Opposing Roles of Grhelin & Leptin- Role of Gastrointestinal Signalling in Satiety (3/4) Flashcards
Where is ghrelin synthesised?
Endocrine cells of the stomach and GI tract
Which receptors detect ghrelin?
Growth hormone secretagogue receptor (GHSR) in the hypothalamus
How does ghrelin signal into cells?
Binds Gαq to activate phospholipase C (PLC)
When are ghrelin levels permanently high?
Prader-Willi syndrome
Leads to over-eating
What is the role of PLC in ghrelin signalling?
PLC hydrolyses PIP2 into second messengers DAG and IP3
What is the role of IP3 in ghrelin signalling?
Binds its receptor on the sER membrane to mobilise calcium
How is the action of ghrelin signalling similar to that of 5’AMP?
Both pathways activate AMPK to phosphorylate the FKBP38 protein of the mTOR complex
This inactivates mTOR to induce a hunger signal
What is the role of calcium in ghrelin signalling?
Free intracellular calcium binds to calmodulin (CaM), which then binds to CaMkinase kinase (CaMKK)
CaMKK activates AMPK
AMPK phosphorylates phosphorylates and activates TSC1/TSC2
This causes an excess of RhebGDP to build up with prevents the activation of mTOR
What does inactive mTOR do?
Induce a hunger/orectic signal
How does leptin action affect peripheral tissues?
Directly prevents ectopic lipid overaccumulation (not in adipose tissue) during the development of obesity
Spares liver, muscle and other tissues including β-cells from the metabolic trauma of lipid overload
Prevents insulin resistance
What does active mTOR do?
Induce a satiety/anorectic signal
How does leptin deficiency affect peripheral tissues?
Leads to lipotoxicity caused by fatty acid derivatives (e.g., ceramide)
Eventually leads to lipoapoptosis - cell death caused by lipid accumulation
How does leptin signal peripheral tissues?
Leptin activates AMPK
AMPK inhibits (phosphorylates) ACC from producing malonyl-CoA
Malonyl-CoA inhibits CPT1 to prevent fatty acids from entering the mitochondria to be oxidised
Less malonyl-CoA means CPT1 is no longer inhibited and fatty acids can be oxidised in the mitochondria
How does leptin signal in β cells?
Leptin dampens the signal from glucose in β cells- less insulin produced (slow decrease)
Increases amount of glucose to peripheral tissues to be burnt, instead of to adipose tissue to form fat
How does endocrine signalling from adipose tissue change in obesity?
The release of FFA and pro-inflammatory cytokines is increased due to the increased size in adipose tissue
This causes an influx to other organs and fat accumulation there
Increased glucose output from the liver
Decreased glucose uptake by muscles
