Endocrine Control of Food Intake Flashcards
What two factors have to be balanced in body weight homeostasis?
Food intake
Energy expenditure
What controls body weight homeostasis?
Hypothalamus
- All the inputs come into the hypothalamus
- The hypothalamus determines your appetite
Which areas of the hypothalamus are important in regulating food intake?
-
Arcuate nucleus
- The arcuate nucleus is like a switchboard
- It receives signals from the GI tract
- It has different neuronal populations which regulate appetite based on the signals received
- It is the key brain area involved in the regulation of food intake
- This is the main one you need to know
-
Lateral hypothalamus
- Also known as lateral hypothalamic area
- Feeding centre - when stimulated, it causes the sensation of hunger
-
Ventromedial hypothalamus
- Also known as ventromedial nucleus
- Satiety centre - when stimulated, it causes the sensation of fullness
NOTES:
- Nucleus = group of cell bodies in the CNS
- There are two of each structure - one on each side
Give some characteristics of the arcuate nucleus and explain how this helps with its function?
It is a circumventricular organ - so it has an incomplete blood-brain barrier
- This means that the arcuate nucleus is exposed to peripheral hormones
- Allows it to integrate peripheral and central feeding inputs
- Central - i.e. inputs from other brain regions
What are the two neuronal populations in the arcuate nucleus?
- AgRP/NPY = increase appetite
- POMC = decrease appetite
Both sets of neurons extend to other hypothalamic and extra- hypothalamic regions
- Essentially each neuronal population produces these peptides which act as signalling molecules to other neurones
- One population co-expresses the neuropeptides AgRP and NPY - i.e. produce both
- These neurones are orexigenic (stimulates appetite)
- The other population produces POMC
- There neurones are anorexigenic (inhibits appetite)
What is the main way the stomach detects whether your stomach is empty or full?
If you miss a meal, mechanoreceptors in the stomach detect that your stomach is empty.
This triggers vagal nerve firing to the solitary nucleus in the medulla.
The solitary nucleus then stimulates nerves going up to the arcuate nucleus in the hypothalamus
The arcuate nucleus:
- Activates the lateral hypothalamic areas through these orexigenic neurons which coexpress NPY and AgRP
- Inhibits the activation of the ventromedial nuclei by preventing the release of POMC
Describe how the melanocortin system works.
After you’ve eaten:
- POMC is broken down to α-MSH which is then released
- α-MSH is an endogenous agonist of the melanocortin 4 receptor (MC4R)
- Stimulation by α-MSH inhibits food intake - i.e. this makes you feel full
- This also just happens normally to stop you from constanly feeling hungry
When you need to eat:
- There will be an increase in AgRP/NPY neuronal activity so more AgRP is released
- AgRP is an endogenous antagonist of MC4R
- AgRP will block the MC4R receptor - block the inhibitory signal of a-MSH
- This stimulates food intake - i.e. this makes you hungry
MCR4 is present in the paraventricular nucleus
NOTE: This is not the only mechanism involved in appetite regulation as you also have the feeding centre (lateral hypothalamus) and satiety centre (ventromedial hypothalamus)
State some CNS mutations that affect this system and can cause obesity.
- POMC deficiency
- Causes morbid obesity
- Associated with red hair and pale skin due to lack of MSH and therefore melanin
- no ACTH, so HPA-axis is lost
- MC4R mutation
- Causes morbid obesity
- There are no known Agrp or NPY mutations
Morbid obesity because:
- POMC deficiency → no α-MSH released to bind to MC4R
- MC4R mutation → receptor not functioning as it should
- Lack of MC4R activation or functionality prevents appetite inhibition → ravenous eating due to insatiable hunger → obesity
Mutations not responsible for the prevalence of obesity but these clinical examples have been useful to explain signalling (i.e. how signalling in the CNS regulates food intake)
What is leptin?
- 167 amino acid hormone
- Produced by adipocytes and signals to the brain, telling it how much fat there is in storage
- Leptin circulates in plasma in concentrations proportional to fat mass
- Low levels when body fat is low
- High levels when body fat is high
- Leptin circulates in plasma in concentrations proportional to fat mass
- Central or peripheral administration decreases food intake and increases thermogenesis
- Activates POMC and inhibits NPY/AgRP neurons
- This acts to decrease appetite - so leptin acts as a satiety hormone
- Leptin levels increase slightly at night which is responsible for the lack of hunger when you’re sleeping
- Activates POMC and inhibits NPY/AgRP neurons
What is the main function of leptin in the body?
