Food intake Flashcards
1
Q
what is the formula for BMI?
A
weight kg / height m ^2
2
Q
what BMI value is the obesity cut off?
A
30
3
Q
name the health risks associated with obesity
A
type 2 diabetes
cardiovascular disease (hypertension and hyperlipidemia)
sleep-breathing abnormalities (apnea)
gallstones
menstrual irregularities
cancer (colon, endometrial)
4
Q
which 3 brain areas are mostly involved in energy balance
A
hypothalamus, ventral tegmental area, brainstem
5
Q
what system is the ventral tegmental area part of?
A
hedonic system: increases want for food and pleasure
6
Q
from what organs does the homeostatic system for energy balance get input?
A
adipose tissue, pancreas, intestine, stomach, liver
7
Q
which 4 hypothalamic regions regulate food intake?
A
3rd ventricle, dorsomedial nucleus, ventromedial nucleus, arcuate nucleus
8
Q
what is the consequence of lesioning PVN, VMN or DMN?
A
increase in food intake
9
Q
what is the consequence of lesioning lateral hypothalamic area LHA?
A
reduced food intake
10
Q
what is the defect in ob/ob mice? how do we know?
A
ligand (leptin) defect (because when fused with a WT mice, its weight normalizes because it gets the ligand from wt)
11
Q
what is the defect in db/db mice?
A
receptor defect (because when fused with a WT mice, its weight doesn’t normalize and the other (WT or ob/ob) mice dies)
12
Q
what can restore normal body mass in ob/ob mice?
A
leptin
13
Q
what criteria are required for leptin treatment to help loos weight?
A
patient is leptin-deficient or of normal weight
14
Q
what is one cause of obesity we talked about?
A
leptin resistance
15
Q
leptin receptor is in which family?
A
type 1 cytokine receptor family
16
Q
what are the 2 neurons subpopulations in hypothalamus involved in energy balance? location? function?
A
both in Arc
NPY/AgRP neurons: increases food intake
POMC: decrease food intake
17
Q
these Arc neurons subpopulations interact with what receptor?
A
MC3/4R
18
Q
how did they find that NPY and AgRP were expressed in the same neuron population?
A
immunohistochemistry
19
Q
how does Cre work?
A
Cre is a site-specific DNA recombinase that catalyses the recombination of DNA between loxP sequences
20
Q
where do we find the most leptin receptors? what other receptors are found there?
A
Arcuate nucleus.
leptin, insulin, ghrelin, nutrients
21
Q
where else did we find some leptin receptors?
A
hypothalamus: POA, VMH, DMH
brainstem: NTS
22
Q
through which nucleus are the hypothalamus and brainstem connected?
A
PVH -> NTS
23
Q
what happened to mice in which we KO leptin receptors on POMC or AgRP neurons?
A
development of mild obesity
24
Q
what happened to mice in which we KO leptin receptors on VMH neurons?
A
development of very mild obesity
25
what was the difference between whole-body LepRKO and neuron-specific LepRKO mice?
whole-body LepRKO had severe obesity
neuron-specific LepRKO had mild obesity
26
does leptin action on excitatory or inhibitory neurons prevent obesity?
GABAergic inhibitory neurons
27
what cells are the only known LepR neurons that are GABAergic and contribute directly to obesity?
AgRP neurons! but their effect is mild
28
what happened to AgRP expression in AgRP neurons in the Arc when mice are fasted?
increased AgRP expression
29
with what technique did they find AgRP activity?
genetically encoded calcium indicator with GFP and optogenetics
30
what happens to AgRP neurons of fasted mice when they encounter food?
activity rapidly goes down (but it goes back up if they are given false food)
31
what channel do they use for optogenetics?
rhodopsin channel
32
were mice attracted to or avoided food associated with AgRP neurons activation? what does this mean?
avoided... means AgRP neuron activity has negative value
33
what is leptin's primary role?
serve as metabolic signal of energy sufficiency rather than excess
34
what does low leptin levels signal?
low energy -> need to eat!
35
why are excessively lean women infertile?
decreased gonadal hormone due to lack of leptin (due to lack of fat) delays ovulation
36
why are obese women infertile?
too much leptin causes leptin resistance
37
how does leptin treatment help too lean women gain fertility back?
diminishes the fall in hormone levels and improves reproductive function
38
where does ghrelin come from and where does it act?
from stomach / GI tract. acts on AgRP Arc neurons
39
are there other known orexigenic gut hormones?
no ghrelin is the only one
40
describe ghrelin
- 28 amino acid acylated hormone
- appetite-stimulating activities
- growth hormone-releasing activities
41
ghrelin is the endogenous ligand of what receptor?
