Vertebrate Metabolism and Metabolic Control

Liver Metabolism and Blood Regulation

• Dual Metabolic Roles: The liver performs both catabolic and anabolic roles which often occur simultaneously to maintain physiological homeostasis.

• Regulation of Blood Chemistry:

  • The liver is responsible for monitoring and adjusting carbohydrate and amino acid levels in the blood.

  • It synthesizes essential plasma proteins.

• Metabolic Processing:

  • Metabolism of excess amino acids.

  • Catabolism of foreign molecules (detoxification).

Adipose Tissue and Energy Storage

• Triacylglycerol (TAG) Storage: Adipose tissue serves as the primary storage site for TAG.

  • The tissue itself requires very little energy to maintain.

• Metabolic Pathways:

  • Fatty acid synthesis and the pentose phosphate pathway (specifically for the production of $NADPH$) are active under conditions of high energy availability.

• Hormonal Control: The major hormones regulating adipose tissue are insulin and glucagon.

• Brown Adipose vs. White Adipose:

  • White Adipose: Primary energy storage site.

  • Brown Adipose: Characterized by high blood flow and high mitochondria content.

  • Thermogenesis: Brown adipose tissue is specialized for heat production through proton uncoupling involving the protein thermogenin.

Energy Availability and Consumption Rates

• Glycogen supplies: Provides a small portion of total body energy.

• Adipose tissue: Contains the bulk of body energy reserves.

• Energy Metrics:

  • Standard daily energy expenditure: $2400\,kcal/day$.

  • High-intensity daily expenditure: $7200\,kcal/day$.

  • Peak hourly expenditure: $1200\,kcal/hr$.

Muscle Tissue Metabolism and Fuel Preferences

• Skeletal Muscle:

  • Functions through intermittent work.

  • Highly dependent upon oxygen availability for aerobic metabolism.

  • Primary Fuels: Uses glucose during active states and fatty acids during periods of rest.

  • Oxygen Consumption: Accounts for $30\%$ of body $O_2$ consumption while at rest.

  • Fasting Response: Protein degradation occurs during fasting to aid in energy conservation and provide substrates.

• Cardiac Muscle:

  • Characterized by constant activity and requires a constant, uninterrupted supply of oxygen.

  • Fuel Sources (Well-fed conditions): Simultaneous use of glucose and fatty acids.

  • Fuel Sources (Other conditions): Utilizes fatty acids and ketone bodies.

Comparative Energetics: Sprinter vs. Marathoner

• Performance Characteristics:

  • Sprint ($100\,m$):

    • Rate of energy expenditure: $200\,kJ\,min^{-1}$ (approximately $3.3\,kJ\,s^{-1}$).

    • Total energy expended: $33\,kJ$.

    • Fuel: Anaerobic pathways utilizing phosphocreatine and glucose.

    • Cause of fatigue: Increase in intracellular proton ($H^+$) concentration which lowers pH (lactic acid build-up).

  • Marathon ($42.2\,km$):

    • Rate of energy expenditure: $84\,kJ\,min^{-1}$.

    • Total energy expended: $12,000\,kJ$.

    • Fuel: Aerobic pathways utilizing glucose, fatty acids, glycogen, and triacylglycerols.

    • Cause of fatigue: Depletion of muscle glycogen.

• Muscle Contents Data ($\mu mol/g\,muscle$):

  • Glycogen: Rest: $88$; $15\,s$ after exercise: $58$; $30\,min$ after exercise: $70$.

  • Lactate: Rest: $1.1$; $15\,s$ after exercise: $30.5$; $30\,min$ after exercise: $6.5$.

  • Phosphocreatine: Rest: $17.1$; $15\,s$ after exercise: $3.7$; $30\,min$ after exercise: $18.8$.

  • ATP: Rest: $4.6$; $15\,s$ after exercise: $3.4$; $30\,min$ after exercise: $4.0$.

  • $H^+$ (pH): Rest: $7.1$; $15\,s$ after exercise: $6.3$; $30\,min$ after exercise: $7.0$.

Brain Metabolism and Metabolic Control Center

• Energy Requirements: The brain represents $2\%$ of body mass but accounts for $20\%$ of total energy use.

  • The primary energy cost is maintaining membrane potentials.

  • The brain operates $24$ hours a day with no periods of metabolic rest.

