Starvation Lecture 20 Lipolysis FAT Fatty acids P

Starvation Lecture 20

Lipolysis FAT Fatty acids P inactive PKA TGL/HSL Triacylglycerol lipase Hormone Sensitive Lipase Glycerol

Lipolysis • c. AMP lipolysis since c. AMP activates PKA • Glucagon lipolysis since glucagon causes an increase in c. AMP – However, this is not the main cause of the increase in c. AMP • The main cause of the increase of c. AMP is the decrease in the rate of c. AMP 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-4 s 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 Co. A 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-Co. A – 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 Co. A. This stop glucose oxidation

When PDH is off… • Pyruvate cannot be oxidized to acetyl Co. A – 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 – ~30 g glucose from glycerol per day • But the brain needs ~120 g/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 Co. A 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, Co. A 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 Co. A molecules – Tissues have to have mitochondria in order to use ketone bodies • Ketone bodies reduce brain glucose use from 120 g/day to 30 g/day – all 30 g 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 – ~3 g protein 1 g glucose

Ketosis and amino acid use

Extended Starvation • After 2 -3 days of starvation – Losses are 50 -100 g 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