The body cycles between three main metabolic states, each with characteristic hormonal signals and pathway activities.
Fed to starving: the same pathways, re-weighted
Over time
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Glycogen breakdown Gluconeogenesis Ketone body production What the brain is running on
The one constraintThe brain cannot burn fatty acids, and red blood cells have no mitochondria at all. Between them they demand a floor of glucose no matter how long you fast, and every other decision on this chart follows from that single requirement.
Why muscle gets spent, then sparedOnce liver glycogen runs out, the only remaining source of new glucose is amino acids from muscle. Burning your own muscle is survivable for days, not weeks, so the body switches the brain onto ketone bodies. Ketosis is not a failure state; it is the adaptation that stops you consuming yourself.
What the hormones actually doInsulin means store: it activates glycogen synthase, acetyl-CoA carboxylase, and PDH phosphatase. Glucagon means mobilise: it raises cAMP, which activates glycogen phosphorylase and hormone-sensitive lipase and shuts down glycolysis via PFK-2. Every arrow in this book obeys those two.
Nothing new happens as you fast; the same pathways are just re-weighted. Glycogen covers the first day, gluconeogenesis covers the second, and ketone bodies take over the brain from there so that muscle protein survives. Read the three rails as a relay, not as three separate topics.
Fed State (after a meal)
Hormonal signal: high insulin, low glucagon.
Glucose uptake into cells (via GLUT4 in muscle and adipose).
Fat storage in adipose (via LPL) - insulin activates lipoprotein lipase at capillaries, so chylomicron and VLDL triglycerides are hydrolyzed and fatty acids absorbed.
Muscle protein breakdown → amino acids → gluconeogenesis (Cori cycle and glucose-alanine cycle).
Ketogenesis ramps up; ketone bodies rise in blood.
After 3-4 days, brain adapts to use ketones for ~60-75% of energy.
Muscle protein breakdown slows as ketones replace brain’s glucose need.
Fat stores determine how long the body survives.
Which hormone drives the metabolic shift from fed to fasted state?
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Glucagon. Rising glucagon (and falling insulin) activates glycogenolysis, gluconeogenesis, lipolysis, and fatty acid oxidation. The main targets include glycogen phosphorylase (on), glycogen synthase (off), hormone-sensitive lipase (on), PFK-2/F-2,6-BP (lowered), and ACC (off). Glucagon is the “fasting” signal.
What is the main adaptation during prolonged starvation that lets survival extend for weeks?
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The brain’s shift to using ketone bodies for the majority of its energy. Without this adaptation, the body would need to continuously break down muscle protein to make glucose via gluconeogenesis, rapidly depleting protein stores. Ketones spare protein, and fat stores become the main determinant of survival duration. Most adults have enough fat to fuel weeks of fasting; glycogen lasts only a day.
Why does the body preferentially break down muscle protein (rather than, say, collagen) during fasting?
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Muscle has the largest pool of readily catabolized protein. It is metabolically active and can release amino acids (especially alanine) relatively quickly. Structural proteins like collagen, elastin, and most enzymes are not easily mobilized. The body will also spare certain critical proteins (hemoglobin, albumin, enzymes) unless starvation is very severe. The glucose-alanine cycle lets muscle provide carbon and nitrogen to the liver for gluconeogenesis and urea cycle.
