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Neuropharmacology > Body weight > Flashcards

Body weight Flashcards

1
Q

What is energy balance?

A

When energy intake equals energy expenditure

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2
Q

Why was BMI created?

A
  • In 1930s incurance companies wanted to determine how likely someone was to die
  • The best determiner of this was BMI
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3
Q

What is the healthy BMI range?

A

17.5-25

Either side of this likelihood to die increases exponentially

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4
Q

How do you work out BMI?

A

Kg/m^2

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5
Q

What BMI is clinically obese?

A

Above 30

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6
Q

What is a different way to look at body morphology besides BMI?

A

Waist to hip ratio

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7
Q

What are the good values for waist to hip ratio for men and women?

A
  • Men, less than 0.85
  • Women, less than 0.80
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8
Q

When over 30 BMI what are some co-morbidity risks?

A
  • Diabetes x7 in men and x28 in women
  • Cardiovascular disease x3
  • Sleep apnea x3
  • Some cancers such as ovarian, uterine and bowel
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9
Q

How much a year does it cost the NHS to treat obesity comorbidities?

A

10 Bill

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10
Q

What has caused the increase in obesity over the years?

A

Genes haven’t changes much therefore the changing environemnt and where the genes are acting is causing this.

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11
Q

What is the hetirability of obesity?

A

70%

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12
Q

What did GWAS of BMI show?

A
  • Certain loci have different associations with BMI
  • Lots of different genes involved
  • Willer et al 2009
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13
Q

What was an exciting gene discovered in GWAS studies and why?

A
  • FTO
  • Huge amount of variation in terms of BMI but changes are small
  • In KO mice, only 1-2% change
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14
Q

Where are genes showing associations with BMI expressed?

A

In the brain

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15
Q

Where are genes for waist to hip ratio found?

A

Expressed in adipose tissue

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16
Q

Who discovered the importancce of the brain in metabolism?

A
  • Clause Bernard
  • Stimulated different parts of a dog brain
  • If stimulate a part of the spinal cord, increased circulation of blood glucose
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17
Q

What happens in patients with cancer causing the expansion of the pituitary gland?

A
  • Frolics syndrome causing obesity
  • KO pituitary in dogs- no change in body weight
  • The pituitary is pushing against the hypothalamus
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18
Q

What is the dual centre theory?

A
  • 1940s did a set of experiments, made bilateral electrolytic lesions in the ventromedial hypothalamus
  • Rat got fat
  • If made in the lateral part, the rats lost weight
  • During the 1990s they could identify the neurons in these areas which were a good basis for the theory
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19
Q

What is the homeostasis and set point theory for body weight?

A
  • There is a sensor
  • Controller (hypothalamus?)
  • And effector (eating, metabolism)
  • These cause a body weight set point like blood glucose levels and temperature homeostasis
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19
Q

Does the homeostasis and set point theory for body weight hold up?

A
  • No
  • More variation per person in weight, if there was a set point, there wouldn’t be obesity
  • Cannot measure our body weight intrinsically
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20
Q

What is the settling point theory?

A
  • Body weight is determined by input and output
  • The level of output (energy expenditure) is determined by weight
  • If eat more, weight increases and so will energy expenditure as have more tissue to maintain (direct proportion)
  • If eat less, energy expenditure goes down
  • We reach a settling point as body weight is proportional to unregulated input
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21
Q

What is the dual intervention point model?

A
  • The settling theory holds between a certain range
  • If body weight is too low, we hit the lower intervention point- cannot lose more weight as won’t grow, reproduce and will die
  • If body weight is too high we hit the upper intervention limit. Would become a prime target for predators and cannot hunt etc
  • Genetic factors detemine the intervention points. However, the evolutionary pressure for the upper intervention point has been removed allowing genetic drift and obesity
  • Speakman et al 2011
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22
Q

What two theories did electrolytic lesioning lead to?

A
  • Hypothalamus responds to short term signals such as glucose (Sean Mayer)
  • Static theory suggesting that hypothalamus responds to longer term regulators such as fat tissue, measuring the energy that is being stored (Gordon Kennedy)
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23
Q

What did the electrolytic short term signal theory suggest?

A
  • As glucose drops, the hypothalamus detects this and we eat (glucose static theory)
  • Isn’t necessarily true
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24
Q

Outline support for the static theory?

A
  • Bred a large mouse, hyperphagic and diabetic (Db/Db) who had a single gene mutation
  • Bred another large mouse with different genes Ob/Ob
  • Because the phenotype was so similar for the two mice, must be a similar pathway?
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25
Q

Outline the parabiosis experiment in support of static theory

A
  • Douglas Coleman took Ob/Ob mouse and joined its circulation to a normal mouse
  • Ob/Ob mouse lost weight, suggesting there must be a factor in the circulation which it is missing
  • Same with Db/Db mouse, it did not lose weight but the joined mouse did rapidly
  • Db/Db has lots of the factor, so much so that it could lend some and the mouse lost weight. Perhaps obese due to a receptor mutation
  • When Ob/Ob and db/db connected, ob/ob lost weight as got the factor from db/db
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26
Q

What was discovered to be the factor in which ob/ob mouse was lacking?

