The endocrine control of food intake 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? Broadly state their involvement regarding food intake
AgRP (agouti-related peptide)/NPY (neuropeptide Y) = stimulatory (increases food intake)
POMC (proopiomelanocortin) = inhibitory (prevents food intake)
Note that both sets of neurons extend to
other hypothalamic and extrahypothalamic regions
Describe how the melanocortin system works. What effect does AgRP have on this pathway?
- Under normal conditions, POMC is broken down to alpha-MSH, which stimulates downstream MC4 receptors (in VMH or PVN) => prevents food intake.
- When you need to eat, there will be an increase in AgRP activity; AgRP will block the MC4 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 adipocytes and signals to the hypothalamus (via specific receptors), telling it how much fat there is in storage (so plasma concentration correlates with fat mass)
What effect does centrally administered leptin have on leptin deficient individuals?
Decreases food intake
Increases thermogenesis
What effect does leptin have regarding the hypothalamus?
Leptin inhibits the activity of orexigenic NPY/AgRP neurons and reduces expression of NPY and AgRP, whilst leptin activates anorectic POMC neurons
Therefore, with high plasma leptin, the anorectic pathways mediated by POMC are switched on => reducing food intake.
Note that leptin receptors are expressed by the subpopulations of neurons in the arcuate nucleus
What issue do obese people without leptin deficiency have, which means that leptin treatment is not effective as an anti-obesity drug?
They develop leptin 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 (hypogonadism)
This is also the reason why people who are severely underweight get secondary amenorrhoea
Describe the central effects of insulin.
Enters CNS via receptor-mediated uptake across the BBB and acts as an anorectic signal => decreases food intake and body weight
What is ghrelin and how is it activated?
‘Hunger hormone’/orexigenic factor (28 amino acid peptide) produced and released primarily by the gastric oxyntic cells.
It is activated by Ghrelin-O-acyltransferase (GOAT), which adds an acyl side chain to the 3rd serine residue
What central effect(s) does ghrelin have?
- Stimulates Agrp/NPY neurones; Inhibits POMC neurones
- Increases growth hormone (GH) release in the hypothalamus
Although the majority of ghrelin is synthesized in the periphery, ghrelin is also expressed centrally by ghrelin immunoreactive neurons which have terminals on hypothalamic NPY/AgRP and POMC.
Which cells of the GI tract release PYY and GLP-1?
L-cells of the small intestine
What are the effects of PYY and when is it released?
PYY release is post-prandial and is correlated with calorie intake (also depends on macronutrient composition); 2 forms = PYY1-36 and PYY3-36
Has an anorectic effect mediated via the inhibitory Y2 receptor present on arcuate NPY neurons + increased activation of arcuate neurons expressing POMC.
=> reduces food intake, delays gastric emptying, delays pancreatic and gastric secretions
What gene encodes GLP-1/how is it formed?
The preproglucagon gene product is widely expressed in the L cells of the small intestine, in the pancreas (and in the brain stem NTS).
Tissue-specific cleavage of proglucagon by the enzymes prohormone convertase 1 and 2 results in different products (so GLP-1 is produced in small intestine)
What are the 2 important effects of GLP-1?
- GLP-1 is a powerful incretin hormone, (potentiating all stages of insulin biosynthesis)
- Circulating GLP-1 levels are inversely correlated with body mass; GLP-1 acts to inhibit food intake.
Describe the degradation of GLP-1. State its half life
It is rapidly broken down by dipeptidyl peptidase-4 (DPP-IV) when unbound to albumin
It has a half-life of around 1 minute (relatively short)
State a long-acting GLP-1 receptor agonist that is used to treat diabetes and obesity.
Saxenda (liraglutide)
What is the problem with PYY3-36 as a drug target?
High levels of PYY can cause nausea
There is only a relatively small “sweet spot”, in terms of concentration, that will have beneficial effects
State some comorbidities associated with obesity.
Stroke, MI, cancer, diabetes, hypertension, osteoarthritis etc.
What is the thrifty gene hypothesis?
It was evolutionary 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) => specific genes selected for to increase
metabolic efficiency and fat storage.
What is the adaptive drift hypothesis?
- Normal distribution of body weight: the fat are eaten, the thin starve
- Humans learned to better defend/evade predators
- Thus obesity not selected against
- Putting on body fat is then a ‘neutral change’ (neither beneficial nor detrimental to the ability of an organism to survive and reproduce)