• Energy Sources:

  • Glucose (the brain maintains no glycogen stores).

  • Ketone bodies (during starvation).

  • Note: The brain does not ‐export‐ nutrients to other tissues.

• Control Center: Metabolism is centrally controlled by the hypothalamus and pituitary gland.

Postprandial State: Feeding Phase and Insulin Activity

• Hormonal Response: Ingestion triggers gastrin, secretin, and cholecystokinin.

• Digestive Process:

  • Triggering of digestive enzyme secretion.

  • Enterocyte absorption of nutrients, which then move through the portal vein.

  • Pancreatic $\beta$-cells release insulin in response to rising blood glucose.

• Metabolic Effects of Insulin:

  • $\uparrow$ Glucose uptake (muscle/adipose): Targeted via glucose transporter ($GLUT4$).

  • $\uparrow$ Glucose uptake (liver): Targeted via increased expression of Glucokinase.

  • $\uparrow$ Glycogen synthesis (liver/muscle): Targeted via Glycogen synthase.

  • $\downarrow$ Glycogen breakdown (liver/muscle): Targeted via Glycogen phosphorylase inhibition.

  • $\uparrow$ Glycolysis and Acetyl-CoA production (liver/muscle): Targeted via $PFK-1$ (increased by $PFK-2$) and the Pyruvate dehydrogenase complex.

  • $\uparrow$ Fatty acid synthesis (liver): Targeted via Acetyl-CoA carboxylase ($ACC$).

  • $\uparrow$ Triacylglycerol synthesis (adipose): Targeted via Lipoprotein lipase ($LPL$).

The Fasting Phase and Glucagon Regulation

• Immediate Response: Pancreatic $\alpha$-cells release glucagon.

• Overnight Fast:

  • Release of norepinephrine occurs.

  • Norepinephrine prevents muscle protein breakdown, mobilizes fatty acids for muscle fuel, and saves glucose for the brain.

• Metabolic Effects of Glucagon (Mainly Liver and Adipose):

  • $\uparrow$ Glycogen breakdown (liver): Target: Glycogen phosphorylase. Result: Glycogen $\rightarrow$ glucose.

  • $\downarrow$ Glycogen synthesis (liver): Target: Glycogen synthase. Result: Less glucose stored.

  • $\downarrow$ Glycolysis (liver): Target: $PFK-1$ (via $FBPase-2$) and Pyruvate kinase. Result: Less glucose used as fuel in liver.

  • $\uparrow$ Gluconeogenesis (liver): Target: $PEP\,carboxykinase$. Result: Amino acids, glycerol, and oxaloacetate converted to glucose.

  • $\uparrow$ Fatty acid mobilization (adipose): Target: Hormone-sensitive lipase and PKA (perilipin-P). Result: Less glucose used by muscle/liver.

  • $\uparrow$ Ketogenesis: Target: Decreased Acetyl-CoA carboxylase activity. Result: Alternative energy for brain.

Prolonged Fasting, Starvation, and Glucocorticoid Effects

• Prolonged Fasting Phase:

  • Blood glucose is sustained primarily through muscle breakdown.

  • Fatty acids supply fuel for the majority of tissues.

• Extreme Starvation:

  • Brain shifts to utilizing ketone bodies.

  • Muscle wasting declines overall simply because there is a reduced amount of muscle remaining.

• Cortisol (Glucocorticoid hormone of the adrenal gland):

  • Exerts long-term action by changing enzyme levels.

  • In Muscle: Induces protein breakdown.

  • In Adipose: Induces TAG mobilization.

  • Overall Effects: Increased blood glucose.

  • Long-term Risks: Decreased muscle and bone mass; impaired immune response.

Metabolic Calculations and Worked Problems

• Problem 1: Threonine and Gluconeogenesis

  • Task: Determine what is required and produced in the conversion of threonine to glucose.

  • Constraint: Convert any excess $NADH$ or $FADH_2$ to $ATP$ using typical $ATP$ yields.

• Problem 2: Tyrosine and Gluconeogenesis

  • Task: Determine what is required and produced in the conversion of tyrosine to glucose.

  • Assumption: Acetyl-CoA can be used to produce $ATP$.

  • Constraint: Convert any excess $NADH$ or $FADH_2$ to $ATP$ using maximum mitochondrial $ATP$ yields.