A
  • Ob gene encodes for leptin
  • Leptin is produced in white adipose tissue
  • Acts as a permissive hormone for things such as growth and the lower intervention level
  • If introduce leptin into the brain can get rid of the obese phenotype
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27
Q

Explain where leptin deficiency has been seen in humans

A
  • Montague et al 1997
  • Early onset obesity
  • Bood test showed mutation in the leptin gene
  • Injected with recombinant leptin- feeding and body weight dropped immediately
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28
Q

Is leptin deficiency a common form of obesity?

A

No

Normally late onset not early onset obesity

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29
Q

What neurons in the brain are a target for leptin?

A
  • Arcate nucleus
  • VMN
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30
Q

What cells in the arcate nucleus are targetted by leptin and how do we know this?

A
  • Leptin induced phospho STAT3
  • Showed pom C cells
  • Also SF1 transcriptoin factor
  • Hosoi et al 2002
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31
Q

What is creocombinase?

A

Bacteriophage enzyme

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32
Q

Explain what the cre-lox system showed about pom C cells and leptin?

A
  • Made pom C creocombinase (normal expression of pom-Cre)
  • Inserted Lox P into exon 17 of other mouse creating flox mouse
  • Cross the two mice, get both trans genes expressed in the same cell
  • The creocombinase cutes the lox P sites and mutates the leptin receptor
  • Study the offspring
  • With both genes, the offspring were obese- leptin receptors in this neuronal site are important for regulation
  • Balthasar et al 2004
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33
Q

Where have POMC mutations been discovered?

A
  • Issues in the pathway of POMC in pituitary
  • POMC
  • Peptide convertases
  • Melanocortin receptors
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34
Q

What does the VMN contain?

A

Leptin receptor and Sf1

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35
Q

What happened if there were no leptin receptors in the VMN?

A

They no longer responded to leptin

  • Dhillon et al 2006
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36
Q

What happened if SF1 neurons were KO’d in the VMN

A
  • Flox for SF1 and Leprin were obese
  • Dhillon et al 2006
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37
Q

What happened to Sf1-Cre, Pom-cre, lepr mice?

A
  • The most obese
  • Dhillon et al 2006
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38
Q

What is appetite?

A

Any desires to fulfil bodily needs

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39
Q

What is appetite in relation to hunger?

A

To eat food driven by hunger and fulfil the bodies metabolic needs (homeostatic feeding)

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40
Q

What is Ghrelin?

A
  • Hormone isolated in 1999
  • Natural ligand for synthetic growth hormones
  • Produced in the stomach due to pre hormone
  • Is the acetylated version which binds to serine 3 amd produces appetite controlling effects
  • Desacyl ghrelin also circulates
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41
Q

How is Ghrelin acetylated?

A
  • By Ghrelin O-acetyltransferase (GOAT)
  • Adds an octanoyl group
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42
Q

What is ghrelin’s circulation profile throughout the day?

A
  • At each mealtime, there is a increase in the amount of circulating ghrelin
  • Because it is released from the stomach, may be a hunger hormone
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43
Q

What happens if ghrelin is injected into the circulation or brain?

A

Increased food intake

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44
Q

What neurons does ghrelin act on?

A

Archaic nucleus neurons AgRP in hypothalamus

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45
Q

What transcription factor do the NPY, AgRP and GABA neurons release in the archaic nucleus after injected with ghrelin?

A

Fos C- useful marker for cellular activity

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46
Q

What can be given to reduce the effects of ghrelin?

A

NPY antagonist

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47
Q

What neuron has opposing effects to AgRP, explain.

A
  • AgRP increase feeding and decrease energy expenditure
  • POMC decrease feeding and increase energy expenditure
  • Respond to the same input but in opposing directions
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48
Q

What are AgRP neuron inhibited by?

A

Leptin

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49
Q

What areas to AgRP and POMC project to in the hypothalamus?

A
  • PVN
  • DMN
  • Act on cells with receptors for NPY and melanocortin
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50
Q

What is a breakdown product of POMC which has opposing effects to AgRP?

A
  • MSH
  • Is an agonist at MC4 melanocortin
  • AgRP is an antagonist at this receptor
  • Functional antagonisms between the target neurons
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51
Q

Explain the channel rhodopsin-assisted circuit mapping of POMC and AgRP

A
  • Create AgRP-Cre mouse
  • Normally, cre cuts the single lox p site but if use two different types of lox in an antiparallel formation, cre flips it into the other orientation and recombines in the same point
  • Then inject an adeno-virus containing rhodopsin into the archaic nucleus
  • Trans fene is flipped so the AgRP cells only express channel rhodopsin and red fluorescent indicator
  • Also crossed cre with POMC
  • Drove the expression og a green fluorescent marker, to show that channel rhodopsin is only expressed in the AgRP neuron
  • Scott Stoneston
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52
Q

Using optogenetics, how did they do channel rhodopsin-assisted mapping for AgRP?

A
  • Put optical fibre above the nucleus to pulse blue light into the brain and picks up channel rhodopsin
  • Saw an increased food intake when pulsing for an hour
  • Aponte et al 2011
  • Then encorporated into the membrane of neurons and transported down axons to stimulate the terminals of neurons
  • Put an optic fibre into areas where AgRP was projecting to
  • Stimulated the terminals
  • Found PVN increased in feeding and PBN no increase
  • Saw where the AgRP neurons project to
  • Atasoy et al 2012
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53
Q

What are 4 areas that AGRP/NPY neurons project to and 3 that they don’t based on channel-rhodopsin mapping studies?

