Fed-State Cycle

What are the stages of fed-fast cycle?

1. Fed state

• This occurs during a meal and about 3 hours after a meal 

2. Postabsorptive or early fasting state

•  This occurs from about 3 hours to 12-18 hours following a meal 

3. Fasting state 

• This occurs from 18 hours to 2 days without food intake 

4. Starvation state

• This occurs at several weeks 

• This is full adaptation of food deprivation

What hormone regulates fed state?

Insulin

What hormone regulates fasting/postabsorptive state?

Glucagon

What are the effects of insulin in fed state in terms of carbohydrate?

1. This increase glucose uptake in muscles by increasing glucose transporter 

2. This increases glucose uptake in liver by increasing glucokinase activity 

3. This increases glycogen synthesis by increasing glycogen synthase activity 

4. This decreases glycogen breakdown by decreasing glycogen phosphorylase activity 

5. This increases glycolysis by increasing PFK-1 + PDC activities 

What is the glucose metabolism in liver at fed state?

1. Insulin induces glucose intake by stimulating glucokinase and phosphorylating glucose into G6P using ATP

2. G6P undergoes glycolysis then TCA cycle and ETC to produce energy

3. Glycogenesis occurs to replenish glycogen stores

4. Excess glucose is used to form fatty acids 

5. Lactate formed from anaerobic glycolysis in RBCs and brain will enter gluconeogenesis in liver 

What is the glucose metabolism in muscle at fed state?

1. Insulin induces glucose intake by increasing expression of GLUT4 transported 

2. Glucose phosphorylated by hexokinase into G6P using ATP

3. G6P undergoes glycolysis then TCA cycle and ETC to produce energy

4. Glycogenesis occurs to replenish glycogen stores

What are the effects of glucagon in fasting/postabsorptive state in terms of carbohydrate?

1. This increases gluconeogenesis by increasing fructose bisphosphates-2 

2. This decreases glycolysis by decreasing pyruvate kinase 

3. This increases glycogen breakdown by increasing glycogen phosphorylase 

4. This decreases glycogen formation by decreasing glycogen synthase

What happens in the first phase of the postabsorptive state in terms of carbohydrate?

This becomes — source of —

Liver glycogenolysis releases glucose into the bloodstream to supply tissues

Major

energy

What happens in the second phase of the postabsorptive state in terms of carbohydrate?

What are the precursors?

1. Once glycogen stores in liver are depleted, gluconeogenesis in the liver becomes the main source of blood glucose

2. Muscles also perform glycogenolysis to supply muscles with glucose

Lactate (from RBCs and muscles) and alanine (from the glucose-alanine cycle from muscles)

What happens after an overnight fast in during postabsorptive state (third phase) in terms of carbohydrate?

Glycogen stores are depleted in liver and muscles, and body shifts to lipolysis, using fatty acids as the new main energy source

What is lipid metabolism in liver during fed state?

1. Chylomicron remnant enters liver by using apoE receptors

2. Dietary fatty acids from chylomicrons are elongated and incorporated into TAG

3. Fatty acids are activated then re–esterified to form TAG

4. TAG, apolipoproteins (apoB-100, apoC-2, apoE) cholesterol, cholesterol esters are packaged into VLDL and released into blood stream, where VLDL then becomes LDL

5. Ketone bodies formed  in liver from excess acetyl-CoA that can’t be used for energy

What happens when energy intake is greater than energy expenditure, such as after a high carbohydrate meal, where we already completed glycogenesis in the liver, during fed state?

Fatty acids are synthesized

How does the liver know when to do fatty acid synthesis after a high carbohydrate meal?

Insulin will stimulate glucokinase to take up glucose from blood and convert them into G6P

What are the fates of G6P in liver after a high carbohydrate meal, during fed state?

1. Enter glycogenesis

2. Enter glycolysis to produce acetyl-CoA by acetyl-CoA carboxylase, used to from malonyl-CoA for fatty acid synthesis  

3. Enter HMP shunt to provide NADPH, used for fatty acid synthesis 

4. Becomes α‐glycerol‐3‐phosphate, used for triacylglycerol synthesis

What are the fates for cholesterol and cholesterol esters in the liver during fed state?

