Integration of Metabolism
All metabolic pathways are interconnected and regulated to maintain homeostasis. Integrative metabolism describes how organs cooperate and how the body shifts fuel usage depending on nutritional state.
Inter-organ Substrate Exchange
- Liver ↔ Muscle: Cori cycle (lactate/glucose), Alanine cycle (alanine/glucose), VLDL/FA/ketone supply
- Liver ↔ Brain: Glucose supply (fed), Ketone supply (fasting)
- Adipose ↔ Liver: FFA released by lipolysis → FA oxidation + ketogenesis in liver
- Gut → Liver: All absorbed nutrients go to liver first (portal circulation) except chylomicrons
Substrate Cycles (Futile Cycles)
Simultaneous operation of opposing pathways — appears wasteful but generates heat and provides fine metabolic control. Example: Glycolysis (PFK-1) + Gluconeogenesis (F-1,6-BPase). When both active simultaneously → ATP hydrolyzed → heat. Also: FA synthesis + FA oxidation running simultaneously in some tissues.
Pasteur Effect
O₂ inhibits glucose consumption and lactate production. Mechanism: In aerobic conditions, abundant ATP inhibits PFK-1 → less glycolysis needed. Reversal: Warburg effect in tumor cells (aerobic glycolysis despite O₂).
Randle Cycle (Glucose-Fatty Acid Cycle)
Elevated FFA → ↑Fatty acid oxidation → ↑Acetyl-CoA → inhibits PDC → ↑Citrate → inhibits PFK-1 → ↓Glucose oxidation. Explains why high fat diets and obesity impair glucose uptake → insulin resistance. Physiologically important in heart and skeletal muscle.
Key Regulatory Enzymes (Summary)
- PFK-1: Glycolysis on/off switch. AMP/ADP/F-2,6-bisP → on; ATP/Citrate → off
- PDC: Glycolysis→TCA gate. Insulin/AMP → on; NADH/Acetyl-CoA/ATP → off
- ACC: Lipogenesis on/off. Citrate/Insulin → on; Palmitoyl-CoA/Glucagon/AMPK → off
- HMG-CoA Reductase: Cholesterol synthesis on/off. Insulin → on; Cholesterol/Statins → off
- Glycogen Phosphorylase: Glycogen breakdown. Epinephrine/Glucagon/AMP → on; Glucose/Insulin/G6P → off
AMPK vs mTOR (Opposing Switches)
- AMPK (energy deficit sensor): Activated when AMP↑/ATP↓. Promotes catabolic pathways, inhibits anabolic. Exercise, Metformin activate AMPK.
- mTOR (abundance sensor): Activated by insulin, amino acids (Leu), growth factors. Promotes anabolic pathways (protein synthesis, lipid synthesis), inhibits autophagy.
- AMPK inhibits mTOR → cannot both be active simultaneously.
Autophagy
Lysosomal self-digestion of organelles and proteins during nutrient deprivation. Essential for cell survival during starvation. Regulated by mTOR (inhibits) and AMPK (activates). Defective autophagy → neurodegeneration (Parkinson's, Alzheimer's). Rapamycin → inhibits mTOR → induces autophagy.