A

DO
- BNST

  • PVN
  • LHA
  • PVT

DON’T
- PAG

  • CEA
  • PBN
  • Atasoy et al 2012, Betley et al 2012
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54
Q

How is it suggested (2 ways) that AgRP neurons cause increased feeding?

A
  • Targets for AgrP neurons contain sim1 transcription factor and perhaps oxytocin
  • AgRP neurons are inhibitory as are these neurons. Inhibition of these causes disinhibition of the PAG causing feeding
  • Alternatively, another population of MC4 receptors (which AgRP target) are excitatory and project to the PBN
  • Neurons here cause satiety. So when inhibit, we stop the activation of the satiety neurons and get feeding
  • Stachniac et al 2012, Garfield et al 2015
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55
Q

Outline how fibre photometry is used in studying AgRP

A
  • Record the activity of AgRP in normally behaving mice
  • Neurons of interest express activation dependent calcium
  • Most increase calcium when become activated
  • Took the cre animals and crossed with a calcium indicator (GCAMP)
  • Only the AgRP neurons could flip the GCAMP into the right orientation
  • Optic fibre shines excitatory light wavelengths into the brain and is picked up by the indicator
  • Light is emitted on a different wavelength depending on how much calcium is in the cell (more calcium means more reflected wavelength)
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56
Q

Outline the study that found AgRP neurons are inhibited by food detection

A
  • First experiment was in fed animals, expect AgRP to be lower
  • Measured the calcium in these neurons and injected saline (nothing happened) and ghrelin (AgRP was activated)
  • If provided the animals with food at the same time as ghrelin, activity dropped
  • Experiments in fasted animals. Placed food into the cage, activity of AgRP drops immediately
  • Suggestion that these neurons don’t conteol eating itself but telling the animal to go and find food
  • If the animal eats, the activity remains low but if they don’t it increases
  • Repeated this in fed animals, Presenting with food doesn’t make a difference

Chen et al 2015

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57
Q

How was conditioned place preference study used to determine whether ghrelin cause negative or positive valence?

A

Pre-test
- Mouse roamed freely between the chambers for 20 mins and preffered side was measured

  • Put animal into the preferred side and give ghrelin but it cannot move (20 mins), repeat 3 times
  • Inject the mouse with saline in the non-preferred side (20 mins), repeat 3 times
  • measure how much food they eat when returned to cage

Test
- Mouse freely choses which chamber it wants to be in

  • Mouse spent less time in the preffered side with ghrelin- negative valence as hunger
  • When put back in its cage, mouse ate more after ghrelin compared to saline injections
  • Schele et al 2017
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58
Q

Explain the closed loop conditioned place preference for ghrelin

A
  • Similar to place preference
  • During conditioning, the animal is free to roam but when in the preffered side, stimulate AgRP neurons
  • After the conditioning, in the test, lost the preference for side showing the AgRP neuron is causing negative valence
  • Betley et al 2015
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59
Q

What are the direct regulators of feeding?

A
  • Feedforward and feedback mechanisms
  • Food is in the mouth, we chew, then swallow, then move along digestive tract (feedforward)
  • As we continue to eat feedback tells us when we have reached satiation
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60
Q

Where are the direct regulators of feeding located and whats the proof?

A
  • Neuronal apparatus are part of the atrial region of the brainstem
  • Because it is an automated process
  • Did work on a decerebrate rat, if put food into the rats mouth would continue to eat until it reached satiation
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61
Q

What is satiety?

A

Period between meals when we don’t have hunger

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62
Q

What are the indirect regulators of feeding and what do they rely on?

A
  • Environmental cues such as…
  • How much glucose is in the blood stream
  • Stored energy (in fat tissue)
  • If food is available
  • Time of day
  • These need higher brain centres and won’t work in decerebrate animals
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63
Q

What are hormones released by the stomach called?

A

Enteroendocrine cells releasing peptide hormones

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64
Q

When are enteroendocrine cells release their peptide hormones?

A

When we are full

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65
Q

Where are enteroendocrine cells located?

A
  • Dispersed in the epithelial lining of the gut
  • Are sparse with an apical surface pointing into the lumen and sense nutrients in the gut
  • Can act as paracrine hormones on local cells
  • Some enter general circulation and act as endocrine hormones
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66
Q

What is the primary substance that enteroendocrine cells detect?

A

Triglycerides (esters of glycerol and long chain fatty acids)

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67
Q

Whats an 8 carbon chained triglyceride called?

A

Octanoic acid

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68
Q

Whats an 10 carbon chained triglyceride called?

A

Decanoic acid

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69
Q

Whats an 12 carbon chained triglyceride called?

A

Dodecanoic

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70
Q

What is the fatty acid cut off point for the release of CCK?

A

C12, C18

McLaughlin et al 1999

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71
Q

What are most dietary fatty acid lipid chain lengths?

A

> C14

McLaughlin et al 1999

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72
Q

Why is C12 around the cut off for CCK?