GHSR growth hormone secretagogue receptor
42
when do ghrelin plasma levels rise / fall?
rise during fasting and immediately before meals.
fall within an hour of food intake.
43
what does ghrelin induce in mice?
food intake and weight gain (adiposity)
44
when is the peak ghrelin? what varies between subjects?
right before we start eating. the peak amplitude can vary but not the timing
45
why do we think ghrelin is involved in the rebound weight gain?
because plasma ghrelin increases significantly after diet-induced weight loss
46
what is the most efficient way to treat obesity?
gastric bypass surgery
47
how can ghrelin help cancer patients?
can help them increase energy intake
48
what data indicate a link between homeostatic and hedonic control of food intake?
leptin receptor expression in mesolimbic dopamine (reward) system like VTA and nucleus accumbens
49
drug abuse increase which connections? what food also does this?
dopaminergic transmission from VTA to nucleus accumbens.
highly palatable food.
50
do VTA and NA express leptin receptors?
yes
51
what is different between obese vs control people when they are presented high-calorie food?
great activation of nucleus accumbens
52
what is leptin's effect on feeding-induced dopamine release in NA?
reduces dopamine release in nucleus accumbens
53
what is the effect of direct leptin administration on the VTA of rats?
reduction of food intake.
it can normalize enhanced neuronal activation in 7 days
54
what is ghrelin's effect on how we see food? how?
ghrelin dramatically increases the value of food by increasing hedonic activity response to food
55
briefly why do we like palatable (high sugar) diet?
mice can detect calories and prefer high-caloric water, even unsweetened slide 28
56
what happens in mice barrel cortex?
dendritic spine turnover in pyramidal neurons
57
during what 2 processes do we observe plastic changes in the hypothalamus?
parturition and lactation
58
what neurons in what hypothalamic regions experience plastic changes during parturition and lactation?
magnocellular oxytocin neurons in PVN and SON
59
what exactly happens to SON neurons during stimulation (lactation)?
retraction of astrocytic processes allow inter-synaptic cross-talk interactions between neurons
60
are AgRP or POMC neurons oxerigenic (induce appetite)?
AgRP = orexigenic
POMC = anorexigenic
61
what is different with ob/ob mice AgRP and POMC neurons compared to WT?
they had more excitatory synapses in AgRP and less excitatory synapses in POMC! AgRP neurons were more active therefore always hungry
62
how does leptin treatment affect ob/ob mice AgRP and POMC neurons?
silences (diminish excitatory synapses) AgRP neurons.
excites (increase excitatory synapses) POMC neurons.
63
what is different about ob/ob mice neuronal connections?
less processes between Arc and PVN (less communication)
64
what does leptin do to ob/ob mice neuronal connections?
promotes neurite outgrowth from Arc
65
basically what are the 3 ways in which leptin affects the hypothalamus?
1. binds to LepR and effect production and release of neuropeptide AgRP and POMC product
2. rapidly changes number of excitatory vs inhibitory synapses that input on AgRP and POMC neurons.
3. induces neurite outgrowth of Arc to PVN
66
what is different about obesity-resistant vs obesity-prone rats neuronal circuitry?
obesity-resistant rats have more processes from arc to PVN.
obesity-prone rats (DIO) have defective Arc projections
67
what brainstem nucleus mainly regulates diverse physiologies? what does it regulate?
NTS;
food intake, heart rate, breathing, taste
68
in what types of disease is NTS dysregulation highly observed? what does it lead to?
cancer: leads to anorexia
69
what is clearly affecting cancer patient's survival?
cachexia (weight loss in cancer)
70
what is GDF-15?
tumour-secreted factor that is increased under in
a range of cancer types
71
what pathogenic states is GDF-15 involved with?
infection, hepatic fibrosis, mycotoxin exposure (food indigestion)
72
critical feature of cancer pathogenesis that increases GDF-15 mRNA protein levels?
hypoxia development within the tumour
73
how does hypoxia increase GFD-15?
through an ER stress-dependent pathway involving TF CHOP. the tumour itself secretes GDF-15
74
what happens if you KO CHOP TF in states of ER stress and hypoxia?
reduce induction of GDF-15
75
what does a single dose exogenous GDF-15 do?
reduction of food intake and body weight after more doses.
also induces aversion, nausea, and emesis
76
do all tumors reduce body weight and appetite?
no! only GDF-15 tumors (cachexic tumours)
77
what is elevated GDF-15 levels associated with?
worse clinical outcome
78
what happens with you reduce GFRAL? (GDF-15 receptor)
GDF-15 stops affecting body weight
79
where is GFRAL expressed?
in AP area postrema/NTS cells in the brainstem. not expressed in other feeding centers nor in hypothalamus
80
what happens if we KO GDF-15 and/or GFRAL in mice? what can we conclude
mice keep normal energy balance and weight.
