4Obesity - Gut Hormones and Satiety

Question 1

What is ghrelin?

Answer 1

Opposite of leptin
Protein made by endocrine cells of stomach and GI tract
Hypothalamic receptors
Rises just before meals and falls after = Direct response
Ghrelin administration in rats strongly stimulates feeding
Anti-Ghrelin Antibodies suppress feeding = in rats doesn’t work in humans
High Ghrelin levels in Prader-Willi Syndrome = Jordan’s son Harvey has this

Question 2

How is ghrelin produced and where does it bind?

Answer 2

Ghrelin is produced as preproghrelin = spliced
Ghrelin binds to the GSHR1a splice-variant of this receptor which is present in high density in the hypothalamus, pituitary as well as vagal afferent cell bodies and vagal afferent ending throughout the gastro-intestinal tract
While can stimulate hypothalamus directly; doesn’t have to cross BBB can signal through the vagus nerve = quick signalling

Question 3

How does ghrelin signalling to phospholipase via G-alpha-Q?

Answer 3

Ghrelin binds to the GHSR (ghrelin receptor) which is coupled to GalphaQ = GTP converted to GDP
Activation of PLC-beta leading to PIP2 converted to second messenger DAG = IP3 released (second messenger)
Inositol 3,4,5-phosphate (IP3) binds its receptor and causes release of Ca2+ from the smooth endoplasmic reticulum

Question 4

How does a rise in intracellular calcium concentrations lead to an orectic signal?

Answer 4

Intracellular free Ca2+ binds calmodulin (CaM) this binds to CaMkinase kinase (CaMKK) which acts as the activator of AMPK.
This leads to phosphorylation and activation of AMPK.
This leads to phosphorylation of mTOR and activation of TSC1/TSC2. The excess of RhebGDP prevents activation of mTOR, giving rise to an oretic signal (appetite).
Ghrelin is also being released at this time and AMP.
Combination of AMP and calcium release due to ghrelin causes maximum activation of AMP kinase.
Phosphorylation of threonine and serine residues on TSC2 means there is an excess of RhebGDP = FKBP38 remains bound to mTOR preventing its activation and leading to an orectic signal.

Question 5

How does leptin mobilise the PI 3-kinase/PKB pathway?

Answer 5

Leptin mobilises the PI 3-kinase/PKB pathway, through the JAK2-mediated pathway phosphorylation of IRS2

Question 6

How does 5’-AMP lead to an orectic signal?

Answer 6

A lack of glucose interferes with the leptin signal through a pathway that involves 5’ AMP, a monophosphate nucleotide that is generated in a “rescue” pathway where two ADP are used to raise the level of ATP

Question 7

What are orexins?

Answer 7

Neuropeptides synthesised by neurons in posterolateral hypothalamus
Derived from prepro-orexin (131 aa)
Orexin A: 33 aa, N-terminal pyroglutamyl residue, 2 intra-chain disulfide bonds
Orexin B: linear 28 aa
Only orexin A can pass the blood-brain barrier

Question 8

Describe the orexin receptor.

Answer 8

Mediated via G protein coupled receptor
OxR1 (selective for Orexin A) and OxR2 (bind to both Orexin A, B)
Distributed in hypothalamus, thalamus, brainstem (locus ceruleus), spinal cord, GI tract, pancreas and genital tissues

Question 9

What is the role of orexin in feeding?

Answer 9

Orexins neurons in lateral hypothalamus connect and stimulate NPY-, AGRP- neurons in the arcuate nucleus and stimulate food intake
Orexin neurons are stimulated by starvation and hypoglycemia and inhibited by feeding (via vagal sensory pathway) = acute signalling
Also plays an important role in regulation of metabolic rate

Question 10

What is CCK?

Answer 10

CCK = Cholecystikinin
Peptide hormone
Causes the gallbladder (cholecyst) to contract - releasing bile
In response to presence of nutrients
Pylorus to constrict and inhibits gastric contractions

Question 11

What is the distribution of CCK?