A
  • Human body temperature is 37 degrees
  • C12 melting poing is 42 degrees whereas C11 is 34 degrees
  • McLaughlin et al 1999
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73
Q

How does CCK act to cause breakdown of fatty acids?

A
  • Breaking down relies on bile salts from the gall bladder
  • CCK directly acts on the gall bladder causing the release of bile to solubilise hydrophobis, long-chain FAs
  • Also release of enzymes from the acini site in the pancreas
  • Causes a reduction in gastric emptying, slows down the rate at which food leaves the stomach and regulates flow
  • Also signals when we have eaten a meal to clock when full
  • McLaughlin et al 1999
74
Q

Where are CCK receptors found and how this was found?

A
  • In the nerve terminals of the vagus nerve
  • Nodose ganglion is near the brain- can stain transportation into the cell bodies
  • Can co-stain cells for CCK-1 transported down to the gut enabled by vagus terminals
  • They are bipolar, one axon detecting gut and a second to the brainstem in the medulla oblongata nucleus tractus solitarus
  • Dockray et al 2009
75
Q

How does the medulla oblongata control satiety through CCK?

A
  • CCK signal to medulla oblongata via nodose ganglion of vagus nerve
  • Medulla oblongata signals to PBN, PVN, areas of the dorsal, vagal complex
  • Inhibitory synapse between DMX and NTS reduces stomach emptying
  • Controls signals back to the stomach through reflex arcs in the direct regulation of feeding
76
Q

Where are Prolactin-releasing peptide (PrRP) neurons found?

A

Expressed in the NTS

77
Q

What are PrRP neurons activated by?

A

CCK neurons

Lawrence et al 2002

78
Q

Explain the LSL-PrRP x cre transgenic mice study

A
  • Conditional KO mice- stop codon in front of PrRP gene
  • Either side of the stop codon is lox c
  • Cross animal with cre, cut away the stop codon and get re-expression
  • Then add nestin-cre expression (expressed in all all brain cells), re-expression of PrRP in all the brain regions should be epressed
  • Then add TH-cre (catecholinergic neurons), cross with these neurons, which shows expression only in the brainstem region
  • Wild type CCK had a reduction in food intake
  • Knock out is no longer effective, response comes back, hypothalamus may be more important with energy expenditure
  • With Th-cre. response comes back with brainstem neurons showing brainstem importance
  • Dodd et al 2014
79
Q

Explain the PrRP-cre DREADD experiment

A
  • PrRP-cre crossed with DREADD
  • Only get expression of designer receptor in the neurons when crossed
  • In the NTS, switch on CNO neurons
  • PrRP, through CNO can stop the animal and mediate natural stiety from the brain
80
Q

Where is CCK produced?

A

Proximal gut

81
Q

Where is PYY produced?

A
  • Colon- far back in the gut
  • Is a glucagon-like peptide
82
Q

What is a suggestion of temporal PYY release?

A
  • Released into the blood stream before food reaches the colon
  • Could be a reflex arc of CCK
83
Q

What happens if high doses of PYY are given?

A

Nausea

84
Q

What happens to the behavioural satiety sequence when given LiCL?

A

Causes nausea, completely disturbing the sequence

85
Q

What happened to the behavioural satiety sequence when given PYY?

A
  • Acts on Y2 receptor located on NPY neurons (is an autoreceptor)
  • Maintains the sequence but shifts it to the left
  • When give Y2 antagonist with PYY, returns to the vehicle
  • Scott et al 2005
86
Q

Explain how triglycerides cross the epithelial membrane

A
  • Cross the epithelial membrane as get broken by lipases into monoglycerides
  • Then reformed on the other side by fatty acid binding proteins in the endoplasmic reticulum
87
Q

How does orlistat work?

A

Stops the lipase from breaking down triglycerides

They then pass out through the body without being digested

88
Q

What is redux?

A
  • Seretonin releaser
  • Popular in the 70s and early 80s
  • 30 mill prescriptions in the US alone
  • Was good at causing weight loss but people were dying of cardiac valve disease
89
Q

What is sibutramine?

A
  • An SSRI
  • Effective at causing weight loss
  • Contrary indicated against people with susceptibility of heart problems
  • Removed from the market as higher incidence of heart attack and strokes
90
Q

What is Lorcaserin?

A
  • Is a selective serotonin receptor agonist for 5HT2C
  • Were no issues in clinical trials
  • But caused dizziness, headaches and possibly some types of cancer
91
Q

What was the idea when creating drugs targeting the cannabinoid system to combat obesity?

A
  • THC mimics the effect of the natural cannabinoid system
  • Feeling reward and euphoria leading to the muchies
  • If block these receptors using functional antagonist or inverse agonist, could reverse food intake?
92
Q

What is rimonabant (as a drug treatment?)

A
  • Blocks cannabinoids
  • People on the drug were suffering from depression as they block the reward pathways in the brain indiscriminately
93
Q

What are 3 bariatric surgeries for obesity?

A
  • Adjustable gastric banding
  • Vertical banded gastroplasty
  • Roux-en-Y gastric bypass
94
Q

Outline how an adjustable gastric band works?

