integration of body fuel metabolism 2013
TRANSCRIPT
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Integration of body fuel metabolism
Atif Hassan Khirelsied, Ph.D,
Department of BiochemistryFaculty of Medicine
International University of Africa
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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.
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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.
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The amphibolic role of the TCA cycle.
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Key Junctions between Pathways
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Key Junctions between Pathways
• G‐6‐P is a central in carbohydrate metabolism
• It links PPP, glycogenesis, l l i t l l iglycogenolysis to glycolysis.
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Key Junctions between Pathways
• Pyruvate is another important intermediate of carbohydrates and amino acids metabolism
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• It links gluconeogenesis and amino acids metaabolism to glycolysis.
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Acetyl‐CoA is derived from the oxidation of various fuels
Acetyl CoA
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The central role of acetyl‐CoA in fuel metabolism
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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.
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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
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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
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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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Prolonged fasting, Starvation
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.
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Prolonged fasting, Starvation
• 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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Prolonged fasting, Starvation
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