Vagal afferent control of food intake - neuromodulation of food intake

Question 1

How does adiposity work ?

Answer 1

it works as a negative feedback loop
circulating signals inform brain of available energy stores the brain can alter our food intake
also important for regulating energy expenditure

Question 2

What peripheral signals regulate long term energy balance and where do they come from ?

Answer 2

they help the brain integrate information

leptin is released from adipose tissue and insulin is released from the pancreas

Question 3

What form does nutritional info take to provide feedback to the brain ?

Answer 3

absorbed nutrients, neuronal signals and gut peptides

Question 4

What info does the vagus nerve relate to the brain from the stomach and upper small bowel and where does it send it to ?

Answer 4

stomach distention and the chemical and hormonal milieu of the upper small bowel to the NTS

Question 5

What actions do hormones released from the gut have ?

Answer 5

incretin, hunger and satiety stimulating action

incretin hormones, GLP-1, GIP and potentially OXM improve the response of endocrine pancreas to absorbed nutrients

Question 6

Where is OXM and PYY released from ?

Answer 6

released from lower GIT

Question 7

Where is PP released from ?

Answer 7

released from islets of langerhans

Question 8

What does GLP-1 and OXM do ?

Answer 8

they reduce food intake

Question 9

What does gherlin and cck do ?

Answer 9

ghrelin is released from stomach and it stimulates appetite

whereas CCK is a gut hormone which stimulate satiety as it feeds back to the vagus nerve

Question 10

What hormones can travel up the vagus nerve to alter food intake and what effects do they have ?

Answer 10

leptin and CCK are involved in inhibiting food intake
grehlin and orexin are involved in promoting food intake
these signals travel up to the NTS and hypothalamus

the majority are involved in inhibiting food intake
if they come from the intestine then they inhibit food intake (CCK, GLP-1 and PYY)
if they come from the stomach then they can do both so it depends on state of stomach, full or empty

Question 11

What was one of the first things to be discovered to treat obesity ?

Answer 11

CCK because it initially reduces meal sizes
in rats they infused them with CCK and measured their food intake and meal size
- it rapidly reduced their food intake

Question 12

Why did the CCK infusion not work ?

Answer 12

although meal size reduced, their meal number increases so initially there was a decrease in food intake but then it crept up again
the effects were lost after a few days
the food intake increases and rebounds as if there is a set point of normal weight

Question 13

What effect did CCK infusion have on body weight ?

Answer 13

it stayed pretty much the same

Question 14

What experiment was carried out to prove that CCK worked via the vagal nerve ?

Answer 14

took rats and intraperitonally injected them with capsaicin
at high doses it kills cells via the vaniloid receptor which is predominantly present on sensory neurones so it killed some nodose cell ganglions cells which is where the vagal afferent cell bodies are
then they looked at the effect of CCK infusion

Question 15

What effect did CCK have when the rats were pretreated with capsaicin?

Answer 15

had less effect on reduction in food intake compared to control rats with sensory neurones intact
therefore killing sensory cells in this way seems to affect food intake
this effect was also reduced when the 4th ventricle was pretreated with capsaicin- kills sensory neurones via endings in NTS

Question 16

What experiment was carried out to compare vagal afferents and efferents in food intake ?

Answer 16

they cut the vagus as it went to the stomach, just below the diaphragm
also cut just the afferents as they go into the brainstem
tried cutting efferent- vagal roots as they left the brainstem

Question 17

What results were shown when they carried out the lesions to the vagal afferents and efferents?

Answer 17

CCK didn’t have much of an effect when afferents were cut so therefore the reduction in food intake was prevented
whereas when the efferents were cut there was an increased % inhibition demonstrating that the efferents are not important for helping CCK reduce food intake

Question 18

What experiment was carried out to test leptin ?

Answer 18

produced leptin receptor ko sensory neurone mice using cre recombinase
did they expressing cre recombinase in neurones with a specific sodium channel
used immunofluorescence to prove KO in nodose ganglion

Question 19

What happened when leptin receptor was KO of sensory neurones in nodose ganglion ?

Answer 19

didn’t affect light phase(day), but increase meal duration in dark phase (night)

• mice are nocturnal so they dont normally eat much during the day
• due to increased meal size they had increased body weight compared to controls- got fatter
• increased fat mass in subcutaneous, epididymal, mesenteric and retroperitoneal

Question 20

What mistake is often made when carrying out food intake experiments on rats/mice?

Answer 20

do a lot of experiments during the day but this is when they should be asleep so it could affect results

Question 21

What happens when grehlin concentration is increased and where does it act?

Answer 21

it stimulates food intake which increases as doses increase
when the vagus nerve is cut the effects of grehlin are altered so it must act via the vagus nerve
- destroyed sensory nerves with capsaicin and the effects of gherlin were reduced

Question 22

How did they show that grehlin was involved in increasing food intake ?