A
  • A band around the stomach to produce a small pouch
  • People eat more slowly and point of satiation is reached more quickly
  • The band is adjustable so can change the size over time and is also reversibe
95
Q

Outline vertical banded gastroplasty

A
  • Involved a band and stapling to reduce the stomach size
  • Further advancement called a sleeve gastrectomy is where they completely remove the greater curvature of the stomach
96
Q

Outline Roux-en-Y gastric bypass

A
  • Aim is to reduce the area where nutrients are absorbed
  • Stapling to produce a stomach pouch and missing out the duodena
  • Nobody knows why its successful, people beleive its not down to nutrient reabsoption but changing the repetative behaviour
97
Q

How does a roux-en-Y gastric bypass change hunger and fullness?

A
  • Instantly report higher feelings of fulless and lower hunger
  • may be because changing the number of hormones being released by the gut
  • Release of PYY goes up rapidly in the direction which would cause a reduction in hunger
98
Q

Do hormones have a role in bariatric surgery?

A
  • Huge variation in results
  • Overall think that they do
99
Q

How does a gastric bypass change glycaemic control?

A
  • Long lasting improvement in glycaemic control
  • More so than pharmacological treatment
  • Could be due to gut hormones such as glucagon peptide 1
  • Mingrone et al 2012
100
Q

Why is leptin not a good hormone to target pharmacologically?

A

People who are overweight produce a lot of circulating leptin but they become resistant to the hormones

101
Q

Why is PYY a good hormone to target phamacologically?

A

Clinical studies show that it is at low cocentrations in obese people. They are still responsive to it

102
Q

What is the effect of PYY in lean vs obese patients?

A
  • Both reduce food intake
  • Also effect hunger
  • If give patients a meal, over the following hoursm hunger scores go up but if give PYY, the scores stay low
  • Batterham et al 2003
103
Q

What happens when ghrelin and PYY are given in conjunction?

A
  • The effect of ghrelin is reduced and food intake is still reduced
  • Action on the AgRP NPY neuons in the archaic nucleus
104
Q

What is PYY-36 a selective agonist for?

A

Y2 NPY inhibitory autoreceptor found on all NPY neurons in the brain including the AGRP neurons in the archaic nucleus

105
Q

What is NN1273?

A
  • Experimentally made by Novo
  • Has a great affinity for Y2
  • Longer half-life in the bloodstream than PYY
106
Q

What is a problem with PYY and its affinity?

A
  • PYY doesn’t just bind to Y2 but also Y1 and Y3.
  • These NPY receptors have the opposite effect on food intake and increase it instead
107
Q

What were the findings of NN1273 studies?

A
  • Implanted mice with osmotic pumps which can administer drugs overtime
  • Can show that there is a dose dependent reduction in body weight of mice receiving NN1273
  • Some mice aren’t given any of the drug but the same amount of food as the animals receiving the drug
  • They lose the same amount of weight suggesting a loss in appetite and not energy expenditure
  • Jones et al 2019
108
Q

What happens if CCK is infused in patients?

A
  • Get a reduction of the size of individual meals
  • Then feedback suggests that not enough energy has been taken on
  • Compensates by eating more meals
  • No change in body weight
109
Q

What is the solution to problems with CCK infusion?

A

Administer intermittently

110
Q

What happened when infused with natural CCK while eating?

A
  • Hunger drops
  • Fullness goes up
111
Q

Where are the effects of CCK mediated?

A

Receptor 1

112
Q

What is loxiglumide?

A

CCK1R antagonist

113
Q

What happened when loxidlumide was paired with CCK while eating?

A

Combatted the effects of CCK and scores of hunger and fullness went back to normal

114
Q

What is NN9056?

A

An analogue of CCK with a greater half-life in the bloodstream

115
Q

What happened when NN9056 was injected into mini pigs?

A
  • Dose response effect on food intake when inject the drug on a daily basis
  • Different experiment using lower daily doses showerd a reduction in body weight still
  • Effetcs of the drugs aren’t huge but are potential for cotherapy
  • Christoffersen et al 2020
116
Q

What are two incretin receptor mimetics?

A
  • Glucagon-like peptide 1 (GLP-1)
  • Gastric inhibitory peptide (glucose-dependent insulinotropic polypeptide- GIP)
117
Q

What cells produce GLP-1 and GIP?

A

L and K cells in the gut respectively

118
Q

What is the effect of GLP-1 and GIP?

A

To improve the release of insulin after the effect

119
Q

When is GLP-1 released?

A

Each time we eat a meal

120
Q

Where do GIP and GLP-1 travel to?

A
  • Released from the gut
  • Travel to the pancreas along the portal vein
  • Enhance glucose-dependent insulin (incretin effect)
  • Holst et al 2007
121
Q

What does insulin do?

A

Takes up glucose out of the blood stream and put into other tissues such as adipose or muscles where they store it or use it as fuel

122
Q

What is DPP-IV?

A
  • An enzyme that breaks down GLP-1 and GIP
  • Means that by the time the hormones reach the pancreas and liver, they have almost completely been broken down
123
Q

What is sitagliptin?

A
  • Inhibits the breaking down of GLP-1
  • Changes the amino acid sequence or adds a side chain to increase the half-life
  • The peptide doesn’t get broken down so fast
124
Q

What are two examples of incretin mimetic drugs?

