Gut-Brain Axis Flashcards
role of ghrelin
increases food intake
where is the ARC situated
at the leaky BBB
types of neurons the ARC contains
orexigenic neurons: AGRP NPY
anorectic neurons: POMC/CART
what is ghrelin
28 aa hormone
secreted from the duodenum
requires an octanol group
agonist at the GHS-Rla receptor
meal initiator - plasma levels spike prior to meal
where is the site of action for ghrelin
increased ca2+ release
ghrelin response greatest in NPY+ neurons
other role of ghrelin
impacts memory ?
IV infusion of ghrelin in humans
increases energy intake (kJ)
Wren et al., 2001
GHS-RIa antagonists
stop ob/ob mice eating and reduce body weight
orally available
risk of off target effects on the GH axis
L cell secretion
PYY
Neurotensin
GIP
GLP-1/2
OXM
cause feeling of fullness via vagus nerve
PYY
36 aa
produced in L cells (small and large intestine)
aa 1 and 2 (pro and tyr) cleaved in response to DPP4 forms PYY3-36 (truncated) vs PYY1-36
functions mainly in ileum
Y2R agonist in ARC
post-prandial secretion of PYY
satiety signal
obese - very less PYY release
lean
bypass - most PYY release (Le roux et al., 2005)
what occurs after bariatric surgery
GLP-1 enhanced (more effect than banding)
PYY receptor selectivity
1-36 Y1&Y5 (decreases food uptake)
3-36 Y2 (inhibits food uptake responds to fasting)
what occurs if vagus nerve is severed
reduction in PYY3-36 effect
PYY therapeutic issues
high levels cause narrow therapeutic window
short half life
IV administration impractical requires oral
prevents breakdown due to long lasting analogues which inhibit cumulative food intake
GLP-1
produced from preproglucagon in a cells
stimulates insulin release
inhibits appetite
binds to GLP-1 R
forms of GLP-1
exenatide from glia monster venom
WeGovy is a GLP-1 agonist
Liraglutide (accumulates in ARC)
where is the GLP-1 receptor on the ARC neurons
NPY neurons do not have GLP-1R, GLP-1 swtiches off NPY
GLP-1R on POMC neurons (increases firing)
Oxyntomodulin OXM
37aa
preproglucagon
binds to GLP-1R
causes weight loss by increasing energy expenditure
what is AGRP inhibited by
calorie ingestion
caged vs accessible chocolate AGRP inhibited by desire to eat increased firing because caged
PYY switches of AGRP
future directions
PYY&OXM (IV infusion has synergistic effect)
Terzepitide (GLP&GIP)
monomeric peptide triagonists (GLP-1/GIP/glucagon) glucagon works like OXM and increases energy expenditure
needs to identify receptor on intestinal L cells
dietary manipulation
glucose/fatty acids/amino acids stimulate L cells
agonists stimulate macronutrient receptors - deliver macronutrients
consideration for patients
need to be treated for whole life
