Fasting Physiology Overview

Fasting State

• Plasma levels of glucose, amino acids, and triacylglycerols (TAG) decrease.
• Insulin secretion declines, and glucagon release increases.
• The decreased insulin to glucagon ratio results in a catabolic period characterized by degradation of TAG, glycogen, and protein.
• Two main goals of the body during fasting:
  • Maintain adequate plasma glucose levels for brain, red blood cells, and other glucose-requiring tissues.
  • Mobilize fatty acids from adipose tissue and synthesize and release ketone bodies from the liver to supply energy to other tissues.

Brain during Fasting

• During the initial days of fasting, the brain primarily utilizes glucose as fuel.
• Hepatic gluconeogenesis from glucogenic precursors like amino acids from protein breakdown and glycerol from lipolysis occurs.
• During prolonged fasting (more than 2-3 weeks), plasma ketone bodies rise to elevated levels and replace glucose as the primary energy source for the brain.
• This reduces the need for protein catabolism for gluconeogenesis.
• Ketone bodies spare glucose and muscle protein.

Brain Metabolism

• Astrocytes mainly rely on glucose for energy production.
• Glucose enters the brain through astrocytes via GLUT-1, independent of insulin.
• Glucose undergoes glycolysis, generating ATP.
• Astrocytes play a crucial role in supplying neurons with energy and the necessary nutrients for optimal function.

Astrocyte Energy Metabolism

• Two processes within astrocytes require significant ATP:
  • Na+ / K+ pump maintains cell membrane potential.
  • Conversion of glutamate into glutamine, a process essential for neurotransmitter recycling.

Glutamate

• Glutamate, a non-essential amino acid, is the most abundant excitatory neurotransmitter in the brain.
• Glutamate can't cross the blood-brain barrier (BBB) and must be synthesized in neurons from local precursors like glutamine released by glial cells.
• Glutamate can also be synthesized from α-ketoglutaric acid (citric acid cycle) by AST.
• A portion of glucose metabolism in neurons can be used for glutamate synthesis.

Glutamate Cycle

• Glutamate is released from presynaptic vesicles and activates postsynaptic neurons receptors.
• It is then removed from the synaptic cleft by excitatory amino acid transporters (EAATs).
• Glutamate is taken up by astrocytes, where it is converted to glutamine.
• Glutamine is released by astrocytes and transported back to neurons, where it is converted back into glutamate.
• This Glutamate-Glutamine cycle ensures a consistent supply of glutamate for neurotransmission, supporting brain function.

Glutamate Receptors

• Three types of ionotropic glutamate receptors:
  • AMPA receptors: mediate fast excitatory neurotransmission.
  • NMDA receptors: play a critical role in synaptic plasticity and learning.
  • Kainate receptors: involved in modulation of synaptic transmission.
• Three types of metabotropic glutamate receptors:
  • Group I (mGluR1 and mGluR5): generally excitatory.
  • Group II (mGluR2 and mGluR3): inhibitory.
  • Group III (mGluR4, mGluR6, mGluR7, and mGluR8): inhibitory.

Glutamate as an Energy Source

• During hypoglycemia, glucose for glycolysis and lactate production decreases.
• Glutamate can be used as a substitute for glucose as an energy source.
• Part of the glutamate is transaminated to α-ketoglutarate by AST.
• α-ketoglutarate enters the TCA cycle, contributing to ATP generation.

Reactive Oxygen Species (ROS)

• ROS are formed from the partial reduction of molecular oxygen.
• Continuously generated as byproducts of aerobic metabolism, reactions with drugs and environmental toxins, or when antioxidant levels are depleted.
• ROS can damage DNA, proteins, and unsaturated lipids, potentially leading to cell death.
• ROS are implicated in various pathological processes, including reperfusion injury, cancer, inflammatory disease, and aging.

Absorptive (Fed) State

• This phase lasts for 2-4 hours after a meal.
• Plasma levels of glucose, amino acids, and triacylglycerols (TAG) increase.
• Insulin release rises, while glucagon release decreases.
• The elevated insulin to glucagon ratio promotes anabolism characterized by increased synthesis of TAG, glycogen, and protein.
• All tissues utilize glucose as fuel.

Brain Metabolism During the Absorptive State

• Brain does not store significant amounts of glycogen and relies entirely on blood glucose for energy.
• Brain does not store significant amounts of TAG.
• Fatty acids bound to albumin do not efficiently cross the blood-brain barrier.

Brain Energy Metabolism

• The brain is vital for the functioning of all organs and receives the highest priority regarding fuel needs.
• To supply energy, substrates must cross the blood-brain barrier.
• Glucose is the primary fuel for the brain.
• Hypoglycemia (40 mg/100 ml) can impair cerebral function, potentially leading to severe and irreversible brain damage.
• During fasting, ketone bodies become a significant energy source for the brain.

Alternative Brain Substrates

• The brain can utilize alternative fuel sources besides glucose:

  • Glutamate
  • Lactate
  • Ketone bodies

• Unlike heart and skeletal muscles, the brain cannot utilize fatty acids bound to albumin as an energy source due to their inability to cross the BBB.

This quiz focuses on the physiological changes that occur during fasting states, including hormonal adjustments and energy substrate utilization by the brain. It covers key concepts like plasma glucose levels, insulin and glucagon activity, and the role of ketone bodies in energy supply during prolonged fasting. Test your understanding of these crucial metabolic processes.