Transcript No Slide Title

MAMMAMALIAN METABOLISM
Integration and
Hormonal Regulation
Objective
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Consider the major metabolic pathways
in the context of the whole organism
Issues with multicellular organism
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Division of labor: cell differentiation
Organ/Organ system specialization :
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Characteristic fuel requirements
Characteristic metabolic patterns
Hormone Regulation
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Integrate/coordinate metabolic functions of
different tissue
Maximize fuel/fuel precursor allocations to
each organ
Approach
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Recapitulate major pathways and
control systems
Consider how these processes are
divided among tissues and organs
Consider major hormones that control
these metabolic functions
Major pathways and Strategies of
energy metabolism
Glycolysis
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Metabolic degradation of glucose
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Glucose is oxidized to:
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2 molecules of pyruvate
2 molecules of ATP
2 molecules of NADH
Anaerobic Conditions
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Pyruvate converted into Lactate
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Requires oxidation of NADH
Recycles NADH
In yeast:
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Pyruvate converted into ethanol
Aerobic Conditions
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Glycolysis first step for further oxidation
of glucose
NADH is processed through Oxidative
Phosphorylation
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Regenerates oxidized NAD
Generates ATP
Regulation of glycolysis
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Phosphofructokinase (PFK)
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Activated by:
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Increase in AMP, ADP
Fructose 2,6-bisphosphate
Inhibited by:
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Increase in ATP
Citrate
Regulation of glycolysis
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Fructose 2,6-bisphosphate (F2,6P)
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Influenced by [cAMP]:
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Liver:
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Muscle
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Increase [cAmp], decrease [F2,6P]
Increase [cAmp], increase [F2,6P]
Mediated by:
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glucogon
Epinephrine
norepinephrine
Gluconeogenesis
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Synthesis of glucose from simplier,
noncarbohydrate precusor
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Pyruvate
Lactate
Oxaloacetate
Glycerol
Gluconeogenic amino acids
Gluconeogenesis
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Mainly through pathways in the liver
Major intermediate: oxaloacetate
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Converted to phospoenolpyruvate
Then, into glucose
Irreversible Steps
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PFK bypass: Fructose 1,6-bisphosphatase
Hexokinase bypass: glucose 6-phosphatase
Gluconeogenesis
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Reciprical regulation of PFK and FBPase
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Regulates rate and direction through
glycolysis and gluconeogenesis
Both may be active simultaneously
Glycogen: degradation and synthesis
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Storage form of glucose in most animals
In liver and muscle
Enters glycolysis
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Catalyzed by: glycogen phosphorylase
Converted into glucose 6-phosphate (G6P)
Opposed by glycogen synthase
[Enzymes] respond to
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Glucagon
epinephrine
Fatty Acid:
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Degradation and Synthesis
Degradation: beta-oxidation
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In 2 carbon chunks
Form acetyl-CoA
Regulated by [FA]
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Lipase in adipose cells: hormone sensitive
cAMP mediated
Stimulated by:
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Glucogon
Epinephrine
Inhibited by:
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insulin
Fatty Acid:
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Degradation and Synthesis
Synthesis: from acetly CoA
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Acetyl-CoA carboxylase
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Activated by citrate
Inhibited by intermediate (palmitoyl-CoA)
Long term regulation:
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Stimulated by insulin
Inhibited by fasting
Citric Acid Cycle
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Acetyl CoA oxidized to:
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Concomitant production of:
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CO2
H20
NADH
FADH2
Glycogenic Amino Acids
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Enter at a cycle intermediate
Citric Acid Cycle
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Regulatory enzymes
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Citrate synthase
Isocitrate dehydrogenase
Alpha-ketoglutarate dehydrogenase
Controlled by:
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Substrate availability
Feedback inhibition
Oxidative Phosphorylation
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Major products
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NADH is oxidized to NAD+
FADH2 is oxidized to FAD
Coupled to synthesis of ATP
Rate dependent upon:
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[ATP]
[ADP]
[Pi]
Pentose phosphate Pathway
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Generates from G6P:
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Catalyzed by:
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Glucose 6-phosphate dehydrogenase
Regulated by:
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Ribose 5-phosphate
NADPH
[NADP+]
NADPH is needed for biosynthesis
Amino Acid:degradation and synthesis
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Excess AA:
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Degraded to common metabolic
intermediates
Most paths
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Begin with transamination to alpha-keto acid
Eventually amino group transferred to urea
Amino Acid:degradation and synthesis
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Ketogenic AA
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E.g.: leucine, lysine, tryptophane,
phenylalanine, tyrosine, isoleucine
Only leucine, lysine exclusively ketogenic
Converted into
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Acetyl-CoA
Acetoacetyl-CoA
Can not be glucose precursors
Amino Acid:degradation and
synthesis
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Glucogenic AA
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Converted into glucose precursors
Precursors:
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Pyruvate
Oxaloacetate
Alpha-ketoglutarate
Succinyl CoA
fumarate
Amino Acid:degradation and
synthesis
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Other situations:
4 AA are both ketogenic and glucogenic
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Essential AA: cannot be synthesized
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Tryptophan,Phenylalanine,Tyrosine,Isoleucine
Histidine, Isoleucine, Leucine, Lysine, Methionine,
Phenylalanine, Threonine, Tryptophan, Valine, and
Arginine (in young)
Nonessential AA: can be synthesized
Two Key Compounds
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Acetyl-CoA, pyruvate