Answer 11

Small intestine - endocrine l-cells

CCK is synthesised in the brain as well

Question 12

What types of CCK receptors have been discovered?

Answer 12

2 CCK subtype receptors have been discovered:
Alimentary CCK-A receptor
CCK-B Receptor

Question 13

What are the effects of CCK?

Answer 13

Pancreatic enzyme secretion
Bile secretion and contraction of gallbladder and bile emptying
Inhibition of gastric emptying = feel full
Inhibition of gastric secretion
Inhibition of food intake
Gastroprotection against various irritants
Reacting to nutrients coming through the stomach instead of energy balance

Question 14

How are the effects of CCK and stomach stretch integrated in vagal afferent fibres?

Answer 14

Stretch/mechano- receptors in the stomach wall stretch when stomach is fed = signal to vagal afferent fibres =signals to the hind-brain via the nodose ganglion and inhibits food intake (effect is acute)
CCK only really works when stomach stretch takes place too = integrated signal = does not work if you inject CCK into someone with no other signal

Question 15

What is the effect of CCK on food intake?

Answer 15

Acute reaction = cumulative food intake back to normal after 2 hours
Stops stomach bursting from overfilling = MDMA interferes with this = people who have taken ecstasy have drunk so much that their stomach has burst

Question 16

How was PYY3-36 discovered?

Answer 16

PYY3-36 injected into mice = take in a lot less calories than control over 12 hours
Does not work in humans
Mice are inbred and live in sterile, tightly controlled conditions = humans generally do not

Question 17

What are the effects of PYY and PYY3-36?

Answer 17

PYY is released in the gastrointestinal (GI) tract in response to meals. Its biological effects include:
Inhibition of gut motility
Inhibition of fluid and electrolyte secretion in the intestinal tract
Inhibition of pancreatic secretion
Vasoconstriction
Peripherally administered PYY3-36 decreases food intake in both humans and rodents = briefly

Question 18

What evidence is there to support the theory that PYY3-36 inhibits food intake under controlled conditions?

Answer 18

Rats in free-living conditions did not replicate earlier studies on tightly controlled lab mice.
There is an initial reduction in feeding but by 12 hours this has evened out and food intake is comparable to the control.

Question 19

How is vagal afferent signalling linked to PYY3-36?

Answer 19

Many receptors involved = carefully integrated homeostatic signalling = very rarely relying on just one gene or one signalling pathway
PYY3-36 receptor disappears under energy restriction
Expression of receptors on vagal afferent nerve changes depending on fed/unfed state

Question 20

How are neurotransmitters involved in hedonic regulation of food intake?

Answer 20

Hedonic behaviour = driven by the desire to feel good
Mess around with hedonic signalling = become depressed and even to the point of becoming suicidal - all these things can affect emotional well-being while trying to reduce calorific intake:

Dopamine = tyrosine derived neurotransmitter
Endocannabinoids
-anandamide (arachidonoyl ethanolamide, AEA) (meaning “bliss”), binds CB1 and CB2
-2-arachidonoyl glycerol (2-AG)
-2-arachidonoyl glyceryl ethere (noladin ether), binds CB1 anb CB2
-N-arachidonoyl –dopamine (NADA), binds CB1
-Virodhamine (O-arachidonoyl-ethanolamine, OEA), binds CB1 and CB2
Endogenous Opioids
-enkephalin short peptide cleaved from proenkephalin protein (act on m- and d-receptor)
examples tyr-gly-gly-phe-leu (leu-enkephalin) or tyr-gly-gly-phe-met (met-enkephalin)
-endorphins, short peptides cleaved from pro-opiomelanocortin protein (act on m-receptor)
-dynorphin short peptide cleaved from prodynorphin protein (act on k-receptor
GABA, gamma-aminobutyric acid, amino-acid derived neurotransmitter

Question 21

What is the extent of gut-brain communication?

Answer 21

There is an extensive degree of gut-brain communication.

Sweeteners bind to receptors and influence energy uptake