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Feed/fast cycle. ENDO 412. Objectives. 1- Identifying hormones that promote influx & efflux of glucose, fat & protein (nutrients) into & out of energy storage pools. 2- Describing the mechanisms involved in the control of flow intermediates in the metabolic pathways.

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Feed fast cycle

Feed/fast cycle

ENDO 412


Objectives
Objectives

1- Identifying hormones that promote influx & efflux of glucose, fat & protein

(nutrients) into & out of energy storage pools.

2- Describing the mechanisms involved in the control of flow intermediates in

the metabolic pathways.

3-Describing the organ map that traces the movement of metabolites between

tissues.

4- Understanding the alterations in the metabolism of the liver, adipose tissue,

muscles & brain in the absorptive state.

5-Understanding the motion of exchange of substrates among liver, adipose tissue,

muscle & brain to maintain adequate glucose blood level in case of fasting.

6-Creating an expanded & clinically useful vision of the whole body metabolism.


Absorptive fed state
Absorptive (fed) state

Overview of the absorptive (fed) state

  • The absorptive state is the 2 – 4 hours period after ingestion of a normal meal. During this interval, transient increase in plasma glucose, amino acids & triacylglycerols (main nutrients) occur.

  • As a result of elevated glucose & amino acids, insulinsecretion is increased from the pancreas & glucagon secretion is decreased.

  • Elevated insulin/glucagon ration & ready availability of circulating substrates cause increased synthesis of triacylglycerol & glycogen to be stored (anabolic period).

  • During the absorptive period, all tissues use glucose as a fuel.

  • During the absorptive period, metabolic responses of the body is dominated by alterations of the metabolism of 4 organs , liver, adipose tissue, muscle & brain.


Enzyme changes in the fed state
Enzyme changes in the fed state

  • Flow of intermediates through metabolic pathways is controlled by:

    1- Availability of substrates (within minutes)

    2- Allosteric regulation of enzymes (within minutes)

    3- Covalent modification of enzymes (within minutes to hours)

    4- Induction-repression of enzyme synthesis (within hours to days)

    Each mechanism operates on a different time-scale

    (i.e. response occurs within minutes, minutes to hours or hours to days)

    In fed state, these regulatory mechanisms ensure that available nutrients of food (in abundance) are directed to be stored as glycogen, triacylglycerol & protein


Liver n utrient d istribution center
Liver: nutrient distribution center

  • Venous drainage of gut & pancreas passes through the hepatic portal vein (to liver cells) before entry into the general

    circulation

    Thus, after a meal, liver receives blood containing absorbed nutrients (mainly glucose, amino acids & fatty acids) & elevated levels of insulin secreted by the pancreas

  • During the absorptive period, the liver takes up nutrients which are carbohydrates, lipids & most amino acids.

    These nutrients are metabolized

    or: stored

    or: routed to other tissues


Liver nutrient d istribution c enter
Liver: nutrient distribution center

Carbohydrate metabolism:

After a meal containing carbohydrate, liver consumes about 60% of

glucose from portal circulation.

Increased entry of glucose is notinsulin dependent: as GLUT-2 of liver is

not influenced by insulin.

Liver metabolism of glucose is increased by:

1- Increased phosphorylation of glucose (i.e. glucose 6-phosphate by glukokinase)

2- Increased glycolysis of glucose (with production of acetyl CoA fatty acids)

3- Increased glycogen synthesis glucose stored or: energy

4- Increased activity of pentose phosphate pathway of glucose (to provide NADPH)

5-Decreased gluconeogenesis(synthesis of glucose from non-carbohydrate sources)


Liver n utrient d istribution center1
Liver: nutrient distribution center

Fat metabolism:

1- Increased fatty acid synthesis:

Favored by :

- Availability of substrates (acetyl CoA& NADPH from glucose metabolism)

- Activation of acetyl CoAcarboxylase (enzyme of the rate-limiting step in fatty acid

synthesis)

2- Increased triacylglycerol (TAG) synthesis:

Favored by:

- Fatty acid is provided from de novo synthesis from acetyl CoA & chylomicron

remnants taken by the liver.

- Glycerol 3-phosphate is provided by glucose metabolism (glycolysis).

Liver packages TAG into very-low density lipoproteins (VLDL) that are secreted into blood for use by extrahepatic tissues (particularly adipose & muscle).


Liver nutrient d istribution c enter1
Liver: nutrient distribution center

Amino acid metabolism:

1- Increased protein synthesis:

Increase in synthesis of liver proteins to replace any degraded proteins during fast period.

No store of extra protein or amino acids.

1- Increased amino acid degradation:

In the absorptive state, more amino acids are present than the liver can use for synthesis

of proteins (i.e. more than liver capacity to synthesize proteins)

Excess amino acids are notstored in any form

BUT,

they are released to blood to other tissues for protein synthesis

or, deaminated in liver into carbon skeleton & ammonia

Carbon skeleton can be catabolized for energy production or used for fatty acid

synthesis.

Liver can synthesize proteins from abundant diet amino acids to a certain limit after which excess amino acids are either released to other tissues or degraded.


