Metabolism: Anabolic, Catabolic, and Fuel Requirements

Metabolism Overview

• Metabolism involves the interconversion of chemical compounds within the body.
• Metabolic processes follow specific pathways.
• Metabolic mechanisms regulate metabolite flow.

Metabolic Pathway Types

• Anabolic pathways synthesize larger compounds from smaller precursors and are endergonic.
  • For example, protein synthesis from amino acids.
• Catabolic pathways break down larger molecules using oxidative reactions and are exergonic, producing ATP.
• Amphibolic pathways integrate both catabolism and anabolism.
  • For example, the citric acid cycle.
• Catabolic pathways converge on producing Acetyl-CoA.
• Acetyl-CoA is oxidized in the citric acid cycle.
• Digestion products are metabolized into Acetyl-CoA.

Fuel Requirements

• Adults need between 1920-2900 kcal/day depending on physical activity.
• Metabolic fuels include carbohydrates (40-60%), lipids (30-40% mainly TAG), and proteins (10-15%).

Glucose Metabolism

• Glucose is a major metabolic fuel that is metabolized to pyruvate through glycolysis.
• Aerobic glycolysis converts glucose to pyruvate.
• Acetyl-CoA is oxidized into CO2 and H2O through the citric acid cycle, producing ATP through oxidative phosphorylation.
• Anaerobic tissues convert glucose to lactate via glycolysis.

Metabolic States

• The absorptive or "fed" state occurs post-meal during digestion and nutrient absorption and can last up to 4 hours.
• The postabsorptive or "fasting" state is the period when food has been digested.
• Starvation begins after 3 to 4 days without food.
• Organs and tissues work together during fuel metabolism.
• Tissues coordinate by exchanging substrates or compounds.
• Communication between tissues occurs through the nervous system, circulating substrates, and hormones.

Hormonal Control

• Energy metabolism is controlled mainly by insulin, glucagon, and catecholamines like epinephrine and norepinephrine.
• Hormone level changes allow for energy storage during the fed state and mobilization in the fasting state.
• During the absorptive state, the levels of glucose, amino acids, and fatty acids increase in the intestine which leads to release of insulin by β cells of pancreas and release of glucagon by α cells of pancreas.
• During fasting, the levels of glucose and amino acids increase in the blood which leads to release of insulin by β cells of pancreas and release of glucagon by α cells of pancreas.

Insulin Effects

• Insulin facilitates glucose uptake in muscle and adipose tissues by increasing GLUT-4 transporters in the cell membrane.
• Intravenous insulin causes a rapid decrease in blood glucose.
• Insulin promotes glycogen, protein, and fat synthesis.
• Insulin inhibits gluconeogenesis, glycogenolysis, and lipolysis in the liver.

Glucose Update Mechanism

• Insulin stimulates the recruitment of insulin-sensitive glucose transporters (GLUT-4) from intracellular vesicles to the cell membrane.
• Glucose transport increases in skeletal and cardiac muscle, and adipocytes with insulin presence.
• Skeletal muscle, cardiac muscle, and adipocytes are insulin-sensitive tissues.
• GLUT4 enables facilitated transport of glucose down the concentration gradient into muscle and fat cells.
• Glucose-6-phosphate cannot diffuse out of cells, maintaining the glucose concentration gradient.
• Insulin-insensitive tissues do not require insulin for glucose uptake.
  • These include hepatocytes, erythrocytes, nervous system tissues, intestinal mucosa, renal tubules, and the cornea.

Insulin Action

• Insulin binding to its membrane receptor increases glucose transport into adipocytes and muscle within seconds.
• Enzymatic activity changes within minutes to hours due to phosphorylation state changes.
• There's an increase in glucokinase, liver pyruvate kinase, acetyl CoA carboxylase, and fatty acid synthase over hours to days because of increased gene expression.

Glucagon Effects

• Glucagon is a polypeptide hormone secreted by the alpha cells of the pancreatic islets.
• Along with cortisol, epinephrine, and growth hormone, it opposes the actions of insulin.
• It maintains blood glucose by promoting liver glycogen breakdown and gluconeogenesis, leading to an immediate rise in blood glucose.
• Glucagon secretion is stimulated by low blood glucose, amino acids, and epinephrine.
• Glucagon secretion is inhibited by elevated blood glucose and insulin.

