Endocrinology of Appetite Flashcards
Which key area of the hypothalamus is involved in the regulation of food intake?
Arcuate nucleus
What feature of this area allows it to integrate central and peripheral inputs?
It is a circumventricular organ meaning that it has an incomplete blood-brain barrier This means that the arcuate nucleus is exposed to peripheral hormones
What are the two neuronal populations in the arcuate nucleus?
Agrp/NPY = stimulates food intake POMC = inhibits food intake
Describe how the melanocortin system works.
Under normal conditions, POMC is broken down to alpha-MSH, which stimulates the MC4R receptor and prevents food intake When you need to eat, there will be an increase in Agrp activity Agrp will block the MC4R receptor and stimulate an increase in food intake
State some CNS mutations that affect this system and can cause obesity.
POMC deficiency – associated with obesity, red hair and pale skin MC4R mutation – associated with obesity There are NO known Agrp or NPY mutations
What are the features of the leptin deficiency ob/ob mouse?
Obesity Diabetes Decreased energy expenditure Decreased body temperature Infertility Stunted linear growth Decreased immune function
What is leptin?
It is a 167 amino acid hormone It is produced by
white adipocytes and signals to the brain, telling it how much fat there is in storage
What effect does centrally administered leptin have on leptin deficient individuals?
Decreases food intake
Increases thermogenesis
What effect does leptin have on the melanocortin system?
Inhibits Agrp/NPY neurones
Stimulates POMC
Result = decrease in appetite/ expenditure
What issue do obese people without leptin deficiency have, which means that leptin treatment is not effective as an anti-obesity drug?
Circulating leptin is usually proportional to body fat mass So a lot of obese people are leptin resistant
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 This is also the reason why people who are severely underweight get secondary amenorrhoea
Describe the central effects of insulin.
Insulin has a similar effect to leptin as it reduces food intake Chronically – reduced body fat Acutely – if you have a big glucose load, you suppress the intake of more sugar
What is ghrelin and how is it activated?
It is a hunger hormone released by the stomach (28 amino acids long) It is activated by Ghrelin-O-acyltransferase (GOAT), which adds a fatty acid to the 3rd amino acid in the chain
What effect does ghrelin have on the melanocortin system?
Stimulates Agrp/NPY neurones
Inhibits POMC neurones
Result = increase in food intake
Which cells of the GI tract release PYY and GLP-1?
L-cells
What are the effects of PYY and when is it released?
PYY stimulates POMC neurones and inhibits NPY neurones
It is released post-prandially (after meals)
What is GLP-1 and what gene encodes it?
Glucagon-Like Peptide 1
Encoded by pre-proglucagon gene
What are the effects of GLP-1?
Important role in the incretin effect
Decreases food intake
Describe the degradation of GLP-1.
It is rapidly broken down by dipeptidyl peptidase-4 (DP-IV) It has a half-life of around 1 minute
State a long-acting GLP-1 receptor agonist that is used for diabetes and obesity.
Saxenda
What is the problem with PYY 3-36 as a drug target?
High levels of PYY can cause nausea There is only a relatively small beneficial dose, in terms of concentration.
State some comorbidities associated with obesity.
Stroke, MI, cancer, diabetes, hypertension, osteoarthritis etc.
What is the thrifty gene hypothesis?
It was evolutionarily sensible to put on extra weight because it meant that we could survive the times when food was scarce (thinner people would die in these times)
What is the drifty gene hypothesis?
There used to be a normal distribution in terms of body weight Predators would kill the heaviest people But then we got better at defending against predators so increased body weight due to survival in famine
