Metabolism of the Brain

COM

Wilson Mandala PhD wmandala@medcol.mw Department of Biochemistry

Learning objectives
1. Know what the brain uses as its energy source 2. List the processes in the brain that require energy 3. Understand what happens in the brain during starvation

General Energy Sources

1. Energy required continuously but sources available only during meals 2. During and immediately following a meal the body goes into an anabolic state & stores energy supported by Insulin 3. Between meals, catabolism ensues: glycogenolysis, lipolysis, and sometimes protein lysed to Aas to provide energy 4. Catabolism supported by glucagon and growth hormone 5. In stress or strenuous exercise cortisol increases catabolism rate

Brain mainly uses Glucose

Glucose is the primary energy substrate for brain and it is almost entirely oxidized to CO2 and H2O ( total aerobic respiration) Although the brain represents only 2% of the body weight, on average it receives:

a. 15% of the cardiac output b. 20% of total body oxygen consumption c. 25% of total body glucose utilization
The brain thrives on glucose and oxygen!!!

Why such high demand for energy?

1. To fuel electrical impulses that neurons use to communicate with each other.

a. About 2/3 of energy is used to help neurons (nerve cells) send signals. b. This requires a continuous passage of Na+, Ca2+ and K+ ions to ensure that neurons can recharge in order to fire the impulses when required. This requires ATP molecules 2. The remaining 1/3 is used for housekeeping purposes or cell-health maintenance. This helps to keep the brain cells alive. There is need to maintain a proper ionic balance inside and outside cells and this requires ATP too. Any ionic imbalances can cause cells to swell leading to strokes and other precarious conditions.

ATP Production from Glucose

1. Glycolysis 2. TCA Cycle 3. ETC

Glycolysis pathway

Preparatory Phase
Two molecules of ATP consumed

Payoff Phase
four molecules of ATP produced, net gain of 2 ATP molecules

Tri-Carboxylic Acid (TCA) cycle

Other uses of the glucose

Glucose is mainly used as an energy source in the brain. A small percentage of the glucose is: 1. incorporated into lipids, proteins, and glycogen for structural purposes 2. Used as precursor of certain neurotransmitters such as g-aminobutyric acid (GABA), glutamate, and acetylcholine which are very important in the CNS

Brain and Glucose

The brain is the organ most sensitive to glucose Brain requires a constant supply of blood glucose Normally glucose is the only energy source for the brain (can't use fats since fats cannot cross the blood-brain barrier) In conditions when blood glucose levels are low (hypogycemia) brain adapts to using other energy rich compounds. Such conditions include: starvation, DM, low carbs diet, when diabetic takes too much insulin (insulin shock) Symptoms: mental confusion, slurring of speech -> coma -> death Treatment: give glucose

Regulation of Blood Glucose Levels

Immediately after meals blood glucose comes from meal Between meals blood glucose comes from the liver & kidneys
Only the liver and kidneys can release glucose into the blood Liver provides 80% of blood glucose supply between meals, the kidney 20%

Livers Role

Gluconeogenesis
Some molecules can be converted to glucose:

1. Lactate & pyruvate: mainly come from muscles 2. Glycerol: supplied by adipose tissue when triglycerides are broken down3. Fatty acids cannot be converted into glucose, but: Fatty acid metabolism indirectly supports gluconeogenesis by producing AcetylCoA 4. AcetylCoA activates and inhibits key enzymes, promoting glucose formation 5. Amino acids: 20 of the 22 amino acids can be converted to glucose through gluconeogenesis

Glucose supply to brain & other tissues

Delivery of glucose to the blood is controlled by insulin, glucagon and other hormones Brain receives a constant 80 mg/min (doesn't change much in exercise) Amount delivered to other tissues depends upon body state (rest vs exercise)
At rest total glucose output to the blood is about 130 mg/min (80 to brain, 50 to other tissues) During exercise total can increase to about 2500 mg/min and this may reduce brain supply

Alternative energy sources 1. Mannose

1. only molecule that can sustain normal brain function in the absence of glucose. 2. Can cross the bloodbrain barrier and in two enzymatic steps is converted to fructose-6phosphate, intermediate of the glycolytic pathway. 3. However, mannose is not normally present in the blood and cannot therefore be considered a physiological substrate for brain energy metabolism

2. Ketone Bodies
1. Under particular conditions, such as starvation, diabetes mellitus, or in breast-fed neonates, plasma levels of the ketone bodies (acetoacetate and beta-hydroxybutyrate) increase markedly. Under these conditions, these two ketone bodies can be used by the brain as metabolic substrates. This requires their reverse conversion to acety-CoA which rejoins the TCA cycle, the resulting NADH and FADH2 joins the ETC producing more ATP molecules

2. 3.

3. Pyruvate and Lactate

1. Lactate and pyruvate can sustain synaptic activity in vitro but due to their limited permeability across the bloodbrain barrier, they cannot substitute for plasma glucose to maintain full brain function. 2. if formed inside the brain parenchyma, both lactate and pyruvate are useful metabolic substrates for neural cells

In starvation (& DM)

1. Low blood glucose levels, supply to brain reduced, ketone bodies used instead 2. Reduction affects brain function, blurred vision, low response to impulses 3. If levels go even lower, subject can go into coma and die