Hormonal shift and phase 1 (up to 24 hours)
Within the first day of the postabsorptive period, metabolism begins to change radically. The main trigger is a sharp drop in the insulin-to-glucagon ratio. Insulin concentration drops 10-to-15-fold, while counterregulatory hormone levels (glucagon and cortisol) increase.
These hormonal changes activate cAMP-dependent protein kinase A in adipocytes via the adenylate cyclase system. Protein kinase A phosphorylates and activates hormone-sensitive triacylglycerol lipase, initiating active lipolysis.
First 24 hours summary:
- Liver glycogen stores are completely depleted.
- Glucose levels drop to the lower limit of normal (about 60 mg/dL).
- Accelerated gluconeogenesis starts — de novo synthesis of glucose from amino acids and glycerol.
Phase 2: interorgan exchange (up to one week)
Glycogen is gone, and the body must solve two problems: maintain normoglycemia for glucose-dependent tissues (brain, erythrocytes) and find alternative fuel for the rest of the organs. Catabolism predominates over anabolism.
- Adipose tissue massively mobilizes triacylglycerols (TAGs). Fatty acids and glycerol are released into the blood.
- Skeletal muscles actively oxidize fatty acids to Acetyl-CoA. Simultaneously, muscle proteins are broken down, and amino acids are transported to the liver. Protein synthesis is halted.
- The liver takes up free fatty acids and initiates accelerated ketogenesis (synthesis of ketone bodies). At the same time, it produces glucose from incoming amino acids, glycerol, and lactate (supplied by anaerobic glycolysis in erythrocytes via the Cori cycle).
- The kidneys enhance the excretion of nitrogenous waste, primarily urea, which is formed due to intensive protein breakdown.
Due to active ketogenesis, the concentration of ketone bodies in the blood rises sharply, and a characteristic acetone breath appears.
Phase 3: adaptation and protein conservation (several weeks)
The primary threat during prolonged fasting is critical loss of muscle mass (losing a third of all body proteins leads to death). To survive, the overall metabolic rate slows down.
Energy supply pathways adapt:
- The rate of protein breakdown and, consequently, gluconeogenesis from amino acids decreases significantly.
- The brain adapts to glucose scarcity and begins actively oxidizing ketone bodies.
- Muscles virtually stop using ketone bodies, leaving them for the brain, and switch exclusively to fatty acid consumption.
The nitrogen balance remains negative throughout all phases. The key survival factor becomes the ability of tissues to synthesize and utilize ketone bodies. However, their full entry into the tricarboxylic acid (TCA) cycle requires oxaloacetate. During deep fasting, it can be formed only from amino acids, making minimal protein breakdown inevitable.
Briefly: answers to topical questions
Which gluconeogenesis enzymes are induced in the liver during prolonged fasting?
During fasting, the synthesis of gluconeogenesis enzymes is induced in the liver under the action of glucagon and cortisol. Key enzymes include:
- Glucose-6-phosphatase
- Fructose-1,6-bisphosphatase
- Phosphoenolpyruvate carboxykinase (PEPCK)
What metabolic processes occur in the kidneys during prolonged fasting?
During prolonged fasting, the following processes occur in the kidneys:
- Gluconeogenesis — kidneys have the capacity for gluconeogenesis; during prolonged fasting, the kidneys produce half of the glucose entering the blood.
- Excretion of nitrogenous wastes — involvement in the excretion of urea in urine.
Why is the tricarboxylic acid cycle in the liver inhibited during fasting?
The tricarboxylic acid (TCA) cycle in the liver is inhibited due to two main reasons:
- Allosteric inhibition: active $\beta$-oxidation of fatty acids increases the concentration of ATP and NADH, which inhibit regulatory enzymes of the TCA cycle.
- Oxaloacetate deficiency: due to the high concentration of NADH, oxaloacetate is reduced to malate, which exits into the cytosol for use in gluconeogenesis. As a result, oxaloacetate is unavailable in the mitochondria to interact with Acetyl-CoA.
Which specific ketone bodies are synthesized in the liver?
During the synthesis and conversion of ketone bodies in the liver, the following are formed:
- Acetoacetate — the first ketone body.
- $\beta$-Hydroxybutyrate — formed by the reduction of acetoacetate.
- Acetone — formed at high acetoacetate concentrations as a result of its spontaneous non-enzymatic decarboxylation.
Class and exam questions
Why does acetone breath appear during prolonged fasting?
Due to active fat breakdown, Acetyl-CoA accumulates in the liver and is channeled into the synthesis of excess ketone bodies. One of these is acetone, which is excreted via sweat and exhaled air.
Where does the body get glucose when glycogen is completely depleted?
The process of gluconeogenesis is triggered. The liver synthesizes new glucose from alternative substrates: amino acids (from muscle breakdown), glycerol (from fat breakdown), and lactate (from erythrocytes).
Why is hepatic TAG synthesis reduced during fasting?
Under conditions of energy deficiency and glucagon dominance, fatty acids are directed toward $\beta$-oxidation and ketogenesis to produce ATP, while anabolic processes (fat storage) are blocked.
What limits life expectancy during starvation?
The ability to utilize ketone bodies and protein reserves. Ketone oxidation requires oxaloacetate, which during fasting is synthesized solely from amino acids. Depletion of one-third of body proteins leads to death.
What else to study on this topic
- The Cori cycle and lactate exchange between erythrocytes and the liver
- Mechanism of hormone-sensitive lipase activation (role of cAMP and PKA)
- Biochemical stages of ketone body synthesis in the liver
- The role of oxaloacetate in the tricarboxylic acid cycle during fasting
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