orexigenic peptides Flashcards
1
Q
orexigenic peptides
A
Peptides having an orexigenic effect – stimulating the appetite or
increasing food intake
2
Q
Orexigenic peptides Most originally identified in the
A
– esp as GI
hormones
3
Q
Orexigenic peptides Many function as both
A
peptide hormones and as
neuromodulators in the CNS
4
Q
Many function as both peptide hormones and as
neuromodulators in the CNS (3)
A
- Neuropeptide Y
- Ghrelin
- Orexins
5
Q
- Gut-brain axis is responsible for
A
control
of energy homeostasis
6
Q
GUT TO THE BRAIN
A
Microbial-derived signalling molecules
Immune mediators
(cytokines)
Gut hormones
Vagal afferents
Spinal afferents
7
Q
brain to gut
A
Sympathetic efferents
Parasympathetic efferents
Neuroendocrine
- Adrenal cortex
- Adrenal
medulla
8
Q
Leptin
A
NOT a neuropeptide
9
Q
Leptin Obese mice (ob
/ob) carried a
recessive mutation leading to
spontaneous hyperphagy and weight
gain
* Later identified as a
A
mutation in the
leptin gene
10
Q
Leptin is
A
orexilytic
11
Q
orexilytic
A
increases apetite
12
Q
Leptin is a 16 kDa (167 amino acids) protein hormone released from
A
adipose tissue to attenuate appetite
13
Q
Leptin Release signals from site of energy storage to
A
decrease caloric
intake
14
Q
Leptin receptors are found in the
A
arcuate nucleus of the
hypothalamus (main site of action)
15
Q
Inability to signal satiety in ob/ob mice leads to
A
constant hunger
16
Q
Neuropeptide Y
(NPY) Expressed from the NPY gene as
A
preproNPY
17
Q
NPY expression is highest in the
A
arcuate nucleus of the
hypothalamus
18
Q
Orexigenic effects of NPY
A
IV administration of NPY increases food intake in rodents
19
Q
Agonists of NPY increase
A
food intake
20
Q
- IV administration of NPY increases food intake in rodents Hypothalamus has increased permeability of the BBB for
A
monitoring of
blood-borne hormones and release of hypothalamic hormones
21
Q
Antagonists of NPY receptors
A
decrease food intake
22
Q
Antagonists of NPY receptors decrease food intake 5 types of NPY GPCRs
A
NPYR 1,5 are orexigenic
* NPYR 2,4 are autoreceptors (selective agonists decrease food intake)
23
Q
NPY and obesity
A
Genetically obese mice tend to have high levels of
NPY in the hypothalamus
24
Q
NPY interacts with
A
environmental stress
25
NPY interacts with environmental stress Monkeys subject to chronic stress show
increased NPY
levels
26
Chronic stress and a high calorie diet lead to increased
abdominal adipose deposits (trunk obesity)
27
Therapeutic potential of NPY
NPY, as with other neuropeptides, has poor pharmacokinetics
28
NPY, as with other neuropeptides, has poor pharmacokinetics * Short
half-life in circulation
29
* NPY, as with other neuropeptides, has poor pharmacokinetics IV administration
required (peptides are both highly hydrophilic and
sensitive to acid hydrolysis)
30
NPY receptor antagonism leads to
transient effects on NPY
signalling
31
NPY receptor antagonism leads to transient effects on NPY
signalling Short-term
efficacy only – NPY levels readily compensate for changes
32
NPY receptor antagonism leads to transient effects on NPY
signalling Pharmacodynamic
tolerance
33
Ghrelin (GHRL)
GHRL gene expresses preproghrelin and obestatin (which may not have
much to do with obesity)
34
GHRL functions as a classic
gastrointestinal hormone and is released from
the GI to stimulate hunger
35
* GHRL is released constitutively but is inhibited by
a mechanosensitive process
when the stomach is stretched
36
GHRL release
stimulates hunger (orexigenic) and inhibition attenuates hunger
37
Ghrelin acts at the growth hormone
secretagogue type 1A receptor
(GHSR)
38
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.