1. Used for bile acids synthesis in liver 

2. Secreted into bile as neutral sterols to be excreted 

3. Incorporated into VLDL or HDL and released into bloodstream

What are the possible metabolism in adipose tissue during fed state in terms of lipids?

1. Lipid metabolism

2. Excess carbohydrate storage in form of lipids

What is lipid metabolism in adipose tissue during fed state?

1. Adipose tissues to release lipoprotein lipase 

2. Lipoprotein lipase activated by apoC-2 in chylomicrons and VLDL

3. Lipoprotein lipase hydrolyzes chylomicrons and VLDL to released triacylglycerols 

4. Triacylglycerol broken down to be taken into adipose tissues

5. Free fatty acids, monoacylglycerols, diacylglycerols in adipose tissues will reform into triacylglycerol to store energy

how does insulin play a role in lipid metabolism in adipose tissues during fed state? 

Insulin inhibits hormone-sensitive lipase in adipose tissues to prevent hydrolysis of stored triacylglycerols

How is excess carbohydrate stored in lipid form occurs in adipose tissue during fed state?

Insulin will stimulate increase production of insulin-dependent GLUT4 transporters on adipose tissue to increase glucose intake from blood

Glucose phosphorylated  into G6P 

What are the fates of G6P in adipose tissue during fed state?

1. Glycolysis to produce acetyl-CoA by acetyl-CoA carboxylase, used to from malonyl-CoA for fatty acid synthesis  

2. Enter HMP shunt to provide NADPH, used for fatty acid synthesis 

3. Becomes α‐glycerol‐3‐phosphate, used for triacylglycerol synthesis

What is lipid metabolism in adipose tissue during fasting state?

1. Glucagon and epinephrine stimulate hormone sensitive lipase in adipose tissues to hydrolyze triacylglycerol to fatty acids and glycerol 

2. Fatty acids released into blood to bind to albumin and delivered to energy-requiring tissues such as muscle, liver, heart

3. Glycerol released into blood to bind to albumin and enter liver

What is lipid metabolism in liver during fasting state?

1. Liver takes up glycerol and free fatty acids bound to albumin that came from adipose tissues

2. Glycerol enters gluconeogenesis to produce glucose

3. Free fatty acids are activated and re-esterified to form triacylglycerol 

4. Triacylglycerol are incorporated into VLDL or HDL

5. For liver source of energy, fatty acid oxidation occur in mitochondria, where acetyl-CoA is formed by beta-oxidation then it enters TCA cycle and ETC to form ATP

6. Ketogenesis occurs in liver to form ketone bodies to be used by brain

What is ketogenesis?

Alternative process for liver to provide energy precursors when there’s limited carbohydrates

What is formed during ketogenesis? What are the main ones?

ketone bodies

1. Acetone

2. Acetoacetate

3. Beta-hydroxybutyrate

How does ketogenesis occur? 

Excess of acetyl-CoA is converted into ketone bodies such as acetoacetate and beta-hydroxybutyrate to be released into blood, and acetone for liver to use

What happens to acetoacetate and beta-hydroxybutyrate in blood?

taken up by peripherals tissues such as brain, converted into acetyl-CoA and used for energy 

When does ketogenesis or this excess of acetyl-CoA occur?

1. Starvation

2. Low carb diet 

3. Uncontrolled type 1 diabetes

Why does ketogenesis or this excess of acetyl-CoA occur?

1. There’s not enough carbs thus there’s low TCA intermediate 

2. Increase in fatty acid breakdown during fasting state which releases excess acetyl-CoA 

Ketogenic diet is used as a — in — treatment for children as it reduces — and its rich is — and poor in —, and has adequate protein 

therapeutic diet

epilepsy

seizures

fats

carbs

What occurs to proteins during fed state?

1. 30-50% amino acids are retrained in enterocytes

2. 50-70% amino acids are transported to liver

3. 20% of amino acids retained in liver for energy, protein, nitrogen-containing compounds formation

4. 80% of amino acids from liver are transported to peripheral tissues for protein and nitrogen-containing compounds formation

5. Excess amino acids and along with certain amino acids (alanine) enter gluconeogenesis in muscle and liver, forming glucose to be stored as glycogen

What occur during the fasting state of fed-fast cycle?

