Endocrine control of food intake Flashcards
Where inputs does the hypothalamus receive to regulate food intake?
- Ghrelin, PPY and other gut hormones
- Neural input from the periphery and other brain regions
- Leptin
Where is leptin released from and what does it tell the hypothalamus?
From body fat - it tells the brain how much fats store there is
Which nucleus is found above the median eminence?
The arcuate nucleus
Where does the paraventricular nucleus sit?
Above the 3rd ventricle
Which two nuclei are important in food intake regulations?
The arcuate and paraventricular nucleus
Is the arcuate nucleus completely enclosed by the BBB and why?
NO - it allows them nucleus to access peripheral hormones (it is a circumventricular organ that can detect things in the blood to integrate peripheral and central feeding signals)
What are the two neuronal populations in the arcuate nucleus?
stimulatory (NPY/Agrp)
inhibitory (POMC)
What does NPY/Agrp neurones do?
What about POMC neurones?
Where do these neurones extend to?
increase appetite
reduce appetite
other hypothalamic and extra-hypothalamic regions
What is the melanocortin system?
- NPY binds to Y family receptors (particularly in regions like the paraventricular nucleus)
- Downstream from that, NPY stimulates food intake and appetite
- The POMC neurones work via alpha-MSH, which binds to the MC4R receptor and suppresses food intake
- Agrp is an endogenous antagonist of the MC4R
- There is baseline stimulation of the MC4R by alpha-MSH to suppress appetite
- If this signal is taken away, you feel hungry (Agrp blocks the suppressing signal and increases appetite
What does alpha-MSH act on and what happens if this stimulation is removed?
MCR4 receptor
You feel hungry as normally it would suppress food intake.
What are some mutations that can affect appetite?
- No known NPY or Agrp mutations in humans associated with food intake
- POMC deficiency and MC4-R mutations can cause morbid obesity
- People deficient in POMC also lose ACTH -> you no longer have the hypothalamo-pituitary-adrenal axis
How is POMC deficiency spotted?
Obesity Pale Ginger Lack of ACTH Lack of cortisol
What is an ob gene deficiency?
What happens if this exists in someone?
- ob gene codes for leptin that signals to the brain that you are not starving
- It is released from white adipose tissue
- If this gene is missing, the body thinks it is starving and has to keep eating
- The immune system is energetically expensive, so this switches off ‘in starvation’
- The reproductive axis switches off because it is evolutionarily stupid to reproduce when starving
What are the characteristics of ob gene deficiency?
Profoundly obese, diabetic, infertile, have stunted linear growth, low body temp, low immune function
What happens in leptin deficient children?
- They think that they are starving to death, because their brains are signalling this to them
- They will eat virtually anything
- Starvation rewires the brain and makes people behave differently
How much leptin is released in obese and slim people?
Leptin is released from body fat, so if you are not very fat, leptin is low. In obese people, leptin is high (because of high body fat).
Which neurones does leptin activate/inhibit?
Leptin activates POMC and inhibits NPY/Agrp neurones
What is leptin resistance?
- Leptin circulates in plasma in concentrations proportional to fat mass
- Most fat humans have high leptin – but they are not responding to it very well
- Obesity due to leptin resistance: the hormone is present but doesn’t signal effectively
Why is leptin ineffective as a weight control drug?
Most fat people have leptin
What is the effect of leptin absence?
hyperphagia, lowered expenditure and sterility
How can leptin be used in people who are deficient and what are some issues that may occur?
- Leptin therapeutical treatment
- Patients sometimes develop antibodies towards leptin – keep increasing the dose
- Leptin administration restores LH pulsatility in leptin deficient children
- Leptin administration restores LH pulsatility in women with amenorrhea (driven by stress/low body fat
What is the role of insulin in food intake?
- Insulin circulates at levels proportional to body fat
- When you are obese, you get insulin resistance
- There are receptors in the hypothalamus
- Central administration of insulin reduces food intake
What is the body’s largest endocrine organ?
GI Tract - releases hormones to influence gut motility, secretion and appetite
Which hormones are involved in short term regulation of food intake and where are they made?
Peptide YY and GLP-1 are released from L cells of the small intestine
(enteroendocrine cells -side facing the lumen senses whilst other side has secretory granules)
What is the role of peptide YY?
- Peptide YY is released from the intestines – 36 AA
- Released in proportion to the calorie intake
- To become activated, the first two amino acids of PYY are chopped off -> PYY3-36
- PYY3-36 directly modulates neurones in the arcuate nucleus:
- Inhibits NPY release
- Stimulates POMC release
- Decreases appetite
- PYY consistently suppresses feelings of hunger
- Released after you have eaten
What codes for GLP-1?
What is the role of glucagon like peptide (GLP-1)?
- Gut hormone coded for by the pre-proglucagon gene and released post-eating
- Reduces food intake
- It stimulates glucose stimulated insulin release
- Animals stop eating and fall asleep after an ICV injection
How does the glucagon gene product modification vary in different cells?
- It is chopped up in different ways depending on the tissue its present in
- E.g. in alpha cells in the pancreas (glucagon) or in the L cells of the intestine (GLP-1)
How are GLP-1 based drugs used in therapeutics?
GLP-1 based drugs are now a really big class of anti-diabetic medications
- Peripheral GLP-1 inhibits food intake in humans
What breaks down GLP-1?
What does this mean?
DPP4 - has a very short half life, around a minute, hence drugs are synthetic and have a long half life
Give an example of A GLP-1 agonist and its use
saxenda - to treat diabetes and obesity
What is ghrelin?
- Peptide hormone (28aa) that has a fatty acid chain stuck on it at the serine at the 3 position
- GOAT attaches the fatty acid group and activates ghrelin
- Released from the stomach, acts in the brain
What is the role of ghrelin?
- Ghrelin increases before a meal, then it drops when you are full (opposite to PPY)
- It makes you hungry
What does ghrelin act on?
Directly modulates neurones in the arcuate nucleus:
- Stimulates NPY/Agrp neurones
- Inhibits POMC neurones
Why is injecting gut hormones a bad idea?
It can cause nausea as you get a bug sudden spike
What are the co-morbidities associated with obesity?
Sleep apnoea, depression, bowel cancer, osteoarthritis, gout, stroke, MI, hypertension, diabetes
Is obesity genetic?
- Obesity is genetic – your hypothalamus decides how much weight you put on in a given environment
- 60-80% of the body mass index is predicted by your genes
- In twin studies, identical twins are similar in body weight
- Non-identical twins have a lot more discrepancy when comparing their weight
What is the thrifty gene hypothesis?
- Specific genes selected for to increase metabolic efficiency and fat storage
- Where there is plentiful food and little exercise the genes predispose their carriers to obesity, diabetes
- It is evolutionarily sensible to put on weight
- Thin humans didn’t survive famines, so didn’t pass their genes on to modern humans
But then why isn’t everyone obese in an obesogenic environment?
What is the adaptive drift hypothesis?
- Here, there is a normal distribution of body weight
- The fat are eaten (can’t escape predation), whilst the thin starve in the cold
- However years ago, humans learned to defend against predators; so obesity was not selected against
- Putting on body fat then a neutral change
- In current context, the inheritors of these genes become obese
- When you look at people who are genetically prone and genetically resistant to obesity, in a healthy environment, there wouldn’t be much difference between them
- In an obesogenic environment, those genetically predisposed would put on weight
