Obesity and Food Intake Flashcards
1
Q
Hypothalamic regulation of appetite
A
-> draw a diagram of the hypothalamic region and the roles the different nuclei, hormones etc play also which is inhibitory and which is stimulatory
2
Q
MC4-R
A
- important in food intake regulation: appetite suppression
- mutations cause morbid obesity
3
Q
What are the important parts of the hypothalamus in terms of energy expenditure regulation?
A
- arcuate nucleus which houses 2 populations of neurones (Agrp/NPY (stimulatory) and POMC (inhibitory))
- paraventricular nucleus
4
Q
Arcuate nucelus vs infundibular nucelus
A
- it is called arcuate in rodents and infundibular in humans
- arcuate means bow shaped
- houses 2 populations of neurones: Agrp/NPY (stimulatory) and POMC (inhibitory)
5
Q
Arcuate nucelus vs infundibular nucelus
A
- it is called arcuate in rodents and infundibular in humans
- arcuate means bow shaped
- houses 2 populations of neurones: Agrp/NPY (stimulatory) and POMC (inhibitory)
6
Q
Arcuate Nucleus
A
Key brain area involved in the regulation of food intake.
• Incomplete blood brain barrier, allows access to peripheral hormones.
• Integrates peripheral and central feeding signals.
• Two neuronal populations: Stimulatory (NPY/Agrp neuron) Inhibitory (POMC neuron)
- NPY/Agrp neurons INCREASE APPETITE
- POMC neurons DECREASE APPETITE
- Both sets of neurons extend to other hypothalamic and extra- hypothalamic regions.
7
Q
Why is POMC the precursor for a different molecule in the arcuate nucleus and in the anterior pituitary?
A
- there are different sets of enzymes in these cells
- pro-opiomelanocortin can make ACTH (adrenocorticotropic hormone) and alpha-MSH (alpha melanocyte stimulating hormone)
- ## you don’t get ACTH production in the hypothalamus
8
Q
Are there any NPY/Agrp mutations related to appetite in humans known?
A
no
9
Q
What do POMC deficiency and MCR4 mutations in humans cause?
A
- morbid obesity because there is a lack of appetite inhibitory signalling
- no alpha MSH to suppress food intake
POMC deficiency
- stress axis doesn’t work (because you cannot make ACTH) -> unless this is picked up very early they die because they do not have a glucocorticoid response.
- skin pigmentation in also due to MSH: they have red hair and pale skin
10
Q
What happens when you mutate Agrp/NPY neurones in mice?
A
- If you mutate them during childhood, nothing happens the brain seems to rewire itself to compensate
- you only have an effect if you mutate these genes in adulthood
11
Q
What does MSH bind to in the hypothalamus?
A
- MSH from the POMC neurones in the arcuate nucleus binds to the MC4-R in the PVN
12
Q
What is the ob/ob mouse?
A
- discovered in the 1960s when random mutations were introduced to find out what certain genes do
- profoundly obese
- daibetic
- infertile
- recessive mutation
- ob stands for ob-gene (obese)
- stunted linear growth
- Decreased body temperature.
- Decreased energy expenditure. • Decreased immune function.
- Similar abnormalities to starved animals
The mouse thinks that it is starving to death.
The mouse is missing LEPTIN
13
Q
Why are mice more difficult to make obese than humans?
A
- mice have much more ability to make new beta cells than humans
14
Q
Leptin
A
- Low when low body fat
- High when high body fat
- Central or peripheral administration decreases food intake and increases thermogenesis.
- Activates POMC and inhibits NPY/AgRP neurons.
- long-term signal (because adipose tissue does not change over night)
- However, leptin is an anti-starvation hormone rather than anti-obesity hormone.
- Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning- but high leptin has little effect.
15
Q
Leptin resistance
A
- Leptin circulates in plasma in concentrations proportional to fat mass.
- Most fat humans have high leptin.
- Obesity due to leptin resistance - hormone is present but doesn’t signal effectively.
- Leptin is ineffective as a weight control drug.
16
Q
What are the effects of leptin absence?
A
Absence of leptin has profound effects, including
- hyperphagia
- lowered energy expenditure
- sterility
- However, leptin is an anti-starvation hormone rather than anti-obesity hormone.
- Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning- but high leptin has little effect.
17
Q
What are the reproductive effects of leptin?