A
  • Exendin 4 (half-life still low)
  • Liraglutide (big impact)
125
Q

Outline why liraglutide was important

A
  • Is effective at treating diabetes and also reduced body weight
  • Normally diabetes drugs cause weight gain as they release insulin causing the body to take up fatty acids
  • Development of injectable and oral formations of this drug to treat obesity
126
Q

When are the oral and injectable lirglutide prescribed?

A
  • To treat obesity of BMI over 30
  • Or over 27 if had other comorbidities such as diabetes and high blood pressure
127
Q

What percentage of body weight was lost with semaglutide?

A
  • 15% overtime
  • But if came off, put weight back on
  • Wilding et al 2021
128
Q

What is semaglutide?

A

Higher formation of GLP1 mimetic to be given to obese people with additional comorbidities

129
Q

What is tirzepatide?

A

Single molecule with affinity for GLP1 and GIP receptors

130
Q

What drug was more effective semaglutide or tirzepatide?

A

Tirzepatide

Frias et al 2021

131
Q

What are some side effects with the incretin mimetics?

A
  • Nausea and sickness
  • However incidence of this is lower in tirzepatide
132
Q

What is the proposed mechanism of how the incretin mimetics function?

A
  • Still relatively unknown
  • Perhaps, natural hormones (GLP-1 and GIP) are broken down in the bloodstream and don’t reach high enough concentrations to reach the brain
  • But these mimetics have longer half-lifes and may be able to get access to certain areas of the brain
  • May mimic natural brain GLP-1
133
Q

What two neurons release GLP-1 and where?

A

Preproglucagon (PPG) neurnons in the body

Prolactin-releasing peptide (PrRP) neurons in the brain

134
Q

What happens to mice when chemogenetic activation of PPG neurons?

A

GLP-1 cre mice

Reduction in fast-induced refeeding

135
Q

Where does tirzepatide enter the brain and where is activated?

A
  • Access of flurescent tirzepatide systemically in a mouse
  • Gains access through circumventricular organs (no BBB)
  • See mismatched activation of GLP-1 receptors in the brain
  • May be that it accesses is happening at a certain circumventricular organ and this activates the receptors in this area
  • These may then transynaptically activate other areas of the brain causing reductions in food intake
  • find reference in prep
136
Q

What is a GLP-1 X cre study showing the requirement of the brainstem?

A
  • Use GLP1 receptor x cre
  • Ant cells containing GLP1 express cre recombinase
  • Inject into different areas of the mouse with a destructive virus called caspase which kills the cells
  • If the mice have the caspase ablate the GLP-1 in the nodose ganglion- no effect
  • If ablate in the archaic effect- there is a greater effect of the hormone
  • If ablate in the brainstem- get rid of the hormone effects
  • Huang et al 2024
137
Q

How has a GLP1-Flox mouse demonstrated the importance of brainstem receptors?

A
  • GLP1 flox mouse which has a lox p either side of the GLP1 gene
  • Inject cre recombinase virus into the brainstem
  • Neurons in this area will have the GLP1 neurons destroyed
  • Lose the effect of body weight reduction
  • find reference in prep
138
Q

What neurons does Exendin-4 activate?

A
  • GLP1
  • Gfral
  • CCK
139
Q

What happens when Exendin 4 is injected into the brain?

A
  • Activates CCK, one of the most widely distributed neurotransmitters in the brain
  • CCK can express GLP1 receptors in certain areas
  • The CCK neurons with the GLP1 receptor also have a Gfral receptor (for cytokine GDF15)
  • The cytokine is released by damaged or diseased tissues, accts on the brainstem to cause nausea and reduce appetite
  • What we see in patients that take these drugs
  • Costa et al 2022
140
Q

What happens if we disable CCK neurons in the tractus solitarius?

A
  • Get reduction in food intake normally with GDF15 and EX4
  • If disable these by using tetanus toxin, we get rid of the effect
  • Tetanus toxin stops the neurotransmitters from releasing neurotransmitters
  • Worth et al 2020
141
Q

How was nausea due to GLP1 mimetics studied?

A
  • Injected a retrograde tracer into parabrachial nucleus
  • Stain cell bodies in the NTS and LP
  • Also stained for Gfral and CCK
  • Gave an injection of GDF15 and EXN4
  • Shows they project to the parabrachial nucleus
  • Worth et al 2020
142
Q

How was the negative valence in the parabrachial nucleus studied?

A
  • Optogenetic stimulation of CCK terminals that end in the parabrachial
  • Reduction in food intake but also negative valence
  • Control virus didn’t change much but the channel rhodopsin spent less time in the preferred side
  • Pathway cases nausea
  • D’Agostino et al 2016
143
Q

What is the main difference in action between GIP and GLP-1?

A
  • Calcium imaging in a slice with GCAMP shows exitation of glutamatergic GLP-1 neurons
  • GIP doesn’t affect the glutamatergic neurons but local inhibitory GABBA neurons (may reduce nausea)
144
Q

What is a study into exendin-induced anorexia and aversion?

