Notes
Feed Fast Cycle Part II
Sections
FAST CYCLE
- Short term or long term (starvation)
- Occurs after absorptive phase
- Insulin: glucagon ratio is low
- Catabolic processes dominate (nutrients mobilized from storage)
Body's objectives:
- Deliver glucose to brain and red blood cells
- Distribute remainder to the rest of the tissues (TAG & ketone bodies)
Timeline
- Hour 0: ingest meal
- Hour 4: glucose depletes, glycogen stores mobilized
- Hour 18: liver glycogen depletes --> gluconeogenesis --> TAG mobilization --> ketogenesis
- Hour 24: TAG mobilization & ketogenesis peak
Primary functions of each organ italicized for clarity.
LIVER: CENTRAL ROLE IN METABOLISM
- Nutrients drain from gut (primary nutrient source) to liver via hepatic portal vein
- Liver distributes nutrients to remaining organs
- Responds to needs of all organs
Fed state
Most anabolic and storage pathways
- Glucose (glycolysis, HMP shunt-->NADPH)): stored as glycogen
- Fatty acid synthesis (from glucose --> acetyl CoA)
- Chylomicron remnants: TAG synthesized and packaged into VLDL
- Amino acids (synthesis of proteins, pyruvate, acetyl CoA & CAC intermediates)
Fasting state
Responds to body's glucose needs
i. Glycogen --> glucose
ii. Gluconeogenesis: liver only
iii. Ketogenesis: liver only (cannot be used by liver for energy)
- Ketogenesis prevents degradation of essential proteins for gluconeogenesis
- Hepatocyte energy requirements met by fatty acid oxidation
- TAG --> Free fatty acids (--> ATP) + glycerol (--> gluconeogenesis)
BRAIN
Fed state
Glucose: primary energy source (glycolysis --> ATP)
Fasting state
- Glucose still primary energy source
- Extended fast: ketone bodies (can cross blood brain barrier)
ADIPOSE
Fed state
Fatty acids stored as TAG
- Glucose (glycolysis, HMP shunt-->NADPH)
- Fatty acid synthesis
- Chylomicrons (dietary TAG): degrade to chylomicron remnants
Fasting state
- TAG --> Free fatty acids (--> ATP in liver/muscle) + glycerol (--> gluconeogenesis in liver)
RESTING MUSCLE
Fed state
Glucose (glycolysis): stored as glycogen
Branched chain amino acids (preferentially): protein synthesis
- Chylomicrons (dietary TAG): degrade to chylomicron remnants
- Fatty acid oxidation (secondary energy sources)
- Energy needs change during exercise: primary metabolic function depends on own needs
Fasting state
- Muscle glycogen --> glucose (glycolysis)
- Muscle protein mobilized (gluconeogenic amino acids --> liver)
- As starvation progresses: fatty acid oxidation, ketone bodies
Full-Length Text
- Here we will learn the fast cycle, which can either be short-term (while we are sleeping) or long-term (starvation).
- This is part II of a two-part tutorial on the feed-fast cycle, which describes the integration of metabolic processes in different organs just after a meal, and in the post-absorptive phase.
- To begin, lets review some key concepts about the fasting cycle.
- It occurs after the absorptive state, which itself is 2-4 hours after a meal.
- The insulin to glucagon, and therefore catabolic processes dominate.
- Recall that during the feed cycle, our key metabolic organs obtain nutrients from the gut.
- Finally, denote that during the fast cycle (whether short term or long term), nutrients must be mobilized from storage.
Let's start by identifying the stored nutrients in each of the organs.
- Draw a box for carbohydrates in both the liver and the muscle.
- Indicate that both of these organs breakdown stored glycogen to glucose.
- Draw a box for amino acids in skeletal muscle.
- Indicate that skeletal muscle protein can be mobilized for energy during extended fast.
- Finally, draw a box for lipids in both the liver and adipose.
- Indicate that both of these organs mobilize stored triacylglycerol, which can be broken down to fatty acids and further into ATP for energy in the peripheral tissues.
- Now, denote that the body maintains two key objectives during the fast cycle:
- Deliver glucose to the brain and red blood cells, which rely on this source alone for energy.
- Distribute what remains to the rest of the tissues: triacylglycerol and eventually ketone bodies during long-term fast, which can cross the blood brain barrier.
- Draw a box for carbohydrates under the brain and write that it is the primary energy source for the brain and red blood cells.
Before we dive into the fast cycle, let's summarize some key time-points and functions:
- Imagine we ingest a meal at hour 0: this glucose depletes after about 4 hours.
- From here, glycogen stores are mobilized, but they are almost completely depleted after about 18 hours.
- As glycogen stores deplete, gluconeogenesis increases.
- TAG mobilization and ketone body synthesis increase after 18 hours and peak at about 24-hours.
Finally, let's illustrate how our key organs, particularly the liver, distribute their stored nutrients during a short-term fast.
- First, show that the muscle as well as the brain and red blood cells still rely on glycolysis for energy.
- However, the muscle mobilizes its own glucose stores for this purpose. What about the brain and rbc's?
- Show that glycogenolysis in the liver produces glucose for the brain and red blood cells, which are prioritized in times of fast.
- (Again, the liver manages energy for other organs, whereas the muscle is concerned with itself).
- After about 18 hours, however, the liver depletes its glycogen stores
- So how do we maintain blood glucose after 18 hours of fast?
- Gluconeogenesis in the liver generates new glucose. The kidney also contributes to glucose formation, but we will not draw this here.
- Mobilization of fats.
- Although muscle does not perform gluconeogenesis, show that it mobilizes proteins and releases gluconeogenic amino acids to the liver for gluconeogenesis.
- Indicate that adipose tissue mobilizes triacylglycerol to deliver glycerol, also a gluconeogenic precursor, to the liver.
- Also indicate that adipose tissue delivers fatty acids directly to the liver via triacylglycerol mobilization.
- Indicate that the fatty acid oxidation in the liver is the greatest source of energy for hepatocytes in this state.
- Indicate that as starvation progresses, skeletal muscle also harnesses energy from fatty acid oxidation.
- Show that it receives fatty acids from adipose and the liver.
This brings us to our last phase of starvation. As we approach 24 hours with no food, peripheral tissues rely upon ketone bodies for energy.
- Indicate that the liver (and the liver alone) can produce ketone bodies from fatty acids.
- Write that the liver cannot use ketone bodies for energy because it lacks a critical enzyme.
- It continues to use adipose triacylglycerol stores for energy.
- Show that ketone bodies are used by the peripheral tissues, which we simplify here to just the skeletal muscle, and the brain and red blood cells.
- Importantly, note that ketone bodies can also cross the blood brain barrier.
- During extended fast (up to 10 days), peripheral tissues use fatty acids and ketone bodies as fuel.
- Brain and red blood cells use whatever glucose remains and ketone bodies as glucose availability decreases.
- Why do we need ketone bodies at all, if the liver can produce glucose via gluconeogenesis?
- Gluconeogenic substrates include amino acids from skeletal muscle, so ketone bodies help prevent the degradation of essential proteins by reducing the need for more glucose!
As a reminder, recall that the feed-fast cycle is characterized by a changing insulin:glucagon ratio.
- When the ratio is high, insulin activates anabolic enzymes and inactivates catabolic ones.
- Glucagon does the opposite when the ratio is low.
- This regulates the activity of the metabolic pathways that we have just described and allows for an integrated response.