Neurohormonal control of appetite Flashcards
what does the ARC contain
1st order neurons
POMC
CART
AGRP
NPY
role of POMC and CART
inhibits food uptake
ghrelin released from stomach acts on agrp and NPY
POMC (pro-opiomelanocortin)
not a peptide hormone, cannot be secreted
how does POMC act to reduce food intake
increased leptin and adiposity binding to receptors increases POMC
POMC is a precursor of a-MSH
a-MSH binds to melanocortin 4 receptor (MC4R) reduces appetite (2nd order signalling)
a-MSH reduces food intake
what does POMC ablation cause
obesity
red hair
hyperphagia
Agouti related peptide (AGRP)
homologue for agouti protein which causes yellow hair
AGRP coexpressed with NPY in ARC
AGRP is an endogenous antagonist of MC3R & MC4R - blocks a-MSH binding
where does chronic AGRP project to
PVN
AGRP effect on UCP-1
UCP-1 marks energy expenditure (brown adipose tissue)
AGRP reduces UCP-1
Neuropeptide Y (NPY)
appetite stimulant
increased food intake decreases energy expenditure
influx of NPY causes obesity
6 receptors (Y1-6) Y1,2,5 found in hypothalamus
double KO of AGRP and NPY
no lean phenotype due to developmental compensation
NPY/AGRP contain unidentified appetite regulator
optogenetics
Aponte et al., 2011
light directed at ARC
activates AGRP neurons
induces feeding
cocaine and amphetamine regulated transcript (CART)
coexpressed with POMC in ARC
food deprived (low leptin=reduced ARC)
not present in obese animals (ob/ob db/db)
administering leptin increases CART
CART decreases normal/starvation induced feeding, blocks feeding response from NPY
what is the human CART deficiency
obesity and low basal metabolic rate
counter signals
AGRP/NPY = hunger signal (high leptin inhibits)
POMC/a-MSH = satiety signal (high leptin activates)
MC4R mutants
morbid obesity
>4% children morbidly obese
phenotype: hyperphagia, tall stature, hyperinsulinemia, increased bone mineral density
thyrotropin releasing hormone TRH
peptide secreted by PVN, downregulated during fasting
leptin increases production of a-MSH, stimulates TRH release
acts on anterior pituitary , releases TSH, which releases TH from the thyroid gland (increases energy expenditure)
a-MSH increases TSH via leptin
AGRP inhibits and blocks TSH
melanin concentrating hormone MCH - orexigenic
overexpressed in ob/ob mutants
fasting increases MCH in obese and normal mice
MCH injected in lateral ventricles increases food consumption
MCH KO leanness and reduced body weight- reduced feeding and increased metabolic rate
orexins A and B (hypocretins) - orexigenic neurons
exclusively produced in the lateral hypothalamic area (LHA)
orexin deficiency causes nacrolepsy (irregular sleep wake cycle)
regulated by ghrelin/leptin/glucose
3 regions which receive input from AGRP neurons
POMC neurons in ARC
parabrachial nucleus (PBN) in hindbrain
paraventricular hypothalamus (PVH) neurons
PVH lesions
cause hyperphagia and obesity
inhibition in PBN promotes feeding, rescues aphagia
AGRP and OT (from PVH) circuit
increased food intake
PVH is heterogenous
OT is anorexigenic
OT loss of function is implicated in Prader Willi Syndrome
what is required for AGRP induced food intake
NPY and GABA release from AGRP