39
GHSR activation leads to
secretion of
NPY
40
Orexigenic effects of ghrelin
* Systemic administration of ghrelin
increases food intake
41
Gastric bypass surgery
decreases
ghrelin levels in obese patients
42
Ghrelin also interacts with
numerous aspects of mood, stress,
and diet to affect food intake
43
Ghrelin increases
hedonic aspects
of food intake
44
GHSR expression in the CNS in addition to the hypothalamus, GHSR is expressed in
the ventral tegmental area, substantia nigra, raphe
nuclei, hippocampus (dentate gyrus)
45
Ghrelin has pronounced effects on the
e mesolimbic
cholinergic-dopaminergic reward network
46
Ghrelin has pronounced effects on the mesolimbic
cholinergic-dopaminergic reward network
* Natural role for ghrelin in signalling reinforcing aspects of
food reward
47
Posttranslational
modification of
GHRL
Ghrelin is modified at the S3 position
by a medium
-chain fatty acid
(octanoic acid)
48
Ghrelin is modified at the S3 position
by a medium
-chain fatty acid
(octanoic acid) Enzyme responsible for acylation is
Ghrelin
-
O
-acyltransferase (GOAT).
49
GOAT activity
increases after intake of
medium
-chain fatty acids in the diet
–
leading to increased acylation of
ghrelin and increasing huger stimuli.
50
Ghrelin and sleep Ghrelin release follows a
circadian rhythm
51
Ghrelin release follows a circadian rhythm Increases near
expected meal times
52
Ghrelin release follows a circadian rhythm Slow, steady increase from
midnight to dawn
53
Ghrelin is co-expressed with
circadian clock proteins in the gut
54
Ghrelin expression has a
negative correlation with sleep time
55
Decreased sleep leads to
elevated ghrelin
56
ncreased sleep leads to
decreased ghrelin
57
Sleep disruption can
disrupt ghrelin rhythms leading to increased ghrelin levels
58
Sleep disruption can disrupt ghrelin rhythms leading to increased ghrelin levels
Sensitive to light levels during sleep phase (lights, light pollution, possibly backlit screens)
59
Long-term changes in ghrelin Ghrelin release is also inversely proportional to
body weight
60
Weight loss leads to
increased ghrelin release
61
Weight gain leads to
decreased ghrelin release
62
Ghrelin release is also inversely proportional to body weight Proposed to be an endogenous mediator of
weight and
energy stores
63
stress eating
Ghrelin release increases with stress
64
Ghrelin as a potential therapeutic target
* Ghrelin is interesting as a target for obesity treatment
65
obesity vaccine’ has been demonstrated in pigs
mmune reaction against GHSR
66
Increased ghrelin levels correlate with antidepressant
and
anxiolytic effects
67
Increased ghrelin levels correlate with antidepressant
and anxiolytic effects
* High potential for side effects on mood
68
GHRL and addictions
Ghrelin is involved in reinforcing aspects of food
69
Ghrelin also involved in signalling reinforcing aspects of
alcohol
70
Ghrelin also involved in signalling reinforcing aspects of alcohol
Expected as alcohol is also a high calorie vice
71
* Ghrelin has been shown to modulate
addictive behaviours in response to
non-caloric substances
72
Ghrelin administration increases motivation to
self-administer heroin
73
Ghrelin antagonists reduce the behavioural response to
cocaine and nicotine
74
Measuring motivation
Progressive ratio schedule
an increasing response requirement for reinforcer delivery over successive sessions
75
Measuring motivation Breaking point
The highest completed ratio of demand to response
is termed the break point
76
Break point reflects motivation
amount of work
willing to perform to achieve reward
77
Ghrelin and break point
Ghrelin administration increases the break point of
heroin self-administration
78
Ghrelin and conditioned place preference
Ghrelin administration alone can induce a CPP in
animal models
79
Orexin / hypocretin Two peptides
(orexin A/B or hypocretin 1/2) formed from a
single prepropeptide off the HCRT gene
80
Orexin-secreting neurons are
found in the
lateral
hypothalamus but extensively
innervate the brain and spinal
cord.
