Orexigenic peptides Flashcards
What are orexigenic peptides named after?
Peptides having an orexigenic effect – stimulating the appetite or
increasing food intake
What is the role of energy homeostasis?
Gut-brain axis
Describe leptin
- NOT a neuropeptide
- Discovered as a spontaneous
mutation in a mouse line at Jackson
labs in 1949 - Obese mice (ob/ob) carried a
recessive mutation leading to
spontaneous hyperphagy and weight
gain - Later identified as a mutation in the
leptin gene
Describe leptin’s orexilytic effects
- Leptin is a 16 kDa (167 amino acids) protein hormone released from
adipose tissue to attenuate appetite - Release signals from site of energy storage to decrease caloric
intake - Leptin receptors are found in the arcuate nucleus of the
hypothalamus (main site of action) - Inability to signal satiety in ob/ob mice leads to constant hunger
Describe neuropeptide y
- Expressed from the NPY gene as
preproNPY - NPY, C-flanking peptide, and
CPON - Identified in 1982 in the porcine
hypothalamus - NPY expression is highest in the
arcuate nucleus of the
hypothalamus
Describe the therapeutic potential of NPY
- NPY, as with other neuropeptides, has poor pharmacokinetics
- Short half-life in circulation
- IV administration required (peptides are both highly hydrophilic and sensitive to acid hydrolysis)
- Pharmacodynamic tolerance
What genes does ghrelin express?
- GHRL gene expresses preproghrelin and obestatin (which may not have
much to do with obesity)
Describe GHRL receptors
Ghrelin acts at the growth hormone
secretagogue type 1A receptor
(GHSR).
Ghrelin was identified as
endogenous agonist for the GHSR
(hence the disparity in naming).
GHSR is expressed widely in the
periphery (esp. vagus nerve) and in
the CNS on NPY secreting cells of the
arcuate nucleus of the hypothalamus.
GHSR activation leads to secretion of
NPY
Describe orexigenic effects of ghrelin
- Systemic administration of ghrelin
increases food intake - Gastric bypass surgery decreases
ghrelin levels in obese patients - Ghrelin also interacts with
numerous aspects of mood, stress,
and diet to affect food intake - Ghrelin increases hedonic aspects
of food intake
Describe GHSR expression in CNS
- In addition to the hypothalamus, GHSR is expressed in
the ventral tegmental area, substantia nigra, raphe
nuclei, hippocampus (dentate gyrus) - Ghrelin has pronounced effects on the mesolimbic
cholinergic-dopaminergic reward network - Natural role for ghrelin in signalling reinforcing aspects of
food reward
Describe post translational modification of GHRL
Enzyme responsible for acylation is
Ghrelin-O-acyltransferase (GOAT).
GOAT activity increases after intake of
medium-chain fatty acids in the diet –
leading to increased acylation of
ghrelin and increasing huger stimuli.
Describe ghrelin and sleep
- Ghrelin expression has a negative correlation with sleep time
- Decreased sleep leads to elevated ghrelin
- Increased sleep leads to decreased ghrelin
Describe long term changes in ghrelin
- Ghrelin release is also inversely proportional to body weight
- Weight loss leads to increased ghrelin release
- Weight gain leads to decreased ghrelin release
Describe GHRL and addictions
- Ghrelin is involved in reinforcing aspects of food
- Ghrelin also involved in signalling reinforcing aspects of alcohol
- Expected as alcohol is also a high calorie vice
Describe operant conditioning apparatus
Modified Skinner box
Used to study motivation to self-administer