GDF-15 and GFRAL is really a parallel pathway.
81
where do AP GFRAL neurons project to?
to PBN parabrachial nucleus, terminate in external lateral compartment of the PBN. no where else! not in hypothalamus!
82
what else is expressed in elPBN neurons? what happens if we activate them?
CGRP neuropeptide.
activating CGRP neurons = reduced body weight and food intake, promotes aversive behaviours
83
what can activate CGRP PBN neurons?
- pathogenic states, tested by giving gut irritant and bacterial cell wall component to mice -> activated CGRP
- tumour cells implantation
84
what happens when we silence CGRP PBN neurons in cancerous mice? what can we conclude
no weight loss! shows that cancer acts through CGRP neurons and that CGRP PBN neurons are not required for normal body weight
85
how does exogenous GDF-15 affect CGRP PBN neurons?
what about activation of GFRAL AP neurons?
they both activate CGRP PBN neurons! confirms the pathway of AP NTS direct projections to PBN
86
what does silencing CGRP PBN neurons do?
increases food intake! diminishes GDF-15 anorectic properties
87
where does the PBN CGRP neurons project to to reduce food intake?
CeA central amygdala!
88
what molecule can activate PKCd neurons in CeA? what effect does this have?
GDF-15 can directly activate PKCd neurons in CeA.
reduces food intake
89
what are the pathogenic signals that activate CGRP PBN cells?
LPS, LiCl, tumour implantation
90
what are the anorectic and aversive properties of GDF-15 dependent on?
CGRP PBN cells
91
NTS receives physiologic signals from where?
gut, pancreas, leptin
92
describe the signals and pathway from stomach to brain after a meal
mechanosensors sends lumen distension signal & enteroendocrine cells EECs send meal composition signal to the brainstem via nodose
93
what do EECs express?
more than one class of chemical receptors
94
what is the consequence of activating EECs (Cck neurons) with CNO?
reduces food intake
95
how are nodose (NDs) neurons activated in the stomach vs intestine?
in the stomach: same neurons can be activated by stretch and food
in the intestine: different neurons for stretch vs food
96
what did injecting retrograde tracers in nodose neurons show?
each nodose neuron specifically project to individual GI tracts site
97
where do nodose neurons project to in the brain?
AP and NTS in brainstem.
they also communicate with DA neurons of the VTA and SNc
98
what happens if we cut the vagus nerve? what does this mean?
decreases the fat/sugar-mediated NTS neurons activation;
therefore vagus nerve is necessary for NTS response to nutrients
99
what is the effect of stimulating NTS projections from nodose?
decrease of food intake
100
remember: what happens if we put infused nutrients in the stomach? (related to AGRP neurons)
rapidly reduces AGRP neuron activity
101
probably how do NTS neurons affect AGRP neurons?
they reduce AGRP neurons activity. this would be how they reduce food intake
102
2 characteristics of the nodose -> NTS pathway
anorectic and rewarding/reinforcing (involves DA)
103
what increases in the striatum after NTS stimulation?
dopamine levels! shows that reward is involved. mice like NTS stimulation therefore we like to eat
104
what is amylin?
hormone produced by pancreatic beta cells, co-secreted with insulin after a meal
105
what receptor does amylin bind to?
calcitonin receptor in AP/NTS
106
what are the similarities vs differences between CCK and Calcr NTS neurons?
same effect (reduce food intake and BW),
however Calcr activation doesn't cause aversion.
107
what causes the difference in aversion properties between Calcr and CCK NTS neurons?
different circuitry (project to different regions of PBN neurons)
108
remember: what does activating NTS LepR neurons do?
reduces food intake and BW
109
what is pramlintide?
an amylin agonist that reduces body weight. acts on the NTS
110
what does the treatment of antagonizing GDF-15 do?
decreases weight loss, anorexia and emesis.
can increase survival in a mouse cancer model!
111
what is GLP1 and its effect on body weight?
produced by L cells in GI,
has a half life of 2 minutes, acts on the brainstem, especially area postrema.
it decreases body weight in obese humans
112
what drives the aversion effect of GLP1?
GLP1 R area postrema
113
basically, what are the existing obesity therapeutics (cancer anorexia and survival target)?
brainstem CALCr and GLP1 receptors
114
what is the site of the most successful anti obesity therapeutics?
the brainstem