A
  • Condition the mice to different flavours
  • Give WT mice banana milkshake (they like it and increase consumption)
  • On conditioning day they give chocolate milkshake and pair this with either a saline or exendin4 injection
  • Test day, they give them the chocolate milkshake
  • If had saline injection, would drink
  • If had EXN4, would not drink as causes negative valence
  • Both animals respond to banana normally
  • If have CCK knocked out and repeat this, the mice do drink the chocolate milshake even with EXN4 injection
  • CCK neurons are important in this response
  • Costa et al 2022
145
Q

What happens to negative valence if EXN4 is paired with GIP?

A

Reverses the negative valence of EXN4

Costa et al 2022

146
Q

What is LY343843 (retatrutide)?

A

Triple acting agonist on GLP1, GIP and glucagon receptors

Is more effective than tirzepatide

Costa et al 2022

147
Q

What are the three components of energy expenditure?

A
  • Obligatory EE
  • Physical exercise
  • Adaptive thermogenesis
148
Q

What is obligatory EE?

A
  • Basal metabolic rate
  • Digestion, growth, reproduction
  • Cannot control between individuals
  • Is up to 60% of EE
149
Q

What is physical exercise as a component of energy expenditure?

A
  • Form of energy expenditure to do with lifestyle
  • Also non-exercise activity thermogeneis which is the energy spent moving around
150
Q

What are the two types of adaptive thermogenesis?

A
  • Shivering thermogenesis
  • Non-shivering thermogenesis
151
Q

What is non-shivering thermogenesis?

A

Eventually we stop shivering and produce heat through sympathetic nervous system and the stimulation of brown adipose tissue

This can also be acitvated from diet

152
Q

What is white adipose tissue?

A
  • Single large lipid droplet where triglycerides are stored
  • The rest of the cytoplasm forms a thin rind around the periphery
  • Requires energy for its maintenance, explaining why overweight people have a high basal metabolic rate
  • Also have adipokines like leptin
153
Q

What is brown adipose tissue?

A
  • Cells have multiple lipid droplets and lots of mitochondria
  • Due to the stimulation from the sympathetic nervous system, these mitochondria can become uncoupled from using ATP to produce heat
  • The process of BAT mediated thermogenesis uses up a lot of fuel from the doplets stored or active take up of glucose
154
Q

What is the enzyme called that causes the uncoupling of ATP in brown adipose tissue?

A

Uncoupling protein 1

155
Q

What species is BAT most present in?

A

Small mammals and babies

On the brain and between the shoulders (intrascapular fatpad)

156
Q

What does PET scan show about glucose uptake after cold stimulation?

A
  • Spent 2 hours prior to the examination in a warm room (25 degrees)
  • Some uptake and accumulation of radioactive fluorodeoxyglucose into active tissues such as the heart
  • Days later was exposed to cold (18 degrees)
  • Cold induced uptake of radioactive glucose is more extensive
  • Biopsies confirmed BAT
  • Virtanen et al 2009
156
Q

What is the corelation between location living and BAT?

A

Further north the subject lvies, the colder the environment and the more BAT

157
Q

What is the correlation with BAT and BMI?

A
  • Negative correlation with BAT and BMI
  • Lean people have more BAT
158
Q

What is the origin of BAT?

A
  • As seen in the interscapula fat pads
  • Comes from the same lineage as skeletal muscle
  • Kajimura et al 2010
159
Q

What is white adipose tissues origin?

A

Mesodermal

Kajimura et al 2010

160
Q

What are brite cells?

A
  • Prolonged cold exposure can seem to the apparent browning of white adipose
  • However, there is a seperate mesodermal lineage
  • Dormant cells which are recruitable proginators that ca n lie dormant in white adipose depos
  • Brite cells (brown in white) can be stimulated to develop fully if exposed to cold or sympathetic nervous system is activated
161
Q

How does adipose browning occur?

A
  • In basal conditions, the inguinal fat pat is subcutaneous and deep (typical white)
  • When thermogenic stimulus, same fat depo becomes brown
  • Adaptive thermogenesis uses stored fat in the tissue which in the longer term needs to be released from white lipid stores
  • Chao et al 2011
162
Q

Outline the central pathway involved in adaptive thermogenesis

A
  • Cold centres in the skin project information through the DRG, and up to the parabrachial nucleus
  • BAT tissue is controlled by the brain and the sympathetic nervous system
  • Information is relayed to the preoptic area, some neurons here are intrinsically sensitive to temp
  • Signals from the periphery and central heat centres are integrated and passed onto the DMH
  • Regulatory signal from DMH to serotonergic neurons in the rRPa is then sent to preganglionic sympathetic neurons in the intermedial lateral nucleus of the spinal cord
  • DMH can also be stimulated by diet, if fed a high energy diet, increases BAT-mediated non-shivering thermogenesis
  • Causes sympathetic activation and the release of noradrenaline to act on adrenergic receptors
  • Heat is generated by the uncoupling of oxidative phosphorylation
  • Nakamura and Madden et al 2008
163
Q

How does leptin act on the central pathways involved in adaptive thermogenesis?

A

Has leptin sensitive cells (unidentified) that maybe integrate different stimuli and induce thermogenesis

Think a population of leptin sensitive neurons contain PrRP

164
Q

Are there DMN neurons that are responsive to leptin?