A
- Leptin is important in terms of GnRH/LH pulsatility
- binds to kisspeptin neurones which signal downwards
- due to higher weight at younger age children now go through puberty at a younger age because more leptin is present
18
Q
What is the role of insulin in food intake?
A
- Insulin circulates at levels proportional to body fat.
- Receptors in the hypothalamus.
- Central administration reduces food intake.
- regulates carbohydrate metabolism but also protein and lipid
19
Q
What is the role of insulin in food intake?
A
- Insulin circulates at levels proportional to body fat.
- Receptors in the hypothalamus.
- Central administration reduces food intake (works in animals, if you inject insulin into the hypothalamus -> rodents and non-human primates)
- regulates carbohydrate metabolism but also protein and lipid
20
Q
Why is insulin linked to body fat?
A
- there is insulin secretion based on food intake
- however, there is also basal insulin:
- In most people insulin levels are proportional to amount of body fat
- if you have more fat, more likely insulin resistance so more insulin made by the pancreas.
21
Q
Does leptin increase or reduce food intake?
A
reduces
22
Q
does insulin increase or reduce food intake in the hypothalamus?
A
reduces
23
Q
What is the body’s largest endocrine organ?
A
The GI tract
24
Q
The GI tract as an endocrine organ and the release of gut hormones
A
- The gastrointestinal tract is the body’s largest endocrine organ.
- Releases more than 20 different regulatory peptide hormones.
- Influence processes including gut motility, secretion of other hormones, appetite.
- Release regulated by gut nutrient content.
25
Enteroendocrine cells in the gut
- have machinery that allows them to respond to different food types (e.g. fats (different types, different lengths), carbs (glucose going in changes the electrics in the cells), proteins or their degradations products rather such as aa or short peptides.
- can have paracrine effect
- can modulate neuronal action (act on enteric NS OR to brainstem via vagus nerve)
- can have endocrine effect -> go around in the blood and act on e.g. pancreas or brain
26
Ghrelin
- released in the stomach
- 28aa
- modified by GOAT (ghrelin-O-acetyltransferase) because it has a weird fatty acid chain on it which most peptide hormones don't have) -> the enzyme attaches the FA group onto it
- if it doesn't have this modification it isn't particularly effective, it is needed to bind to the receptor and stick to binding proteins in the circulation
- it can attach different FAs which also seems to modulate its activity a little
- increases when you haven't eaten for a while, drops after you eat.
27
What actions does Ghrelin have in the arcuate nucleus?
* Stimulates NPY/Agrp neurons
* Inhibits POMC neurons
* Increases appetite (if you give someone ghrelin, they will eat more than if you hadn't given additional ghrelin)
28
Is there more control stimulating hunger or stopping food intake?
- There is more control that helps stop food intake.
- reacting what has gone into the gut, nutrient information and signals to the brain
- satiation and satiety
29
Satiation vs. Satiety
- Satiation: when you've had enough of the meal that you've eaten
- Satiety: when you will have your next meal -> pattern of food intake reg by hormones
30
GLP-1
- released from L-cells
- post prandial release
- Gut hormone coded for by the preproglucagon gene (same gene as for glucagon)
- half life of 1 min because it is inactivated by DPP4
- Well characterised incretin role in stimulating glucose-stimulated insulin release
- also reduces food intake
- most important incretin
31
PYY
- released from L-cells
- 36 aa
- AA 1 and 2 are chopped off to release PYY 3-36 after you have had a meal
32
L-cells
- open type cells: contact lumen of the gut
- release GLP-1 and PYY
- nucleus and secretory granules at basolateral side
- flask shape (broad base, finger like structure towards lumen)
- pseudopod/neuropod: can directly talk to neurones and contain synaptic machinery that can propagate neuronal signal
- post prandial secretion, related to kcal
33
What are the actions of PYY 3-36 in the arcuate nucleus?
* Inhibits NPY release.
* Stimulates POMC neurons
* Decreases appetite.
34
Ghrelin and PYY 3-36 in the arcuate nucleus
- they have opposite effects
- ghrelin stimulates appetite by stimulating NPY/Agrp neurones and inhibiting POMC neurones
- PYY 3-36 inhibits appetite by stimulating POMC neurones and inhibiting NPY/Agrp neurones
35
What happens if you give someone PYY?
What happens if you give someone ghrelin?
- PYY: they eat less because their brain receives a signal that they have just had a meal
- ghrelin: they eat more because appetite is stimulated
36
What is the building block similarity in glucagon and GLP-1?
