Glucose-6-phosphateThe first fork. G6P can be stored as glycogen, burned through glycolysis, or diverted to the pentose phosphate pathway for NADPH and ribose-5-P. It cannot leave the cell: only liver and kidney have glucose-6-phosphatase to turn it back into free glucose.
PyruvateThe last cytosolic fork. With oxygen it crosses into the mitochondrion for PDH; without oxygen it becomes lactate; in muscle it is transaminated to alanine; and in the fasting liver it is carboxylated to oxaloacetate to start gluconeogenesis.
Acetyl-CoAThe great convergence: carbohydrate, fat, and ketogenic amino acids all arrive here. It burns in the TCA cycle, leaves as citrate for fatty acid and cholesterol synthesis, or condenses into ketone bodies. It can never become glucose, which is why fat is not a gluconeogenic fuel.
OxaloacetateGatekeeper of the TCA cycle and the doorway out of it. Acetyl-CoA cannot enter the cycle without OAA, so when OAA is drained for gluconeogenesis during fasting, acetyl-CoA backs up and is shunted into ketone bodies. OAA also trades with the urea cycle as aspartate and fumarate.
Read it top to bottom for catabolism, bottom to top for anabolism. Fuels enter at the top, carbon funnels through four junction metabolites, and the electron carriers cash out at the electron transport chain. The four navy pills are the only molecules you need to reason from: know what enters and leaves each one and you can rebuild the rest of the map from memory.
All three major fuels converge at acetyl-CoA, which feeds the TCA cycle:
Amino acids → various entry points (pyruvate, TCA intermediates, acetyl-CoA).
Tissue Fuel Preferences
Different tissues prefer different fuels:
| Tissue | Preferred fuels | Notes |
|--------|-----------------|-------|
| Brain | Glucose (always), ketones (starvation) | Cannot use fatty acids directly |
| Heart | Fatty acids (first choice), then ketones, then glucose | Huge aerobic capacity |
| Red blood cells | Glucose (only) | No mitochondria, no alternatives |
| Skeletal muscle | Fatty acids (rest), glycogen (exercise) | Also uses ketones in starvation |
| Liver | Amino acids, fatty acids | Makes glucose and ketones for other tissues |
| Adipose | Fatty acids | Stores and releases them |
Fed vs. Fasted vs. Starvation
Fed state (insulin high): glucose uptake, glycogen and fat storage, protein synthesis, fatty acid synthesis. Liver buffers blood glucose by storing excess.
Fasted state (glucagon high): glycogenolysis, gluconeogenesis, lipolysis. Brain still uses glucose mostly.
Starvation (days without food): glycogen depleted; fat mobilized; ketone bodies produced; brain adapts to use ketones; muscle protein breakdown minimized by this ketone adaptation.
The Pecking Order During Starvation
Hours: blood glucose maintained by liver glycogen.
Day 1-2: liver glycogen depleted; gluconeogenesis from amino acids (muscle protein) and glycerol.
Day 2-3: fat mobilization ramps up; ketone production begins.
Day 3+: ketones rise; brain adapts to use them; protein breakdown slows to spare muscle.
Weeks: fat stores determine survival. Once fat is gone, the body cannibalizes essential proteins, leading to death.
Where do carbohydrate, fat, and protein catabolism converge?
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All three converge at acetyl-CoA, which feeds the TCA cycle. Carbohydrates → glycolysis → pyruvate → PDH → acetyl-CoA. Fatty acids → beta-oxidation → acetyl-CoA. Amino acids → various entry points, some directly to acetyl-CoA, some to TCA intermediates. Acetyl-CoA is the central metabolic hub.
How does the body adapt to prolonged starvation after ~3-4 days?
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The brain begins using ketone bodies for up to 75% of its energy needs. This reduces the demand for glucose, which had been met by gluconeogenesis from amino acids (muscle protein). The ketone adaptation spares muscle protein and dramatically extends survival. Fat stores then become the main determinant of how long a person can survive without food.
Why is the liver unique in metabolism?
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The liver does jobs no other tissue does: gluconeogenesis (releases glucose to blood), ketogenesis (releases ketones), the urea cycle (detoxifies ammonia), bile acid synthesis, lipoprotein synthesis, and drug metabolism. It also uniquely expresses glucose-6-phosphatase (free glucose release) and HMG-CoA lyase (ketone production) while lacking thiophorase (so it cannot use ketones). The liver acts as a metabolic factory for the whole body.