Liver nutrient d istribution c enter2
Liver: nutrient distribution center

Liver

in the absorptive

state


Adipose tissue energy s torage d epot
Adipose tissue: energy storage depot

Carbohydrate metabolism:

1- Increased glucose transport:

GLUT-4 of adipocytes are insulin-sensitive.

In the absorptive state, insulin conc. is elevated resulting in increased influx of

glucose into adipocytes.

2- Increased glycolysis:

due to increased intracellular levels of glucose

Glycolysis provides glycerol 3-phosphate for triacylglycerol synthesis.

3- Increased activity of pentose phosphate pathway (PPP)

Increased PPP results in increased formation of NADPH essential for fatty acid

synthesis.


Adipose tissue energy s torage d epot1
Adipose tissue: energy storage depot

Fat metabolism:

1- Increased synthesis of fatty acids(NOT A MAJOR PATHWAY):

Fatty acid synthesis in adipose tissue is not a major pathway.

Instead, most fatty acids added to adipose tissues are provided by diet

fat (in chylomicrons) with a lesser amount supplied by VLDL of liver.

2- Increased triacylglycerol synthesis:

Exogenous fatty acids (from diet fat: chylomicrons & liver fat: VLDL) &

glycerol 3 phosphate (from glycolysis of glucose) are used for synthesis of

triacylglycerol in adipose tissue.

Thus, in well-fed state (absorptive state),

storage of triacylglycerol (fat) in adipose tissue is favored


Adipose tissue energy s torage d epot2
Adipose tissue: energy storage depot

Adipose tissue

in the absorptive

state


Resting skeletal muscle
Resting skeletal muscle

Overview:

  • Skeletal muscle is able to respond to changes in demand for ATP that accompanies muscle contraction.

  • At rest, muscle account for about 30% of oxygen consumption of the body

    During vigorous exercise, muscles account for up to 90% of total oxygen consumption.

  • Skeletal muscle depends on anaerobic & anaerobic glycolysis metabolism for getting energy (while heart muscle depends on aerobic metabolism only).

  • Skeletal muscles have stores for energy in the form of glycogen & lipids, (while heart muscle does not have these stores).


Resting skeletal muscle1
Resting skeletal muscle

Carbohydrate metabolism:

1- Increased glucose transport:

GLUT-4 of skeletal muscles cells are insulin-sensitive.

In the absorptive state (after a carbohydrate rich meal), insulin conc. is elevated

resulting in increased influx of glucose into skeletal muscle cells.

Glucoseprovides energy to muscles during the fedstate (in contrast to the fasting state in which ketone bodies & fatty acids are the major fuels of resting muscles.

1- Increased glycogen synthesis:

During absorptive period, glucose (which is abundant after a carbohydrate rich meal), is stored in the form of glycogen in skeletal muscles.


Resting skeletal muscle2
Resting skeletal muscle

Amino acid metabolism:

1-Increased protein synthesis:

During the absorptive period, amino acid uptake & protein synthesis is increased to replace degraded protein since the previous meal.

2- Increased uptake of branched-chain amino acids (leucine, isoleucine & valine)

These amino acids escape metabolism by the liver & are taken up by muscle.


Resting skeletal muscle3
Resting skeletal muscle

Skeletal muscles

in the absorptive

state


Brain
Brain

Overview:

  • Brain accounts for 20% of basal oxygen consumption of body at rest (although it is only 2% of adult weight).

  • Brain uses energy at a constant rate.

  • Brain is vital for proper functioning of all organs of the body & so, special priority is given to its energy needs.

  • Glucose normally serves as the primary fuel as the concentration of ketone bodies in the fed state is too low to serve as an alternate energy source.

  • If blood glucose falls to below 30 mg/100 ml (Normal: 70 – 90 mg/100 ml), cerebral functions are impaired.

    If hypoglycemia occurs for even a short time, severe & irreversible brain damage may occur.

    N.B. During fast, ketone bodies play a significant roles.


Brain1
Brain

Carbohydrate metabolism:

In the fed (absorptive) state, the brain

uses glucose exclusively as a fuel.

(140 grams/day is oxidized to

carbon dioxide & water)

Excess glucose is not stored

(no glycogen stores).

Accordingly, the brain is completely

dependant on availability of blood

glucose.


Organ map during the absorptive state showing intertissue relationship
Organ map during the absorptive stateshowing intertissue relationship


Fasting
Fasting

Overview of fasting

Fasting may result from:

- Ramadan fasting for Muslims

- Inability to obtain food

- Desire to lose weight rapidly

- Clinical situations in which an individual cannot eat (trauma, surgery , etc..)

In absence of food, plasma levels of glucose, amino acids & triacylglycerol (main nutrients) fall

with a resulting decline in insulin secretion & increase in glucagon release.

The decreased insulin/glucagon ratio & decreased availability of circulating substrates, favors

a catabolic periodin which degradation of triacylglycerol, glycogen & protein is characteristic.

Exchange of substrates between liver, adipose tissue, muscle & brain is guided by two priorities:

1- Need to maintain adequate plasma levels of glucose to secure energy metabolism to brain, RBCs &

other tissues utilizing glucose as sole fuel.