Leptin is mainly an anti-starvation hormone rather than an anti-obesity hormone
- Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning but high leptin has little effect
- Leptin levels which are high will make you feel full to an extent so you are not constantly hungry
- But extremely high leptin won’t have any more of an effect - you won’t stop eating completely
- So if a lack of leptin signalling indicates to the brain that you are starving
What are the features of the leptin deficiency ob/ob mouse?
Recessive mutation
- Profoundly obese
- Leptin acts as a satiety hormone
- Lack of leptin → excessive hunger and eating (hyperphagia) → obesity
- Diabetic
-
Infertile/sterile
- Lack of leptin signalling to brain shuts down reproductive axis
- Stunted linear growth
- Energy-consuming process
- Decreased body temperature
- Lack of leptin → decreased thermogenesis
-
Decreased energy expenditure
- If body is in starvation, then you would want to preserve more energy
- Decreased immune function
- Immune system is energy-consuming
Aside from obesity and diabetes, similar abnormalities to starved animals - essentially leptin deficiency signals body to go into starvation mode
In bold - main effects of leptin deficiency
What leptin-related issue do most obese people have?
- Most obese people have high leptin
- Because leptin circulates in plasma in concentrations proportional to fat mass
- Therefore, obesity is due to leptin resistance
- i.e. The hormone is present but doesn’t signal effectively
- This means that leptin is ineffective as a weight control drug
REMEMBER: However, people with leptin deficiency (rare) will respond well to leptin therapy as they have never seen it before so there is no resistance
Why won’t people with leptin deficiency go through puberty?
- Leptin has a permissive effect on GnRH release
- Without GnRH release, you will not get sufficient LH and FSH release to cause puberty
- If you inject a leptin deficient person with leptin, you see LH pulsatiility restored
- This is also the reason why people who are severely underweight get secondary amenorrhoea
- You can make these people start having periods again by giving leptin - it gives the illusion of having sufficient body fat
Describe the central effects of insulin.
- Insulin circulates at levels proportional to body fat
- This may be partly due to the fact that fat people are more likely to be insulin resistant so more insulin is needed
- It is generally accepted that lipids play a role in insulin secretion signaling, but the precise pathways and molecules involved in the process remains uncertain
- There are insulin receptors in the hypothalamus
- Insulin signals in a similar way to leptin in the sense that central administration of insulin reduces food intake
- Insulin can cross the BBB to have certain effects:
- Chronically - reduce body fat
- Acutely - if you have a big glucose load, you should suppress having more sugar
What is ghrelin? Give some characteristics of ghrelin.
- Hunger hormone
- Gastric = released by stomach
- Peptide
- 28 AAs long
- Converted to the active form by Ghrelin O-Acyltransferase (GOAT)
Describe how ghrelin levels change throughout the day.
Ghrelin levels drop after every meal and then slowly rises (before the next meal)
- It is high in the morning and then goes down after breakfast and rises again until lunch
NOTE:
- This pattern works when you’re awake
- But ghrelin levels reduce during sleep because you don’t need as much energy and therefore food intake when alseep
How is PYY released?
Peptide YY (PYY) is released post-prandially (after a meal)
- The amount of PYY released is dependent on the size of the meal
What is the problem with satiety gut hormones as a drug target (i.e. basing a drug on the hormones)?
- These hormones have short half lives
- Therefore if you inject the hormone, you will get a big, transient increase in drug concentration and then a relatively rapid drop
- High levels of the drug will cause nausea
- At low levels the drug is not really effective
- Only small period of time when the drug is in the effective part of the response curve
- There is a relatively narrow range of drug concentration at which the drug wil be effective
- Effective in reducing appetite, increasing insulin secretion
- You want to mofidy these molecules to give them better pharmacokinetic profiles
- You want the plasma drug concentration to increase enugh to get to the effective range, but not too much that it causes nausea
- So the dose should be high enough but not too high
- And you want the drug concentration to stay within the effective range for a long time
- So you want to increase half-life
- You want the plasma drug concentration to increase enugh to get to the effective range, but not too much that it causes nausea
- The structure of saxenda means it has a longer half-life than GLP-1
- However, the main side effect of saxenda is nausea
State some comorbidities associated with obesity.