What is the main source of energy?

Fatty acid is main source of energy

→ Fasting state focuses on glucose formation in liver where precursors includes: 

1. Amino acids from protein breakdown in muscles (most used precursor)

• Except for leucine and lysine as they are ketogenic amino acids 

• High rate of amino acid degradation results in large loss of nitrogen through urine 

2. Glycerol from lipolysis 

• Fatty acids becomes major source of energy 

3. Lactate from anaerobic metabolism (least used precursor)

→ Ketogenesis occurs in liver to form ketone bodies to be used by brain 

What occur during the starvation state of fed-fast cycle?

What is the main source(s) of energy?

Fatty acids main source of energy for tissues

Ketone bodies main source of energy for brain 

1. Plasma fatty acids increases to fuel heart, liver, skeletal muscle

2. Ketogenesis in liver to form ketone bodies to be used by brain

3. Lipolysis increases, releasing glycerol to enter gluconeogenesis in liver to provide glucose for RBC’s

What occur during the prolonged starvation state of fed-fast cycle?

What is the main source(s) of energy?

Fatty acids and ketone bodies becomes major source of energy

1. Depletion of TCA cycle intermediate, oxaloacetate, for gluconeogenesis in liver thus accumulation of acetyl-CoA

2. Accumulation of acetyl-CoA from fatty acid degradation

3. Ketogenesis increases in liver due to accumulation of acetyl-CoA, to form ketone bodies to be used as fuel in brain, skeletal muscle, heart

4. Gluconeogenesis occurs now in kidney for glucose formation from glycerol, glutamate, α-ketoglutarate

5. Kidney produces NH3 to neutralize ketosis

Duration of starvation state depend on body fat:

• An adult with normal weight and body fat, starvation state can last 3 months

• An obese adult, starvation state can last 1 year, although they will have physiological damage due to ketosis

During prolonged starvation, after depletion of body fat, — is used to form glucose and — + — (organs) functions are lost

protein

liver and muscle

What are the sources that provide body with energy?

1. Carbohydrates

• This breaks down into glucose to enter glycolysis, forming pyruvate to enter TCA cycle, producing ATP 

2. Lipids

• This breaks down into fatty acids to enter beta-oxidation, forming acetyl-CoA to enter TCA cycle, producing ATP

3. Proteins 

• This breaks down into amino acids (C-skeleton) to enter TCA cycle (glycogenic amino acids) or enter ketogenesis (ketogenic amino acids), producing ATP 

After eating a can of tuna, — are your main source(s) of energy

protein

fat

After eating a slice of white toast with jam, — are your main source(s) of energy 

carbs

After eating a burger with fries, —- are your main source(s) of energy

carbs

protein

fat

A meal rich in carbs causes:

• Fast digestion

• Sharp blood glucose increase so increase insulin

• Shorter postabsorptive state

A meal rich in fats causes:

• Slow gastric emptying, digestion 

• Delay blood glucose increase

• Long postabsorptive state 

A meal rich in proteins causes:

• Moderate digestion

• Small blood glucose increase

• Semi long postabsorptive state

A meal rich in fibers causes:

• Slow gastric emptying, digestion, absorption 

• Slow and low blood glucose increase

• Causes satiety, very long postabsorptive state

During post-absorptive state, source of energy is no longer — instead it’s —

ingested glucose

endogenous glucose

Timing of day (diurnal timing) impacts energy sources during — state

postabsorptive

 1.During fed state:

• Glucose is used as main energy source 

• Insulin is high 

• Increase fat storage in adipose tissues 

2.During postabsorptive state:

• Glucose remains main energy sauce 

• Insulin shows large spikes after meals, then drops quickly

• Glycogen stores decrease 

3.During overnight or long postabsorptive state:

• Glycogen stores are depleted

• Insulin falls 

• Fats are released from adipose tissues

• Glucose reserved for brain and RBCs

Meal timing determines when the body switches from — to — fuel sources

external

internal

Skipping meal before sleeping accelerates —

shift into fat-based metabolism before morning