Orexigenic Peptides Flashcards
Peptides having an orexigenic effect do what
Stimulates appetite or increases food intake
Where are most orexigenic peptides identified and what do they function as in the CNS
- most originally identified in the periphery-> esp as GI hormones
- functions as both peptide hormones and as neuromodualtors-> neuropeptide Y, Ghrelin, Orexins
What is responsible for the control of energy homeostasis
Gut-brain axis
True or false: leptin is a neuropeptide
false
true or false: leptin is 16kDa (167 amino acids) protein hormone released from adipose tissue to reduce appetite
true
where are the leptin receptors found
in the arcuate nucleus of the hypothalamus (main site of action)
what does the inability to signal satiety in mice with a mutation to the leptin gene (ob/ob) lead to?
constant hunger
where was neuropeptide y (NPY) identified and is expressed from the NPY gene as _______
-in the porcine hypothalamus
- preproNPY
where is NPY highly expressed in
in the arcuate nucleus of the hypothalamus
what does IV administration of NPY do to rodents
increases food intake
_________ has increased permeability of the BBB from monitoring of blood-borne hormones and release of hypothalamic hormones
hypothalamus
true or false: agonists of NPY decrease food intake
false: increase
what are the receptors of NPY
5 types of NPY GPCRs
- NPYR 1,5 are orexigenic (most important ones)
- NPYR 2,4 are autoreceptors (selective agonists decrease food intake)
where do genetically obese mice tend to have high levels of NPY in
the hypothalamus
true or false: NPY interacts with environmental stress
true
______ ______ and __ _____ ______ _____ leads to an increase in abdominal adipose deposits (trunk obesity)
Chronic stress; a high calorie diet
True or false: just like other neuropeptides, NPY has good pharmacodynamic
false; poor
short half-life circulation
what is required for NPY
IV administration since peptides are both highly hydrophilic and sensitive to acid hydrolysis
what does NPY receptor antagonism lead to
transient effects on NPY signalling and has pharmacodynamic tolerance
what is meant by short-term efficacy only
NPY levels readily compensate for changes
Gherlin (GHRL) gene expresses what
expresses preproghrelin and obestatin (which may not have much to do with obesity)
what does GHRL function as, when does it release, and what does the release result in
- functions as a classic gastrointestinal hormone and is released from the GI to stimulate hunger
- is released constitutively but inhibited by a mechanosensitive process when the stomach is stretched/ full
- release stimulates hunger and inhibition attenuates hunger
what does GHRL act at and what is identified as
- acts at the growth hormone secretagogue type 1A receptor (GHSR)
- identified as an endogenous agonist for the GHSR
GHSR is widely expressed in the _________ (esp the vagus nerve) and in the ________ on ______ ___________ ______ of the arcuate nucleus
- periphery
- CNS
- NPY secreting cells
what activation leads to secretion of NPY
GHSR
what kind of administration of ghrelin increases food intake and what does gastric bypass surgery do
- systematic
-decreases ghrelin levels in obese patients
what does ghrelin also interact with and what does ghrelin increase
- interacts with numerous aspects of mood, stress, and diet to affect food intake
- increases hedonic aspects of food intake
hedonic- emotional eating/ comfort food
in addition to the hypothalamus, where else is Gherlun expressed in and what area does it have pronounced effects on
- ventral tegmental area, substantia nigra, raphe nuclei, hippocampus (dentate gyrus)
- mesolimbic cholinergic-dopaminergic reward network
what is the natural role of gherlin
the signal reinforces aspects of food reward
What is the enzyme responsible for acylation of ghrelin? Where does it occur?
GOAT; at S3 position by a medium-chain fatty acid
GOAT actigvity _______ after intake of medium-cahin fatty acids in the diet - leading to _____________ acylation of ghrellin and _____________ hunger stimuli.
increases; increased; increasing
Describe the circadian rhythm of ghrelin.
- increase near expected meal times
- slow, steady increase from midnight to dawn
- co-expressed with circadian clock proteins in the gut
Ghrelin expression has a ___________ correlation with sleep time. Decreased sleep leads to __________ ghrelin. Increased sleep leads to ___________ ghrelin.
negative; elevated; decreased
Sleep disruption can disrupt ghrelin rhythms leading to ____________ ghrelin levels.
increased
TRUE or FALSE: if you are exposed to light during sleep phase, ghrelin will decrease
FALSE: it will spike/increase
TRUE or FALSE: ghrelin release is proportional to body weight
FALSE: inversely proportional
i.e. lose weight = increased ghrelin
i.e. gain weight = decrease ghrelin
Which hormone is proposed to be an endogenous mediator of weight and energy stores?
ghrelin
TRUE or FALSE: ghrelin release increases with stress
TRUE
What is a potential therapeutic target for obesity? What are the side effects? What animal was it demonstrated in?