81
Orexin functions Orexigenic
Orexin neurons are downstream of ghrelin and leptin sensitive neurons of the arcuate nucleus
82
Ghrelin & NPY stimulate
orexin release
83
Leptin & CART inhibit
orexin release
84
Orexin k/o mice show no
orexigenic effects of ghrelin administration
85
Orexin functions Sleep
Proposed to link sleep and metabolism
86
Long-term sleep deprivation (in rodents) increases
s food intake and energy metabolism (with
eventual lethal consequences)
87
Orexin administration stimulates
wakefulness
88
Orexin and narcolepsy Orexin receptors were identified as a common cause of
canine
narcolepsy
89
* Orexin receptors were identified as a common cause of canine
narcolepsy
Receptor loss-of-function mutation leads to decreased function of
orexin
90
Orexin and narcolepsy * A common cause of narcolepsy is a mutation in the
HLA antigen
leading to autoimmune disease against orexin neurons
91
Knockout mice for orexin develop
narcolepsy
92
Orexins and wakefulness
Orexinergic neurons receive indirect input from suprachiasmic nucleus (SCN) – important in
circadian rhythms
93
Orexin projects to systems involved in wakefulness (4)
* Locus ceruleus norepinephrine systems
* Dorsal raphe seratonin systems
* Tuberomamillary histamine systems
* Basal forebrain cholinergic system (BFCS)
94
Locus ceruleus
norepinephrine systems
95
Dorsal raphe
seratonin systems
96
Tuberomamillary
y histamine systems
97
Orexin activity increases just before
e waking, orexin neurons are more active during wake period
than sleep
98
In mouse models optogenetic stimulation of orexin neurons cause
waking within several second
99
Pharmacological target for sleep disorder Suvorexant
an OX receptor antagonist (dual orexin receptor
antagonists, DORA) for insomnia treatment
- contraindicated in patients with narcolepsy
100
Almorexant
a DORA developed by GlaxoSmithKline –
discontinued in 2011 during phase III trials for unspecified reasons (likely
adverse side effects)
101
Orexins and addictions
As with the other orexigenic peptides, orexin is implicated in addictions
102
As with the other orexigenic peptides, orexin is implicated in addictions - Expected as the systems interact in the
ARC of hypothalamus
103
As with the other orexigenic peptides, orexin is implicated in addictions Interactions with the
dopaminergic reward pathways in VTA
104
* OX receptor antagonists decrease
self-administration of alcohol, opiates,
nicotine
105
Administration of orexin into the lateral hypothalamus results in
increased
alcohol consumption or reinstatement of extinguished alcohol or nicotine
seeking
106
Orexins and emotional memory Orexinergic neurons receive inputs from the
limbic system
107
Orexinergic neurons receive inputs from the limbic system
Modulate physiological responses to emotional stimuli
108
* Orexin k/o mice show
decreased responses to intruder mice, air-jet stress
109
OX receptor antagonists
decrease cue-conditioned fear responses
110
Human narcolepsy patients show
diminished autonomic responses to emotional
stimuli, esp. aversive
111
* Altered orexin levels observed in patients with
anxiety or PTSD
112
Orexins and emotional memory Proposed to maintain
n wakefulness in response to emotional arousal via limbic
inputs
113
Orexins in motivational activation
Orexins interact with systems involved in both wakefulness/arousal and reward, motivation, and
salience (dopamine!)
114
Roles of orexin in food intake and wakefulness suggest
involvement in motivational activation
115
Phasic orexin activity increases during
adaptive behaviour
116
During food deprivation orexin stimulates
food seeking behaviour
117
Orexins facilitate reward seeking only when
motivated by an underlying physiological (e.g. hunger)
or psychological need (e.g. cues, stressors)
