Starvation
Lecture 20
Lipolysis
Lipolysis
FAT
Fatty acids
P
inactive
active
PKA
TGL/HSL
Triacylglycerol lipase
Hormone Sensitive Lipase
Glycerol
Lipolysis
•  cAMP   lipolysis since cAMP activates PKA
• Glucagon   lipolysis since glucagon causes an
increase in cAMP
– However, this is not the main cause of the increase in cAMP
• The main cause of the increase of cAMP is the decrease
in the rate of cAMP breakdown
– Because of the decrease in phosphodiesterase activity
Fatty acid oxidation
• Lipolysis releases FAs into the blood
• Note, even in starvation, GLUT-1 is still present in
muscle
– Even though a lack of insulin has led to GLUT-4s being
endocytosed
– So muscle is responsible for much glucose uptake
• Need to preserve glucose:
– Get tissues to stop using glucose, and use FAs
instead
– FAs will be oxidised to provide the acetyl CoA for the
Krebs Cycle
– But need to avoid oxidation of glucose, which is an
irreversible reaction
PDH
• PDH = pyruvate dehydrogenase
Glucose-Fatty Acid Cycle
• In starvation we want PDH to be off
– PDH kinase >> PDH phosphatase
– PDH kinase is stimulated by acetyl-CoA
– PDH is inactive when phosphorylated
– Prevents wasteful oxidation of pyruvate
– Pyruvate only made into lactate
• FA released from WAT (from lipolysis), causes [FA]blood to
increase and the uptake of FA into the muscle is also
increased
• Oxidation of FA (b-oxidation) switches PDH off by
producing a lot of acetyl CoA. This stop glucose
oxidation
When PDH is off…
• Pyruvate cannot be oxidized to acetyl CoA
– Then there is only one fate for pyruvate in the muscle,
--- to be converted into lactate by LDH
• LDH = lactate dehydrogenase
• Lactate can be taken up by the liver
– Made into glucose by gluconeogenesis
• Glucose recycling (glucose conservation)
– Cori-cycle
– Muscle Glucose  Pyruvate  lactate  liver glucose (via gluconeogenesis)
 glucose to the bloodstream again
• Gluconeogenesis can also happen from glycerol
– Up to 30 g glucose per day can be made from glycerol
In Early Starvation…
Glucose Accounting
• Glycerol (from lipolysis) is the only souce of DE
NOVO gluconeogenesis
– The lactate fuelled gluconeogenesis is just
recycling
– ~30g glucose from glycerol per day
• But the brain needs ~120g/day,
– not enough!
– can brain glucose consumption be reduced?
Lipolysis & b-Oxidation
• After ~2-3 days of starvation, the rate of lipolysis
approaches a maximum
– FA released into bloodstream  [FA]blood  
– There is a limit to how fast muscles will use FA
• rate of b-oxidation depends on the demand of ATP by the
muscles
• Regeneration of CoA by Krebs cycle needed to keep FA
oxidation going
• BUT liver can do b-oxidation on FA even if there
is no need for ATP
– In the liver, CoA can be regenerated in a pathway other than the
Krebs cycle
Ketone Bodies
• Ketone bodies – typically acetoacetate
– Can be taken up & oxidised by the brain
– Where they are split to 2 x acetyl CoA molecules
– Tissues have to have mitochondria in order to use ketone bodies
• Ketone bodies reduce brain glucose use from 120g/day
to 30g/day
– all 30g could be provided by glycerol….
• …. If it wasn’t for the use of glucose by the other
carbohydrate-hungry tissues like skin, etc.
Proteolysis
• Hypoinsulinemia
– Occurs when insulin level is really low
• Especially for a long period (>48 h)
• Proteins start to breakdown – PROTEOLYSIS
• Gives rise to amino acids
• Channeled to the liver for gluconeogenesis
– Not all amino acids can be made into glucose
• Glucogenic - can be made into glucose
• Ketogenic - cannot be made into glucose
– ~3g protein  1g glucose
Ketosis and amino acid use
Extended Starvation
• After 2-3 days of starvation
– Losses are 50-100g protein/day
– Even though ketone bodies inhibit proteolysis and prevent
protein being lost too rapidly
• Proteins are lost from all tissues
– Although inactive muscles tend to slightly preferentially degraded
– From heart, liver, brain, etc, as well  may cause severe
damage to body
• Will reach equilibrium
– where the amount of protein breakdown = the amount of glucose
needed
• But the loss of body protein is ultimately what kills us