Metabolic control

1
Metabolic control
2
Hormonal regulation

• Hormones regulate metabolism to a large extent by
• Altering substrate availability
• Eg sympathetic response to exercise increases FFA
  mobilisation
• Affecting activity of enzymes in metabolic
  pathways
• Eg epinephrine increases PFK activity
• Although hormonal control overlies all cellular
  metabolism
• Cellular metabolism dependent on substrate
  availability
• Cells have intracellular mechanisms for
  regulating their own metabolism

3
Substrate availability

• Availability of substrate plays predominant role
  in determining flux through metabolic pathway
• Example
• During marathon glycolytic flux decreases when
  liver and muscle glycogen exhausted
• Glucagon released in response to declining blood
  glucose
• Increases triacylglycerol lipolysis to increase
  availability of alternative fuel
• Hormonal control secondary to reduced
  availability of substrate for glycolysis

4
Intracellular regulation of substrate utilisation

• Even when substrate available, fuel utilisation
  regulated by intracellular signalling mechanisms

5
Regulation of fatty acid oxidation by skeletal
muscle at onset of exercise

• AMP increase during onset of exercise activates
  AMP dependent protein kinase (AMPK)
• AMPK phosphorylates acetyl CoA carboxylase ?
  (ACC?)
• ACC? forms malonyl CoA from acetyl CoA
• Phosphorylation inhibits ACC? and thereby
  reduces malonyl CoA formation
• Malonyl CoA inhibits carnitine acyl transferase I
  (cytosolic enzyme in carnitine transporter in
  inner mitochondrial membrane)
• Reduction in malonyl CoA increases entry of fatty
  acids into mitochondria and increased fatty acid
  oxidation

6
Integration of CHO and fat metabolism

• At rest and during low-moderate intensity
  exercise FFA oxidation can meet energy
  requirements of muscle
• CHO metabolism inhibited by Glucose-fatty acid
  cycle

7
Glucose - fatty acid cycle

• Adequate Acetyl CoA production from ?-oxidation
  results in
• Inhibition of PDH complex
• Reduced formation of Acetyl CoA from pyruvate
• High mitochondrial citrate concentration
• Leads to increased cytosolic citrate
  concentration (citrate transporter in inner
  mitochondrial membrane)
• Cytosolic citrate inhibits PFK

From Summerlin LR (1981) Chemistry for the Life
Sciences. New York Random House p 543.
8
Glucose - fatty acid cycle

• Inhibition of PFK (by citrate) will lead to
  increase in its substrate (F 6-P)
• Will lead to increase in G 6-P
• Increased G 6-P will inhibit Hexokinase

From Summerlin LR (1981) Chemistry for the Life
Sciences. New York Random House p 543.
9
Glucose - fatty acid cycle

• As exercise intensity increases ?-oxidation will
  be unable to produce acetyl CoA at sufficient
  rate to maintain concentration
• Will result in
• Reduced inhibition of PDH complex
• Increased formation of Acetyl CoA from pyruvate
• Reduced mitochondrial citrate concentration
• Will lead to reduced cytosolic citrate
  concentration
• Less inhibition of PFK and glycolysis will speed
  up

10
Glucose - fatty acid cycle

• Reduced inhibition of PFK will
• decrease concentration of substrate (F 6-P)
• reduced G 6-P concentration
• Will reduce inhibition of Hexokinase

11
Glucose-fatty acid cycle

• Glucose-fatty acid cycle operates at rest and
  low-moderate intensity exercise, but
• Fats release energy more slowly than CHO
• Transport into mitochondria before oxidation
  slows process of energy delivery
• No substrate level phosphorylation
• ATP must come from ETC
• Therefore, fatty acid oxidation less able to meet
  energy requirements as exercise intensity
  increases
• Additionally, reduced blood and tissue pH during
  high intensity exercise inhibits lipolysis
• Further increases reliance on CHO oxidation

12
Stimulation of CHO metabolism during
high-intensity exercise

• As exercise intensity increases CHO metabolism
  increases due to
• reduced inhibition of glycolysis by glucose-fatty
  acid cycle
• Increase in muscular AMP concentration which
• activates glycogen phosphorylase
• activates PFK
• Results in further stimulation of CHO oxidation