Download pdf - Integration of Body Fuel Metabolism 2013

Integration of body fuel metabolism

Atif Hassan Khirelsied, Ph.D,

Department of BiochemistryFaculty of Medicine

International University of Africa

Integration of Metabolism

1. Interconnection of pathways

2. Metabolic profile of organs

3 Food intake starvation and obesity3. Food intake, starvation and obesity

4. Fuel choice during exercise

5. Hormonal regulation of metabolism

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Connection of Pathways

1 ATP is generated by oxidation of1. ATP is generated by oxidation of glucose, fatty acids, and amino acids ; common intermediate ‐> acetyl CoA ; electron carrier ‐> NADH and FADH2

2. Synthesis and degradation pathways almost always separated ‐> Compartmentation !!!

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Biosynthetic functions of glycolysis. Compounds formed from intermediates of glycolysis are shown in blue.

In the liver, TCA cycle intermediates are used for fatty acids synthesis, amino y y yacids synthesis, gluconeogenesis, and heme synthesis.

In the brain α ketoglutarate is converted to neurotransmitter glutamate and In the brain, α-ketoglutarate is converted to neurotransmitter, glutamate and GABA.

The amphibolic role of the TCA cycle.

Key Junctions between Pathways

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• G‐6‐P is a central in carbohydrate metabolism

• It links PPP, glycogenesis, l l i t l l iglycogenolysis to glycolysis.


• Pyruvate is another important intermediate of carbohydrates and amino acids metabolism

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• It links gluconeogenesis and amino acids metaabolism to glycolysis.

Acetyl‐CoA is derived from the oxidation of various fuels

Acetyl CoA

The central role of acetyl‐CoA in fuel metabolism

Metabolic Profile of Body Organs

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Metabolic Profile of Organs

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1. Metabolic Profile of Brain

• Glucose is fuel for human brain >• Glucose is fuel for human brain ‐> consumes 100‐120g/day ‐> 60‐70 % of utilization of glucose.of utilization of glucose.

• In starvation ‐> ketone bodies can

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replace glucose.

1. Metabolic Profile of Muscles

• Major fuels are glucose fatty acids and ketone bodies• Major fuels are glucose, fatty acids, and ketone bodies

• Has a large storage of glycogen ‐> about ¾ of allHas a large storage of glycogen > about ¾ of all glycogen stored in muscles

• Glucose is preferred fuel for burst of activity ‐> production of lactate (anaerobe)p oduc o o ac a e (a ae obe)

• Fatty acid major fuel in resting muscles and in heart y j gmuscle (aerobe)

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2. Metabolic Profile of Muscles

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3. Metabolic Profile of Adiposite tissue

• Triacylglycerols are stored in tissue ‐> enormous reservoir of metabolic fuel.

• Needs glucose to synthesis TAGTAG.

• Glucose level determines if fatty acids are released into blood.

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4 M b li P fil f Kid4. Metabolic Profile of Kidney

• Production of urine ‐> secretion of waste products.

• Blood plasma is filtered (60 X per day) ‐> water and glucose reabsorbed.

• During starvation ‐> important site of gluconeogenesis, produces ½ of blood glucose.

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5. Metabolic Profile of the Liver (Glucose)the Liver (Glucose)

• Essential for providing fuel to brain, muscle, other organs

• Most compounds absorpt by diet passabsorpt by diet pass through liver.

• It regulates the levels of metabolites in blood.e abo es b ood

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Metabolic Activities of the Liver (Amino (Acids)

α‐Ketoacids (derived from amino acid d d ti )degradation) ‐> liver’s own fuel

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Metabolic Activities of the Liver (Fatty ( yAcids)

• Cannot use acetoacetate as fuel.

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Fuel Metabolism During Fed andFuel Metabolism During Fed and Fast State Conditions

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Food Intake, Starvation, and Obesity

Normal Starved‐Fed Cycle:

1. Postabsorptive state ‐> after a meal

2 Early fasting state > during the night2. Early fasting state ‐> during the night

3. Refed state ‐> after breakfast

4. Prolonged fasting ‐> 12 hrs.

5. Starvation ‐> days

‐> Major goal is to maintain blood‐glucose level!

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1.Postabsorptive state

• Glucose + Amino acids ‐> transport from intestine to bl dblood

• Dietary lipids transported ‐> lymphatic system ‐> bl dblood.

• Glucose stimulates ‐> secretion of insulin.

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l

1.Postabsorptive state

Insulin:

‐> signals fed stateg

‐> stimulates storage of fuels and synthesis of proteins

‐> high level ‐> glucose enters muscle + adipose tissue (synthesis of TAG)

‐> stimulates glycogen synthesis in muscle + liver

‐> suppresses gluconeogenesis by the liver> suppresses gluconeogenesis by the liver

‐> accelerates glycolysis in liver ‐> increases synthesis of fatty acids

‐> accelerates uptake of blood glucose into liver ‐> glucose 6‐phosphate more rapidly formed than level of blood glucose rises ‐

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> built up of glycogen stores

Insulin Secretion –Stimulated by Glucose Uptake

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Insulin Secretion –Stimulated by Glucose Stimulated by Glucose Uptake

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PostabsorptiveState -> after a MealMeal

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2 E l F i S2. Early Fasting State

Bl d l l l d ft l h ft• Blood‐glucose level drops after several hours after the meal ‐> decrease in insulin secretion ‐> rise in l tiglucagon secretion

• Low blood‐glucose level ‐> stimulates glucagon secretion of α‐cells of the pancreasp

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2. Early Fasting StateGlucagon:Glucagon:

‐> signals starved state

‐> mobilizes glycogen stores (break down)

> inhibits glycogen synthesis‐> inhibits glycogen synthesis

‐> main target organ is liver

‐> inhibits fatty acid synthesis

> stimulates gluconeogenesis in liver‐> stimulates gluconeogenesis in liver

‐> large amount of glucose in liver released to blood stream ‐> maintain blood‐glucose level

Muscle + Liver use fatty acids as fuel when blood‐glucose level

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y gdrops

Early Fasting State ‐> During the Night

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3. Refed State

•Fat is processed in same way as normal fed state

•First > Liver does not absorb glucose from blood (diet)•First ‐> Liver does not absorb glucose from blood (diet)

•Liver still synthesizes glucose to refill liver’s glycogen y g g y gstores

•When liver has refilled glycogen stores + blood‐glucose level still rises ‐> liver synthesizes fatty acids from excess glucose

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Prolonged fasting, Starvation

Well‐fed 70 kg human ‐> fuel reserves about 161,000 kcal

‐> energy needed for a 24 h period ‐> 1600 kcal ‐ 6000 kcal

ffi i t f t ti t 1 3 th‐> sufficient reserves for starvation up to 1 – 3 months

‐> however glucose reserves are exhausted in 1 day

Even under starvation ‐> blood‐glucose level must be above 40 mg/100 ml

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First priority ‐> provide sufficient glucose to brain and p y p gother tissues that are dependent on it.

Second priority ‐> preserve protein ‐> shift from p y p putilization of glucose to utilization of fatty acids + ketone bodies.

‐> mobilization of TAG in adipose tissues + gluconeogenesis by liver ‐> muscle shift from glucose to

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g g y gfatty acids as fuel.


• After 3 days of starvation ‐> liver forms large amounts of ketone bodies (shortage of oxaloacetate) ‐> released into blood ‐> brain and heart start to use ketone bodies as fuel

• After several weeks of starvation ‐> ketone bodies major fuel of brain.

• After depletion of TAG stores ‐> proteins degradation accelerates ‐> death due to loss of heart, liver, and

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kidney function


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