From the Guidelines
During the fasting state, the body undergoes a complex series of metabolic adaptations to maintain energy homeostasis, with the liver, adipose tissue, muscle, and brain playing critical roles in this process, as described in the study by 1.
Metabolic Pathways
The liver becomes the central metabolic hub, initiating glycogenolysis to release glucose into the bloodstream. Glycogen phosphorylase catalyzes this process, breaking down stored glycogen into glucose-1-phosphate, which is then converted to glucose-6-phosphate by phosphoglucomutase. Glucose-6-phosphatase then removes the phosphate group, allowing glucose to enter the circulation to supply the brain and other glucose-dependent tissues.
As fasting continues and glycogen stores deplete (typically after 12-24 hours), the liver shifts to gluconeogenesis, synthesizing glucose from non-carbohydrate precursors. Key substrates include lactate (from muscle glycolysis), alanine (from muscle protein breakdown), and glycerol (from adipose tissue lipolysis). Critical enzymes in this pathway include pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase, as noted in the study by 1.
Organ-Specific Contributions
- Adipose Tissue: Undergoes significant lipolysis during fasting, with hormone-sensitive lipase and adipose triglyceride lipase breaking down triglycerides into glycerol and free fatty acids. These fatty acids travel to the liver where they undergo beta-oxidation, generating acetyl-CoA which enters the Krebs cycle or is converted to ketone bodies (acetoacetate, beta-hydroxybutyrate) through the action of HMG-CoA synthase and HMG-CoA lyase.
- Muscle Tissue: Contributes by releasing amino acids, particularly alanine and glutamine, from protein breakdown. Alanine enters the liver for gluconeogenesis, while glutamine is utilized by the kidneys for ammoniagenesis and also contributes to gluconeogenesis.
- Brain: Normally relies heavily on glucose, but gradually adapts to using ketone bodies for up to 70% of its energy needs during prolonged fasting. This metabolic flexibility preserves glucose for tissues that cannot use alternative fuels and represents a critical survival adaptation during food scarcity, as discussed in the study by 1.
Key Substrates and Enzymes
- Substrates: Lactate, alanine, glycerol, and fatty acids play critical roles in the metabolic pathways during fasting.
- Enzymes: Glycogen phosphorylase, phosphoglucomutase, glucose-6-phosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, HMG-CoA synthase, and HMG-CoA lyase are essential for the metabolic adaptations during fasting, as highlighted in the study by 1.
From the Research
Integrated Metabolic Pathways during Fasting State
The metabolic pathways during fasting involve a complex interplay between various organs, substrates, products, and enzymes. The key organs involved in this process include:
- Liver: plays a central role in glucose and lipid metabolism, including glycogenolysis, gluconeogenesis, and ketone body production 2, 3, 4
- Adipose tissue: involved in lipolysis, releasing free fatty acids into the bloodstream 2, 3
- Muscle: contributes to proteolysis, providing amino acids for gluconeogenesis, and also undergoes changes in energy/nutrient-sensing pathways during fasting 2, 5
- Kidneys: help conserve ketone bodies and maintain blood fuel homeostasis 2
Substrates, Products, and Enzymes
The main substrates, products, and enzymes involved in the metabolic pathways during fasting are:
- Glycogenolysis:
- Substrate: glycogen
- Product: glucose
- Enzymes: glycogen phosphorylase, glycogen debranching enzyme 4
- Gluconeogenesis:
- Substrate: amino acids, lactate, glycerol
- Product: glucose
- Enzymes: various, including phosphoenolpyruvate carboxykinase and fructose-1,6-bisphosphatase 3
- Lipolysis:
- Substrate: triglycerides
- Product: free fatty acids
- Enzymes: hormone-sensitive lipase 3
- Ketone body production:
- Substrate: free fatty acids
- Product: ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone)
- Enzymes: various, including HMG-CoA synthase and HMG-CoA lyase 6
- Fatty acid β-oxidation:
- Substrate: free fatty acids
- Product: acetyl-CoA
- Enzymes: various, including carnitine palmitoyltransferase and acyl-CoA dehydrogenase 3
Metabolic Pathways
The metabolic pathways during fasting can be summarized as follows:
- Initial phase (0-24 hours): glycogenolysis and lipolysis provide glucose and free fatty acids, respectively 2, 5
- Intermediate phase (24-72 hours): gluconeogenesis and ketone body production increase, with a shift towards lipid oxidation 2, 3
- Prolonged fasting (beyond 72 hours): ketone bodies become the primary energy source, with a decrease in glucose production and an increase in fatty acid β-oxidation 2, 6