Answer 22

they infused rats with gherlin, some of the rats were pretreated with capsaicin so the effects of gherlin were abolished
- there was no c-fos labelling in the capsaicin treated rats but there was c-fos labelling in 3rd ventricle, hypothalamus demonstrating increased activity - in control rats there was c-fos activity in neurones of arcuate nucleus, of NPY neurones and GHRH neurones in ARC

Question 23

Where is the gherlin receptor present and how was this determined?

Answer 23

using PCR, took nodose ganglions and mashed it up to look for mRNA
also used in situ hybridisation
in the nodose ganglion and hypothalamus the gherlin receptor is present
receptor is produced in vagal nerve cell and transported to terminal

Question 24

What often co-localised with ghrelin receptor?

Answer 24

the vanilloid receptor

Question 25

What effect does gherlin have on vagal nerve discharge?

Answer 25

decreases vagal afferent nerve discharge
prep in rats and recorded electrical activity of the nerve
conversely cck increased the discharge activity

Question 26

What serendipitous finding was discovered about vagal nerve stimulation ?

Answer 26

it decreases BMI
tested it to see if it affected food intake
patients were being treated with VNS for depression but it caused on average a 7kg weight loss and in general greater reductions in weight loss occurred in those with the highest BMIs
-some normal people put on weight

Question 27

What experiment was carried out in mini pigs that were overfed to make them fat?

Answer 27

bilateral subdiaphragmatic vagal nerve stimulation
- it decreases weight gain in diet induced obese mini pigs
the controls were good because they were implanted but stimulator was not switched on - these controls increased body weight significantly and faster compared to those that received stimulation

Question 28

What other effect was induced by VNS of the mini pigs ?

Answer 28

the VNS pigs ate significantly less than before the surgery- 18% less
it also altered their preference for foods- with a 46% reduction in high carbohydrate foods

Question 29

What happens with rats were had chronic VNS?

Answer 29

over a 4 week treatment period- rats didn’t put on as much weight as sham rats and had a decrease in food intake over the period of the experiment
appears to be very effective

Question 30

What was shown in humans with VNS?

Answer 30

it increases energy expenditure in relation to brown adipose tissue activity
- it increases the basal metabolic rate
each person was its own control so perfect type of control
- when the stimulation was switched off the basal metabolic rate decreased significantly

Question 31

What did pilot studies of VNS show in humans ?

Answer 31

thought it is only effective in lean people
lean people had reduced calorie content with VNS on whereas in overweight/obese people it didn’t make a significant difference but they didnt measure energy expenditure which could have made a huge difference

Question 32

What did vagus nerve blocking do ?

Answer 32

caused weight loss in humans
developed to induce intermittent intra-abdominal vagal blocking using high frequency electrical currents - stimulates vagus at stomach
this puts it into depolarisation block stopping action potentials travelling through stimulation site
it causes weight loss - on average there were reductions, with reductions in calorie intake and fat intake

COULD IT BE A TREATMENT STRATEGY

Question 33

In VBLOC where are the electrodes positioned?

Answer 33

positioned laparoscopically on anterior and posterior vagal trunks near esophagogastric junction without anatomic modification or tissue compression of the alimentary tract

Question 34

What other stimulation method decreases food intake ?

Answer 34

DBS in rats caused a decrease in food intake
implanted electrodes into the brain to induce stimulation - however there was a decline in food intake even in the control rats that received the surgery but no stimulation
surgery and stimulations keeps body weight down near starting levels- the stimulated rats ate the same amount as the non-stimulated rats yet their weight was less so that means stimulation must have increased energy expenditure

Question 35

What activity is increased in obese people ?

Answer 35

muscle sympathetic nerve activity
- underlies essential hypertension and heart failure
was no change in plasma noradrenaline levels

Question 36

What is bariatric surgery and what does it do ?

Answer 36

it is when the stomach is tied or bypassed
when it is carried out in obese people there is a decline in waist circumference, muscle sympathetic nerve activity, leptin levels due to less fat

there was also declines in leptin and MSNA in controls

Question 37

What is tVNS and what effect did it have in rats ?

Answer 37

transcutaneous vagal nerve stimulation- rather than implanting a vagus nerve stimulator they activate the auricular branch by the ear which is much less invasive
- reduced body weight in rats fed a high fat diet - no difference at 8 weeks but at 14 weeks there was a decline in weight - the stimulated rats took in more energy so it may have caused an increase in energy expenditure

Question 38

What other effects did tVNS have ?

Answer 38

compressed ECG, BP and muscle sympathetic nerve activity

decreases the frequency of MSNA and this doesn’t return to normal after 20mins