Energy substrate balance and feeding rhythm
Calorie intake is based on the energy value of nutrients: carbohydrates and proteins yield 4 kcal/g each, while fats yield 9 kcal/g.
Normally, a person eats with intervals of 4–5 hours during the day and 8–12 hours at night. The active digestion period takes only 10–15 hours per day. However, cellular energy expenditure occurs around the clock. Therefore, some of the ingested nutrients must be converted into stored forms (glycogen and fats) to supply the body during intervals between meals.
Depending on the time elapsed since a meal, metabolism switches between two global states: absorptive (storage) and postabsorptive (mobilization).
Absorptive state: storage mode
Lasts 2–4 hours after a meal. During this time, glucose, fatty acids, and amino acids enter the blood directly from the gastrointestinal tract. The glucose concentration peak reaches ~8.0 mmol/L within the first hour, causing a sharp release of insulin (up to ~120 µIU/mL) and a decrease in glucagon levels.
Changes in the liver: 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: the activity of phosphofructokinase and pyruvate kinase increases, while gluconeogenesis is inhibited (fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase are suppressed).
- Pentose phosphate pathway and lipogenesis: NADPH is produced, which, together with acetyl-CoA, ensures intensive fatty acid synthesis.
Changes in muscles: Glucose transport into myocytes increases. It is used for oxidation to produce energy and stored as glycogen. Simultaneously, the influx of amino acids increases, stimulating protein biosynthesis. Fatty acids play a minor energetic role during this period.
Postabsorptive state: mobilization mode
Begins after digestion is complete. The main reason for this metabolic shift is a decrease in the insulin-glucagon ratio. Insulin concentration drops while glucagon rises. The goal is to maintain glucose within the 3.5–5.5 mmol/L range to nourish the brain and erythrocytes (insulin-independent tissues).
Metabolism in the liver (central organ of homeostasis):
- Glycogenolysis: glycogen stores are actively broken down into glucose.
- Gluconeogenesis: 4–6 hours after a meal, the synthesis of new glucose from non-carbohydrate substrates begins to accelerate (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 coming from adipose tissue is triggered. Excess acetyl-CoA goes into ketogenesis—the synthesis of ketone bodies.
Adaptation of other tissues: Lipolysis is stimulated in adipose tissue: glucagon activates hormone-sensitive TAG lipase, which hydrolyizes triacylglycerols. In skeletal muscles, fatty acids and ketone bodies become the main source of energy, and muscle proteins undergo proteolysis to supply amino acids to the liver.
Steroidogenesis and substrate influx (using 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 cholesterol esters in lipid droplets. Cholesterol comes from LDL.
Compartmentalization stages:
- Mitochondrion: free cholesterol enters and is converted into pregnenolone (rate-limiting step).
- Endoplasmic reticulum: pregnenolone is converted into progesterone and then into 11-deoxycortisol.
- Mitochondrion (finale): 11-deoxycortisol returns and is converted into cortisol, which diffuses into the bloodstream.
Briefly: answers to topical questions
Which enzyme catalyzes the rate-limiting step of cholesterol conversion to pregnenolone in the mitochondria?
The rate-limiting step of cholesterol conversion to pregnenolone in the mitochondria is catalyzed by the enzyme desmolase, also referred to as P450scc.
In genetic nomenclature and biochemical literature, this enzyme has several names:
- Desmolase (P450scc) — catalyzes the reaction of pregnenolone formation.
- 20,22-Desmolase (CYP11A1) — the enzyme that cleaves the side chain of cholesterol.
This reaction occurs after free cholesterol is transported into the mitochondrion with the help of the specific StAR protein.
Which hormones are counter-regulatory and stimulate reserve mobilization?
Counter-regulatory hormones include insulin antagonists that raise blood glucose levels.
The sources indicate:
- Glucagon;
- Epinephrine;
- Cortisol;
- Growth hormone (GH);
- Iodothyronines — thyroid hormones.
In the postabsorptive state, the mobilization of energy reserves is associated with a decrease in the insulin-glucagon ratio: insulin levels decrease and glucagon levels increase. In adipose tissue during fasting, the effect of glucagon predominates; epinephrine and cortisol also participate. Glucagon and epinephrine activate hormone-sensitive TAG lipase via adenylate cyclase, cAMP, and protein kinase A, which stimulates lipolysis.
In the absorptive period, INsulin rules (INvests in reserves); in the postabsorptive period, GLUCagon (saves GLUCose).
Class and exam questions
Why is glucose so important for the brain and erythrocytes in the postabsorptive state?
These are insulin-independent tissues. Erythrocytes completely lack mitochondria and can only derive energy via anaerobic glycolysis, whereas the brain oxidizes glucose to carbon dioxide and water, requiring a continuous supply.
Where does the liver get substrates for gluconeogenesis?
Lactate from erythrocytes and working muscles, glycerol from hydrolyzed fats of adipocytes, and amino acids (the result of muscle protein proteolysis) enter the liver.
Why does the liver synthesize ketone bodies during fasting?
During active $\beta$-oxidation of fatty acids, acetyl-CoA accumulates. The liver converts it into ketone bodies, which are exported into the blood and used by muscles (and the brain during prolonged fasting) as an alternative energy source.
What else to study on this topic
- Mechanism of activation and repression of key glycolysis enzymes by insulin
- The link between the pentose phosphate pathway and fatty acid biosynthesis
- Hormonal regulation of adipocyte hormone-sensitive TAG lipase
- The role of the Cori cycle in preserving carbohydrate reserves
- Ammonia utilization in the postabsorptive state (urea synthesis)
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