- ghrelin
- if we decrease ghrelin, could lead to depression and anxiety
- pigs –> immune reaction against GHSR
How is GHRL implicated in addictions?
- ghrelin signals reinforcing aspect of alcohol (high calorie)
- ghrelin administration increases motivation to self-administer heroin
- ghrelin antagonists reduce the behavioural response to cocaine and nicotine
Describe the operant conditioning apparatus. What is it used to study?
- modified Skinner box
- IV or oral self-administration
- operant training for drug/substance reward
- animals have catheter implanted into jugular and affixed to infusion pump
- lever press results in dose of drug of choice
- used to study MOTIVATION to self-administer
How do you measure motivation?
- progressive ratio schedule –> response demand is increased progressively starting from 1
- determine breaking point (highest completed ratio of demand to response)
- break point reflects motivation - amount of work willing to perform to achieve reward
How does ghrelin affect break point of heroin self-administration?
increases break point
Describe the conditioned place preference.
- Pavlovian conditioning paradigm
- drug injection paired with neutral envvironemtnal stimulus to create conditioned stimulus
- 2-3 chamber conditioning box
- 3 phase CPP protocol (pre-, conditiong, post-)
(see slide 23)
How does ghrelin affect CPP in animal models?
ghrelin administration alone can induce a CPP in animal models
Orexin A/B are formed from a single __________ off the ________ gene.
prepropeptide; HCRT
Where are orexin-secreting neurons found?
lateral hypothalamus (but extensively innervate brain and spinal cord)
(see diagram on slide 25 for details on input and output areas)
What are the functions of orexin?
- orexigenic (food)
- sleep
How doe ghrelin, NPY, leptin, and CART affect orexin?
- ghrelin and NPY stimulate orexin release
- leptin and CART inhibit orexin release
How do we know that ghrelin and NPY do not directly lead to increased eating?
- orexin K/O mice show no orexigenic effects of ghrelin administration
- i.e. need to active orexin to increase eating
How does orexin affect sleep?
- link sleep and metabolism
- orexin adminstration stimulates wakefulness
How does long-term sleep deprivation affect food intake and metabolsim?
increase food intake and energy metabolism
Receptor ______________ mutation leads to decreased funtion of orexin, leading to __________.
loss-of-function; narcolepsy
A common cause of narcolepsy is a mutation in the ___________leading to ___________________ against ________.
HLA antigen; autoimmune disease; orexin neurons
where does oreixigenic neurons receive indirect input from?
SCN
Where does oreixn project to for wakefulness?
- Locus ceruleus norepinephrine systems
- Dorsal raphe seratonin systems
- Tuberomamillary histamine systems
- Basal forebrain cholinergic system (BFCS)
When does orexin activity increae? When is it more active?
- increase just before waking
- active during wake (vs. sleep)
What is suvorexant?
dual OX receptor antagonist (DORA) for insomnia treatment
What is almorexant?
dual OX receptor antagonist (DORA) discontinued in 2011 during phase III trials
How are orexins implicated in addiction?
- orexin increases consumption in animals that are already addicted, but not creation of new addiction
- intreact with dopaminergic reward paths in VTA
- OX receptor ANTAGONSITS decrease self-administration of alcohol, opiates, nicotine
Administration of orexin into the lateral hypothalamus results in _____ alcohol consumption or _________ of extinguished alcohol or nicotine seeking
increased; reinstatement
How are orexins implicated in emotional memory? (reword this question)
- orexinergic neurons receive inputs from limbic system
- orexin K/O mice show decreased response to stress/fear stimuli
- human narcolepsy patients show diminished autonomic responses to emotional stimuli
- altered orexin levels with anxiety/PTSD
- KEY: proposed to maintain wakefulness in response to emotional arousal via limbic inputs
How are orexins implicated in motivational activation?
ghrelin act on motivation itself; orexin is not a motivator itself, but it play a role during food intake and wakefulness
phasic orexin activity increases during ________________ ___________.
adaptive behaviour
orexins facilitate reward seeking only when motivated by _____________.
an underlying physiological (e.g. hunger) or psychological need (e.g. cues, stressors)
