Energy Fuel Balance and Feeding Rhythm
Caloric intake is based on the caloric value of nutrients: carbohydrates and proteins yield 4 kcal/g, while fats yield 9 kcal/g.
Normally, humans eat with intervals of 4–5 hours during the day and 8–12 hours at night. The active period of digestion takes up only 10–15 hours per day. However, cellular energy expenditure occurs round-the-clock. Consequently, a portion of the ingested nutrients must be converted into stored forms (glycogen and triglycerides) to supply the body during intervals between meals.
Depending on the time elapsed since the last meal, metabolism switches between two global modes: absorptive (storage) and postabsorptive (mobilization).
Absorptive State: The Storage Mode
Lasts for 2–4 hours following a meal. During this time, glucose, fatty acids, and amino acids enter the blood directly from the gastrointestinal tract. The peak glucose concentration reaches ~8.0 mmol/L within the first hour, triggering a sharp release of insulin (up to ~120 µIU/mL) and a decrease in glucagon levels.
Liver Changes: Insulin activates glucokinase mRNA synthesis, accelerating glucose uptake and its conversion to glucose-6-phosphate. This metabolite is distributed along three pathways:
- Glycogen synthesis: glycogen synthase is activated, while glycogen phosphorylase is inactivated.
- Glycolysis acceleration: phosphofructokinase and pyruvate kinase activity increases, whereas gluconeogenesis is inhibited (fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase are suppressed).
- Pentose phosphate pathway and lipogenesis: NADPH is generated, which, together with acetyl-CoA, ensures intensive fatty acid synthesis.
Muscle Changes: Glucose transport into myocytes increases. It is used for oxidative energy production and stored as glycogen. Concurrently, amino acid influx rises, stimulating protein biosynthesis. Fatty acids play a minor energetic role during this period.
Postabsorptive State: The Mobilization Mode
Occurs after digestion is complete. The primary driver of this metabolic shift is a decrease in the insulin-to-glucagon ratio. Insulin concentration drops while glucagon rises. The goal is to maintain blood glucose within the 3.5–5.5 mmol/L range to fuel the brain and erythrocytes (insulin-independent tissues).
Liver Metabolism (Central Organ of Homeostasis):
- Glycogenolysis: stored glycogen is actively broken down into glucose.
- Gluconeogenesis: 4–6 hours postprandial, hepatic synthesis of new glucose from non-carbohydrate substrates accelerates (lactate from the Cori cycle, glycerol from adipocytes, amino acids from muscles).
- Lipid metabolism: fatty acid synthesis is suppressed (inactivation of acetyl-CoA carboxylase). Active $\beta$-oxidation of fatty acids arriving from adipose tissue is initiated. Excess acetyl-CoA is channeled into ketogenesis — the synthesis of ketone bodies.
Adaptation of Other Tissues: In adipose tissue, lipolysis is stimulated: glucagon activates hormone-sensitive lipase (HSL), which hydrolyzes triacylglycerols. In skeletal muscles, fatty acids and ketone bodies become the primary energy sources, while muscle proteins undergo proteolysis to supply amino acids to the liver.
Steroidogenesis and Substrate Delivery (Cortisol as an Example)
Hormones play a key role in regulating energy metabolism. The synthesis of the stress hormone cortisol in the adrenal cortex is triggered by the signaling molecule ACTH.
ACTH binds to its receptor, activating adenylate cyclase. The secondary messenger cAMP triggers a cascade that stimulates the hydrolysis of cholesteryl esters in lipid droplets. Cholesterol is supplied via LDLs.
Compartmentalization Steps:
- Mitochondria: free cholesterol enters and is converted to pregnenolone (rate-limiting step).
- Endoplasmic reticulum: pregnenolone is converted into progesterone and subsequently into 11-deoxycortisol.
- Mitochondria (final step): 11-deoxycortisol returns and is converted into cortisol, which diffuses into the bloodstream.