Hypoglycemia

• Hypoglycemia is characterized by confusion, aberrant behavior, and coma.
  • It is also indicated by a blood glucose level of <40 mg/dl.
• Hypoglycemia can be triggered by receiving insulin treatment or alcohol consumption by undernourished individuals.
• It prompts the immediate secretion of glucagon and epinephrine.
• Hypoglycemia is treated with immediate administration of glucose

Energy Homeostasis

• The body needs continuous supply of glucose.
• Body processes the food you eat both to use it immediately and, importantly, to store it as energy for later use.
• Distinct mechanisms are in place to facilitate energy storage, and to make stored energy available during times of fasting and starvation.

Metabolic States Revisited

• Absorptive (fed) state occurs post mean when your body is digesting the food and can last up to 4 hours.
• The postabsorptive (fasting) state occurs when food has been digested, absorbed, and stored and usually involves overnight fasting.
• Starvation sets in after 3 to 4 days without food.
• During the day, metabolism switches between absorptive and postabsorptive states.
• Starvation is rare in well-nourished individuals.

Absorptive State Details

• The absorptive state lasts 2-4 hours.
• It is characterized by increased synthesis of TAG and glycogen to replenish fuel stores and enhanced synthesis of proteins.
• Tissues use glucose as fuel during this state.

Enzymatic Changes

• In the fed state, available nutrients are captured as glycogen, TAG, and protein through regulatory mechanisms.
• Allosteric effects, enzyme regulation via covalent modification, and induction/repression of enzyme synthesis occur.

Allosteric Regulation

• Glycolysis in the liver is stimulated by fructose 2,6-bisphosphate which acts as an allosteric activator of phosphofructokinase.
• Gluconeogenesis is inhibited by fructose 2,6-bisphosphate which acts as an allosteric inhibitor of fructose 1,6-bisphosphatase.

Liver Metabolism

• During carbohydrate metabolism in the liver, phosphorylation of glucose (6-phosphate) occurs.
• Glycogen synthesis is favoured.
• HMP accounts for 5-10% of glucose metabolized.
• There is increased activity of pyruvate kinase.
• Gluconeogenesis is inhibited.
• Increase in liver glucokinase occurs in response to high blood glucose, increasing the phosphorylation of glucose.

Hexokinase vs Glucokinase

• Hexokinase is present in all cells with lower Km, for faster glycolysis.
• Glucokinase in liver cells is responsible for converting glucose to glycogen with higher Km, for slower glycolysis.

Tissue Specific Metabolism

• Adipose tissue: constitutes about 14kg in a 70-kg man and up to 70% in overweight individuals to include increased glucose transport,

• The 3 fates of Glucose 6-P following glucose transport include -Glycolysis - intracellular glucose is enhanced. -HMP - leads to produce NADPH essential for fat synthesis.

• Skeletal muscle: Responds to energy demand for muscle contraction.

  • At rest, accounts for 30% of the oxygen consumption of the body, and up to 90% during vigorous exercise.

• Brain metabolism: -Accounts for 20% of basal oxygen consumption at rest, with glucose as the primary fuel (70-99mg/dL), but during fasting, it plays an important role, reducing its dependence on glucose.

Fasting State Details

• Changes are opposite of the fed state.
• Food ↓ →plasma glucose.

Priorites During Fasting State

• The body will maintain adequate plasma.
  • Levels of glucose to sustain energy.
  • Glucose-requiring cells such as liver cells. -Mobilize fatty acids by synthesizing ketone bodies to supply energy to tissues, specifically the brain.

Metabolic Fuel Levels During Start of Fasting

• Fats store is > 3months.
• Protein should not drop below 1/3 to fatally compromise.

Fasting States in Liver and Brain

• Liver: Liver glycogenolysis leads to 80g of glucagon which becomes fully active depleted after 4-6 hours.

• Brain: During prolonged periods of fasting, plasma will replace ketone bodies.

  • Ketone bodies acetoacetate and beta (B)-hydroxybutyrate are reconverted produce energy, via the Krebs cycle.