine (Adrenal Medulla): Rapid, stress-induced response.
    • ↑ Glycogenolysis (liver, muscle)
    • ↑ Lipolysis
    • Stimulates glucagon secretion, inhibits insulin secretion.
  • Cortisol (Adrenal Cortex): Slower, permissive & prolonged effect.
    • ↑ Gluconeogenic enzyme synthesis (liver)
    • ↑ Muscle proteolysis (provides amino acids for gluconeogenesis)
    • ↑ Lipolysis
  • Growth Hormone (GH; Pituitary): Glucose-sparing.
    • ↓ Peripheral glucose uptake by tissues
    • ↑ Lipolysis

⭐ Glucagon is the primary counter-regulatory hormone in early fasting, stimulating both glycogenolysis and gluconeogenesis.

Fuel Factory Frenzy - Tapping the Reserves

• Primary Goal: Mobilize stored energy (glycogen, triglycerides) to maintain blood glucose & fuel vital organs.

• Key Hormonal Shift: ↓Insulin, ↑Glucagon, ↑Epinephrine.

• Fuel Sources Mobilized:

  • Liver Glycogen:
    • Glycogenolysis $→$ Glucose.
    • Sustains blood glucose for ~12-18 hours.
  • Adipose Triglycerides (Lipolysis):
    • Triglycerides $→$ Fatty Acids (FAs) + Glycerol.
    • FAs: β-oxidation in liver/muscle for ATP.
    • Glycerol: Gluconeogenic substrate in liver.
  • Muscle Protein (Prolonged Fasting):
    • Proteolysis $→$ Amino Acids (e.g., Alanine).
    • Alanine $→$ Liver for gluconeogenesis (Glucose-Alanine cycle).

⭐ Hormone-Sensitive Lipase (HSL) is key for lipolysis in adipose tissue, activated by epinephrine and glucagon (via cAMP) and inhibited by insulin.

Liver's Labors - Central Processing Unit

• Core Functions: Maintain blood glucose; supply ketone bodies (alternative fuel).
• Glucose Output:
  • Glycogenolysis (early fasting, 12-24 hrs): Glycogen → Glucose. Key: Glycogen Phosphorylase.
  • Gluconeogenesis (GNG) (sustained): De novo glucose from Lactate, Alanine, Glycerol. Liver = major site.
    • Essential for brain, RBCs. Reg: ↑ Glucagon, ↑ Cortisol; ↓ Insulin.
• Ketogenesis (active GNG):
  • Excess Acetyl-CoA (from FA β-oxidation) → Ketone bodies (Acetoacetate, β-Hydroxybutyrate).
  • Fuel for brain, muscle, heart; glucose-sparing. Key: HMG-CoA Lyase.
• Fatty Acid β-Oxidation:
  • Fuels GNG (ATP); provides Acetyl-CoA for ketogenesis.
• Urea Cycle:
  • Manages $NH_3$ from AA catabolism (AAs for GNG). Excretes N as Urea.

⭐ The key regulatory enzymes of gluconeogenesis are Pyruvate Carboxylase, PEP Carboxykinase, Fructose-1,6-bisphosphatase, and Glucose-6-phosphatase. (📌 Mnemonic: Pathway Produces Fresh Glucose)

Peripheral Power‑Play - Organs Adapting

• Muscle:
  • Initial: Own glycogen (lasts hours).
  • Switches to fatty acid oxidation (from adipose) as primary fuel.
  • Prolonged fast: ↑ Ketone body uptake.
  • Proteolysis → Alanine & Glutamine to liver for gluconeogenesis.
• Adipose Tissue:
  • HSL activation (↓Insulin, ↑Glucagon, ↑Epinephrine).
  • Lipolysis: Triglycerides → FFAs + Glycerol.
  • FFAs (bound to albumin) fuel liver, muscle; Glycerol → liver gluconeogenesis.
• Brain:
  • Early fast: Glucose-dependent.

  ⭐ During prolonged starvation (>2-3 days), brain adapts to use ketone bodies for up to 70% of its energy needs, sparing glucose & protein.

• RBCs: Obligate glucose users (anaerobic glycolysis).
• Kidney:
  • Gluconeogenesis (significant in prolonged fast, up to 50% of total).
  • Excretes excess H⁺ (from ketogenesis), NH₄⁺ (from glutamine).

High‑Yield Points - ⚡ Biggest Takeaways

• ↓Insulin & ↑Glucagon drive fasting metabolism, prioritizing blood glucose homeostasis.
• Liver initially performs glycogenolysis, then shifts to gluconeogenesis using lactate, alanine, glycerol.
• Adipose tissue lipolysis releases FFAs (energy for most tissues) and glycerol (gluconeogenic).
• Muscle protein breakdown supplies amino acids (especially alanine) for hepatic gluconeogenesis.
• Prolonged fasting activates hepatic ketogenesis; ketone bodies become crucial fuel for brain and muscle.
• Tissues utilize FFAs/ketones, sparing glucose for brain & RBCs.