At metabolic crossroads
Acetyl-CoA
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Degradation products of most fuels
Oxidized to CO2 and H2O in citric acid
cycle
Can be used to synthesize FA
Pyruvate
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Product of:
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Glycolysis
Dehyddrogenation of lactate
Some glucogenic AA
Can yield acetyl-CoA
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Enter CAC
Biosynthesis of FA
Pyruvate
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Carboxylated via pyruvate carboxylase
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Forms oxaloacetate
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Replenishes intermediates
Gluconeogenesis
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Via phosphoenolpyruvate
Bypass of irreversible step in glycolysis
Precursor to several AA
Sites
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Cytosolic:
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Glycolysis
Glycogen synthesis, degradation
FA synthesis
Pentose Phosphate pathway
Sites
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Mitochondrial:
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FA degradation
Citric Acid cycle
Oxidative Phosphorylation
Sites
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Both:
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Gluconeogenesis
AA degradation
Location controlled by specific
membrane transporters
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Esp. inner mitochondrial membrane
Controls flow of metabolites
Regulation
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Intercellular Regulating Mechanisms
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Hormones
Trigger cellular response
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Short-term: second messenger
Long-term: protein synthesis
Molecular Level
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Feedback
Substrate availability
Tissue Specific Metabolism
TSM: LIVER
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Liver: central processing and
distributing role
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Furnishes other tissues/organs with
appropriate mix of nutrients via the blood
Other tissues and organs are termed
extrahepatic or peripheral
Handles carbohydrates, amino acids and
fats
TSM: LIVER
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Extremely adaptable to prevailing
conditions
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Can shift enzymatic ally from one nutrient
emphasis to another within hours
Responds to the demands of
extrahepatic tissues/organs for fuels
Maintains blood levels of nutrients
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Well located for the task
Sugars
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Role as Blood glucose “Buffer”
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Absorbs and releases glucose
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Response to levels of:
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Glucagon
Epinepherine
Insulin
Response to [glucose]
Glucose absorption
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Hepatocytes are permeable to glucose
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Convert glucose to G6P
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Not insulin dependent
Absorption driven by [blood glucose]
Catalyzed by glucokinase (not hexokinase)
Blood glucose
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Normally lower than max phosporylation rate of
glucokinase
Uptake about equal to [blood glucose]
Glucose absorption
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Other monosaccarides
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Can be converted to G6P
Includes
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Fructose
Galactose
Mannose
Release of glucose
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No food
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Blood glucose levels drop
Liver keeps blood glucose at about 4mM
Fate of glucose
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Varies with metabolic requirement
G6P to glucose
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G6P to glycogen
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Requires glucose 6-phosphatase
Blood transport to peripheral organs
When demand for glucose is low
Glycogen to G6P
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When demand for glucose is low
Signaled by increased:
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Glucagon
epinephrine
Fate of glucose
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G6P to acetyl-CoA
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By glycolysis
Need pyruvate dehydrogenase
Used for synthesis of
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FA
Phospholipids
Cholesterol to bile acids
Fate of glucose
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Substrate for the Pentose phosphate
pathway
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NADPH needed for biosynthesis of:
Fatty acids
Cholesterol
D-ribose 5-phosphate
precursor for nucleotide biosynthesis
Fate of Fatty Acids
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Increased demand for metabolic fuel:
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FA converted into acetyl-CoA into ketone
bodies
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KB are transportable form of acetyl
Exported via blood to tissues
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Up to one third of energy in heart
60-70% in brain during prolonged fast
Major oxidative fuel of the liver
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FA converted into acetyl-CoA to CAC
Fate of Fatty Acids
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Decreased demand for metabolic fuel
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FA converted into liver lipids
Some acetyl from FA (and glucose) converted into
cholesterol
Specialized mechanisms for transport of lipids
in blood
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Converted into lipoproteins, then to adipose for
storage
Bound to albumin as free FA, transported in blood
to skeletal and cardiac muscle
FA: degradation and synthesis
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Compartmentalized
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Prevent futile cycling
FA oxidation: in mitochondria
FA synthesis: in cytosol
FA: degradation and synthesis
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Interactions
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Carnitine Palmitoly Transferase I (CPTI)
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CPTI inhibited by Malonyl-CoA MCoA)
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Transport FA into mitochondria
MCoA is key intermediate in FA synthesis
When FA are synthesized, can not
transport FA into mitochondria
FA: degradation and synthesis
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Interactions
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When metabolic demand for fuel is low:
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acetyl-CoA comes from glucose
When metabolic demand for fuel is high:
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Inhibits FA synthesis
FA into Mitochondria into ketone bodies
Fatty Acids
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Liver can not use Ketone Bodies
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Lacks 3-ketoacyl-CoA-transferase
When metabolic demand is increased:
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Fatty Acids are the liver's main source of
acetyl-CoA
Fate of Amino Acids
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AA degraded to variety of intermediates
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Glucogenic AA
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Pyruvate