2- Need to mobilize fatty acids from adipose tissue, synthesis & release of ketone bodies to supply energy

to other tissues.


Fuel stores at the beginning of fasting
Fuel stores at the beginning of fasting

For a normal 70 kg man at the beginning of a fast:

N.B. Only 1/3 of body`s protein can be used for energy production without fatally compromising vital function.


Enzymatic changes in fasting
Enzymatic changes in fasting

  • Flow of intermediates through metabolic pathways is controlled by:

    1- Availability of substrates (within minutes)

    2- Allosteric regulation of enzymes (within minutes)

    3- Covalent modification of enzymes (within minutes to hours)

    4- Induction-repression of enzyme synthesis (within hours to days)

    The metabolic changes in fasting are generally opposite to those in fed state.

    In fasting, substrates are not provided by diet, but are available from the

    breakdown of tissues stores (e.g. lipolysis: with release of fatty acids & glycerol

    from adipose tissue & proteolysis with release of amino acids from muscles.


Liver in fasting
Liver in fasting

Overview

The primary role of liver in energy metabolism during fasting is

maintaining of blood glucose through production & release of energy

molecules for use by other organs.


Liver in fasting1
Liver in fasting

Carbohydrate metabolism:

In liver during fasting, glycogen is degraded first (10-18 hrs of fasting) & then

gluconeogenesis (after 18 hrs to secure glucose to brain & other tissues utilizing

glucose as a sole fuel).

1- Increased glycogen degradation (glycogenlysis) to produce glucose to blood:

exhausted after 10 – 18 hours of fasting (early fasting).

2- Increased gluconeogenesis:

Gluconeogenesisis the synthesis of glucose from non-carbohydrate sources:

amino acids & lactate from muscles & glycerol from adipose fat.

Gluconeogenesisplays an essential role during overnight & prolonged fasting.

Gluconeogenesisbegins 4 - 6 hours after the last meal & becomes fully active

when stores of glycogen are depleted (after about 18 hours).


Liver in fasting2
Liver in fasting

Fat metabolism:

1-Increased fatty acid oxidation:

Fatty acids obtained from adipose tissue is the major source of energy to liver during the fasting state.

2- Increased synthesis of ketone bodies:

The liver can synthesize & release ketone bodies from fatty acids to tissues for use as a fuel.

(BUT: liver cannot use ketone bodies as a fuel).

Ketone bodies formation is favored by the availability of fatty acids obtained from adipose

tissue (fatty acids are degraded to acetyl CoA, the precursor of ketone bodies).

In this case, acetyl CoA produced from fatty acids exceeds the capacity of citric acid cycle.

Significant synthesis of ketone bodies starts during the first days of fasting.

Ketone bodies (unlike FA) are water-soluble & appears in blood & urine by the second day of a fast.

Ketone bodies in blood during fasting is important as they can be used as fuel for most tissues including

the brain tissue (can pass BBB).

Accordingly, it reduces the need for gluconeogenesis from amino acids & thus slowing the loss of

essential protein.

or


Liver in fasting3
Liver in fasting

Liver

in the fasting

state


Adipose tissue in fasting
Adipose tissue in fasting

Fat metabolism:

1-Increased degradation of triacylglycerols:

Activation of hormone-sensitive lipase with subsequent hydrolysis of stored triacylglycerol

are enhanced by elevated catecholamines(epinephrine & norepinephrine) released from

sympathetic nerve endings in adipose tissue

2- Increased release of fatty acids from adipose tissue:

Fatty acids produced from hydrolysis of triacylglycerol are released to blood & are

transported to tissues to be utilized as a source of energy.

Fatty acids are also transported to liver to be converted to ketone bodies

Glycerol produced from hydrolysis of triacylglycerol in adipose tissue is taken by the

liver & is converted to glucose (gluconeogenesis).

So, fat is a source of glucose (carbohydrate) in fasting state.



Resting skeletal muscle in fasting
Resting skeletal muscle in fasting

Resting muscle uses fatty acids as its major fuel source.

By contrast, exercising muscle initially uses its glycogenstores as a source of energy.

Carbohydrate metabolism:

Because of low levels of insulin, glucose transport & glucose metabolism are depressed.

Lipid metabolism:

During first 2 weeks of fasting , muscle uses fatty acids from adipose tissues & ketone bodies from liver as sources of energy

After 3 weeks, muscles depend only on fatty acids.

Protein metabolism:

During the first few days of fasting, there is a rapid breakdown of muscle proteins,

providing amino acids that are used by the liver for gluconeogenesis.

After several weeks of fasting, rate of proteolysis s is decrease as there is a decline in need for glucose as a fuel for the brain (which begins use ketone bodies as a source of energy)



Brain in fasting
Brain in fasting

During the first few days of fasting, the brain continues to use glucose only as a source of energy.

In prolonged fasting (more than 2 -3 weeks), plasma ketone bodies reach elevated levels & are used in addition to glucose in as a source of energy the brain. This reduces the need for protein degradation for gluconeogenesis.



Organ map during the fasting state showing intertissue relationship
Organ map during the fasting stateshowing intertissue relationship


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