- they come from the same precursor: Preproglucagon
- in alpha cells of the pancreas this is chopped up to make glucagon
- in L-cells in the gut this is chopped up to make GLP-1 (and also GLP-2)
- there is a different set of enzymes in these cells
37
DPP4
- ''dipeptidyl peptidase 4''
| - turns off GLP-1 signal by making GLP-1 inactive
38
Incretin effect
- you have a bigger insulin response after taking glucose orally rather than having it injected
- highlights the role of gut hormones.
39
Incretins
- Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels
- Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism.
- in presence of glucose they greatly exacerbate insulin release
- e.g. GLP-1 (most important incretin)
A lot of insulin release is due to incretins and not only direct effects of glucose on beta cells.
40
Which is the most important incretin?
GLP-1
41
GLP-1 as treatment
- you have to modify it because it breaks down quickly (longer half life)
- inhibit DPP4 to raise GLP-1 levels and increase insulin lrelease
- helpful in some T2DM patients
- for most people there is also some reduction of food intake
- good as a diabetes drug because in contrast to many other drugs it does not cause weight gain.
42
Saxenda
- Long-acting glucagon-like peptide-1 receptor agonist (liraglutide) from Novo Nordisk
- has fatty acid on it (moves through circulation well and is not degraded that easy)
- used for weight loss (not as life-changing as bariatric surgery but can still help e.g. reduce cardiovascular disease)
- Double the dose used for T2DM.
- Approved by FDA in 2014 and EMEA in 2015.
- currently prescribed privately, not on NHS
- SE: nausea
- you have to ramp up the dose slowly to avoid nausea and allow patients to get used to it.
43
What are the 3 types of satiety actions by gut hormones?
Post prandial
- reduces food intake
- following meal
- suppresses appetite
- PYY 3-36 and GLP-1 shorten your meal (but not by a karge amount because these hormones need time to work)
Chronic
- in gut disease
- there is chronic elevation of hormones
- suppression of appetite
- to reduce the stress on the gut and give it a chance to recover
Acute nausea
- toxin ingestion -> causes a big spike in GLP-1 release (acutely very high levels)
- this makes you either stop eating or empty stomach contents
44
Problem with gut hormones as drug targets
- too high concentration: nausea
- too low concentration: no effect
- only small window of concentration when it helps
- only short part is useful in the response curve
- short half life
- you have to modify
45
Dietary manipulation?
- can you manipulate food in a way that maximises hormone release?
- If we understand how the gut detects food, can we hijack these mechanisms?
- Synthetic nutrients to stimulate nutrient receptors.
- Delivering nutrients to specific regions of the gut.
- get calories down without big meal with many calories -> long term satiety
46
What comorbidities is obesity associated with?
- depression
- gout
- diabetes
- stroke
- myocardial infarction
- hypertension
- sleep apnoea
- bowel cancer
- peripheral artery disease
- osteoarthritis
47
Genetics of obesity
- classic twin studies: tremendous assocaition in monozygotic twins
- variability in body weight is 60-80% heritable
- in a given environment genetics have a tremendous influence on how much weight you will put on in that environment
48
Thrifty gene hypothesis in terms of obesity
- James Neel 1962.
- Specific genes selected for to increase metabolic efficiency and fat storage. In the context of plentiful food and little exercise these genes predispose their carriers to obesity and diabetes
- Evolutionarily sensible to put on weight.
- last time evolution worked on us we didn't know where our next meal was coming from
- Thin humans didn’t survive famines, so didn’t pass their genes on to modern humans.
- Evidence? Populations historically prone to starvation become most obese when exposed to Western diet and sedentary life-style (e.g. Pima Indians, Pacific Islanders).
49
Adaptive (drifty gene) hypothesis
• Normal distribution of body weight: the fat are eaten, the thin starve.
• 10-20K yrs ago, humans learned to defend against predators.
• Thus obesity not selected against.
• Putting on body fat then a neutral
change (genetic drift). (though unlikely to put on much weight) -> in today's environment it is not selected against
• In current context, the inheritors of these genes become obese
• GENETICALLY PRONE VS GENETICALLY RESISTANT INDIVIDUALS
50
summary
* Specific neuronal circuits in the hypothalamus and other brain regions regulate food intake.
* Insulin and leptin signal to regulate long term food intake.
* The gastrointestinal tract signals to regulate short-term food intake
* Obesity driven by the effects of environment on genetic background.