Citric acid intermediates
Ketogenic AA
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Ketone bodies (sometimes)
Fate of Amino Acids
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After about 6 hour fast
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Glycogen stores are depleted
Gluconeogenesis from AA
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Mostly muscle protein
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Degrated to alanine and glutamine
Animals can not convert Fat to Glucose
Proteins are an important fuel reserve
Fate of Amino Acids
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AA degraded to variety of intermediates
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Glucogenic AA
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Pyruvate
Citric acid intermediates
Ketogenic AA
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Ketone bodies (sometimes)
TSM: Brain
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High Respiratory Rate
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About 2% of body weight; 20% of resting
O2 consumption
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Independent of activity level
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Most: power (Na+-K+)-ATPase
TSM: Brain
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Most conditions
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Only fuel: glucose
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Extended fasting: ketone body
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Needs steady suppy
TSM: Brain
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With blood glucose below half normal
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Brain dysfunction
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Drop more
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Coma
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Irreversible damage
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death
TSM: Muscle
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Major Fuels
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Glucose from Glycogen
FA
Ketone Bodies
Storage: Glycogen
Can Not Export Glucose:
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No gluconeogenesis
No G-6-phosphatase
No receptors for Glucagon
TSM: Muscle
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Energy Reservoir
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Proteins into Amino Acids
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Amino Acids into Pyruvate
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Pyruvate into Alanine into the liver into
pyruvate into glucose
Epinephrine Receptors
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Regulates glycogen breakdown and synthesis
Increase cAMP in muscle
 Activates glycogen breakdown
 Activates glycolysis
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Increase glucose consumption
Epinephine acts independently of glycogen
 With insulin
 Regulates general blood glucose levels
Muscle Contraction
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Skeletal Muscle at rest:
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Can increase 25% in exercise
Shifts to glycolysis of G6P from
glycogen
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about 30% of O2 consumption
Much of G6P into Lactate
Cori Cycle
Respiratory burden shifted to liver
Delay of O2 dept
Muscle Fatigue
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Definition
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Inability of muscle to maintain a given
power output
About 20% drop in contraction strength
Aerobic ( Red Fiber: slow twitch)
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Difficult to fatigue
Oxidative Phosphorylation
Good vascular supply
myoglobin
Muscle Fatigue
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Anaerobic
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With in about 20 sec in max exertion
I.E.: Tetanic Exertion
Results from sustained contraction of
white fibers (fast twitch)
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Depends on glycolysis
Creatine phosphate (CP)
Glygogen storage
Cause of Fatigue
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Drop in intramuscular pH
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From 7.0 to as low a 6.4
From glycolytic proton generation
How does increased acidity cause muscle
fatigue?
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Maybe decresed enzyme activity?
Esp PFK
TSM: Cardiac Muscle
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Continuous activity
Aerobic
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Many mitochondria
Fuel
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FA: fuel of choice
Ketone bodies
Stored glycogen to glucose (with heavy
workload)
Pyruvate
lacctate
TSM: Adipose Tissue/Adipocytes
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General Metabolism
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Location
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Under skin
Abdominal cavity
In skeletal muscle
Around blood vessels
In mammary glands
TSM: Adipose Tissue/Adipocytes
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General Metabolism
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Quanity
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Normal male: about 21%
Normal female: about 25%
Functions:
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Energy storage
Maintenance of metabolic homeostasis (second
only to the liver)
TSM: Adipose Tissue/Adipocytes
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General Metabolism
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Source of Fatty Acids
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Liver
Diet
To form stored triglycerides
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Fatty acyl-CoA esterified with PGA
Glycerol-3-Phosphate
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Formed from reduction of DAP
Glycolytically generated from glucose
Adipose cells lack enzyme to phosphorylate
endogenoous glycerol
TSM: Adipose Tissue/Adipocytes

General Metabolism

Hydrolyze triglycerides to Fatty Acids and
Glycerol

In response to levels of:
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Glucogon
Epinephrine
Insulin
Catalyzed by “hormone-sensitive” lipase
Increased [PGA]: reform triglycerides
Decreased [PGA}: release FA to blood
TSM: Adipose Tissue/Adipocytes

Rate of Glucose uptake by adipocytes

Regulated by:
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Insulin
Glucose availability
Controlling factor in

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Formation of triglycerides
Mobilization of triglycerides
TSM: Blood
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Mediates metabolism between organs
Transports:

Nutrients
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Waste products
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Tissues to kidneys
Respiratory gases
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Small intestine to liver
Liver to adipose tissue, other organs
O2: lungs to tissues
CO2: tissues to lungs
Regulatory molecules (hormones)
TSM: Blood
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Composition
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About 5-6L in average adult
Cells/formed elements

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Erythrocytes
Leukocytes
Platelets
TSM: Blood
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Composition
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Plasma
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90% water
10% solutes

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Plasma proteins
Inorganic components
Organic components
Major effort of homeostasis to keep values
within normal ranges
Blood glucose levels are regulated by:

Epinephrine, glucagon and insulin