A
  • DMN PrRP is an important target for leptin
  • Have leptin receptors but only a small percentage
  • Dodd et al 2014
165
Q

What happens in kockouts of leptin receptors in PrRP neurons?

A
  • Selectively in the hypothalamus
  • Offspring become obese
  • Similar to when leptin is knocked out of OMC or Sf1 neurons
  • Pop of neurons in DMH nucleus poses leptin receptors and are important for leptin signalling
  • When receve an injection after awaking, PrRP receptors do not cause thermogenesis because they do not switch on brain adipose tissue
  • Normally leptin causes sustained rise in temp
  • Dodd et al 2014
166
Q

What is the receptor for PrRP?

A

A GPCR- GPR10

167
Q

What happens in knockout GPR10 mice?

A
  • Males and females become obese on a low calorie diet when compared with WT mice
  • Daily food intake is normal, and also normal locomotor activity
  • They have low overall energy expenditure (measured using O2 consumptionm indirect colourimetry)
  • These mice also gave a very low mean arterial BP
  • Luckman
168
Q

How have human GRP10 mutations been found?

A
  • Using exome sequencing of a large obese cohort of humans
  • Found 15 mutations in the human GRP10 gene
  • Not a lot of phenotypic data but interestingly they have low BP
  • Most common variant of the receptor found is a single nucleotide substitution of proline for serine at amino acid residue 193 (same as in mice)
  • Talbot et al 2021
169
Q

How could BAT thermogenesis be switched on?

A
  • Administering beta 3 adrenerfic agonists
  • Such drugs would be unsafe as it is hard to target BAT selectively without activating other sympathetic nervous system (increasing BP and HR0
  • Central targets such as PrRP might have adverse effects on BP
170
Q

What happens if inject 2-DG into a rat?

A

Causes them to eat as perceives it is low in glucose (negative valence)- mimicking homeostasis

Dodd et al 2010

171
Q

What is 2-DG?

A

Form of glucose taken up by cells but cannot be phosphorylated by hexokinase to make ATP

172
Q

When is THC effective in causing increased food intake?

A
  • Only effective when the rats have been fed previously
  • Homeostatic viewpoint no feeding is required- hedonistic
  • If not pre-fed, will not cause an increase in eating
  • Dodd et al 2010
173
Q

What is Hemopressin?

A

Is a novel peptide that activates homeostatic systems

174
Q

What happens when inducing homeostatic feeding using hemopressin (fMRI)?

A

Increased activity in the VMN of the hypothalamus after injection

175
Q

What is AM251?

A

Drug containing cannbinoid receptors

176
Q

What happens when inducing hedonistic feeding using AM251 (fMRI)?

A
  • Hypothalamic areas are activated
  • Also VTA, NA, PFC
  • These are part of the reward circuitary
  • Cannabinoid act to effect motivation to eat
177
Q

How were liking and wanting differentiated?

A
  • Liking is when we tase something like suger, responses are innate and help us survive
  • For example, sucrose on the tongue of a baby, can measure positive orofacial expressions but if bitter can see negative ones
  • Different tastes are either postitive, neutral or aversive and can be modified by experience
  • For example if pair a sweet with lithium chloride it will dislike or can stimulated parts of the brain with opioid or cannabinoids to make like (these are hedonic hotspots)
  • The innate orofacial responses to taske only require the brainstem but higher areas modify these responses positively or negatively
  • The hotspots lie in regions of the brain comprising of the reward structures but doesn’t involve the dopiminergic system
  • However wanting does involve this
178
Q

Outline mesolimbic dopiminergic pathways in wanting food

A
  • Linking the forebrain and the limbic system signalling the valence of the reward
  • The flooding of dopamine in the forebrain was evolved not as a drug pathway but as a system to help a species survive
  • Useful behaviours such as eating energy dense foods have positive valence
  • Stimulus is reinforced by releasing dopamine from the VTA
179
Q

How do dopamine receptors in the NA function in obese individuals?

A
  • PET scans
  • The first used uptake of radioactive glucose molecule to see in normal and obese humans (was similar)
  • Second used radiolabelled dopamine agonist, can measure binding in vivo
  • Obese patients have decreased dopamine receptors in the forebrain, NA in particular
  • There are negative correlations between dopamine binding and BMI
  • Have downregulated dopamine receptors, need more to satisfy the drive
180
Q

Are homeostatic and hedonistic functions completely seperate?

A
  • No, they interact
  • We are aware salience is dependent on nutritional status
  • Food looks and tastes better when we are hungry
  • For example, food pictures are rated higher and produce a larger activation of the reward systems in the brain when hungry (but not when fed in comparison to non-food pics)
181
Q

What happens to hunger when leptin deficient participants are treated with leptin?

A
  • Before treatment, subjective scores on rating food and non-food pics
  • Food pics are rated higher always no matter if thet have eaten
  • Treated for 7 days
  • Respond differently to pictures of food once they were fed and corresponding with the reward systems
  • They lost the motivation to eat
  • Farooqi et al 2007
182
Q

Why was overeating a benefit?

A
  • Allows animals to stock up with energy dense food when it is available in the environemnt
  • Would have been an evolutionary pressure not to get fat however, due to predation and hunting but this has been removed from the environment

Neuropharmacology (6 decks)

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