14. Obesity and the endocrine control of food intake Flashcards
what does body weight homeostasis refer to?
a balance between energy (food) intake and energy expenditure (BMR, exercise)
what inputs does the hypothalamus receive regarding body weight?
- ghrelin, PPY and other gut hormones
- neural input from the periphery and other brain regions
- leptin
where is the arcuate nucleus and what is it involved in?
at the base of the brain, above the median eminence where lots of hypothalamic releasing factors exist
it is involved in the regulation of food intake
where is the paraventricular nucleus and what is it involved in?
above the 3rd ventricle
it is involved in the regulation of food intake
how does the arcuate nucleus detect factors in the blood?
it is not completely isolated from the circulation by the BBB and so the incomplete BBB allows access to peripheral hormones so that peripheral and central feeding signals can be integrated
what are the 2 neuronal populations in the arcuate nucleus and what do both sets do?
- stimulatory (NPY/Agrp neurons) increase appetite
- inhibitory (POMC neurons) decrease appetite
both sets extend to other hypothalamic and extra-hypothalamic regions
how does NPY stimulate food intake and appetite?
it binds to Y family receptors in regions like the paraventricular nucleus
how do the POMC neurones work?
POMC neurones in the arcuate nucleus are enzymatically cleaved to produce alpha-MSH, which binds to the MC4R receptor in the paraventricular nucleus to decrease food intake
how does Agrp work?
Agrp is an endogenous antagonist of MC4R. there is baseline stimulation of the MC4R by alpha-MSH to suppress appetite. if the signal is taken away you feel hungry as Agrp blocks the suppressing signal and increases appetite
how do human cns mutations affect appetite?
- POMC deficiency and MC4R mutations can cause morbid obesity
- people with POMC deficiency also lose ACTH and can present with paleness and ginger hair
why do people with POMC deficiency also lose ACTH?
because POMC is the precursor for ACTH in the pituitary gland
what does the ob gene code for?
leptin - a protein hormone released from white adipose tissue which signals to the brain that you are not starving
what happens when leptin is not produced?
obese, diabetic, infertile, stunted linear growth, low body temp, low immune function
symptoms are characteristic of starvation except for obese and diabetes - the individual thinks they are starving and continues to eat, the immune system is energetically expensive so is switched off, the reproductive axis is switched off because it is evolutionarily ineffective to reproduce when you are starving
how does leptin influence other neurones?
leptin activates POMC
leptin inhibits NPY/Agrp neurones
what can leptin resistance lead to?
obesity as the hormone is present (usually leptin circulates in plasma in a proportional concentration to fat mass) but doesn’t signal effectively
why is leptin ineffective as a weight control drug?
most fat people have leptin but are just resistant
why is leptin a ‘hormone of absence’?
the absence of leptin results in hyperphagia, lowered expenditure and sterility
the presence of leptin tells the brain that there are sufficient fat reserves for normal functioning but high leptin has little effect
when is leptin useful therapeutically? what are its risks?
useful for people who are actually leptin deficient
HOWEVER
patients may develop antibodies towards leptin
what are the effects of leptin administration in children and women?
restores LH pulsatility in children with leptin deficiency
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
- obesity leads to insulin resistance
- central administration of insulin reduces food intake
which gut hormones are released by the stomach and what do they do?
ghrelin - hunger, growth hormone release
gastrin - acid secretion
which gut hormones are released by the duodenum and what do they do?
cholecystokinin - gall bladder contraction, GI motility, pancreatic exocrine secretion
secretin - pancreatic exocrine secretion
GIP - incretin activity
motilin - GI motility
which gut hormones are released by the pancreas and what do they do?
insulin and glucagon - glucose homeostasis
pancreatic polypeptide - gastric motility, satiation
amylin - glucose homeostasis, gastric motility
which gut hormones are released by the large intestine and what do they do?
GLP-1 - incretin activity, satiation
GLP-2 - GI motility and growth
oxyntomodulin - satiation, acid secretion
PYY(3-36) - satiation
how is food intake regulated in the short-term?
peptide YY and ghrelin - they are released from the L cells of the small intestine
what is the role of peptide YY?
tells the brain you are full
peptide YY is released from the intestines proportional to the calorie intake. to become activated the first 2 amino acids of PYY are cleaved off. PYY(3-36) then:
- inhibits NPY release
- stimulates POMC release
- decreases appetite
what is the role of glucagon-like peptide (GLP)?
satiety
- coded for by the pre-proglucagon gene and is released post-prandially
- stimulates insulin release and reduces food intake
what is GLP-1 broken down by and how quickly?
broken down by DPP4
has a half-life of 1min
what is used instead of GLP-1?
saxenda - synthetic version of GLP-1 that is a long-acting GLP-1 receptor agonist used to treat diabetes and obesity
what is the role of ghrelin?
tells the brain when you are hungry
- released from the stomach and acts on the brain
- ghrelin increases before a meal then drops when you are full (opposite to PYY)
- stimulates NPY/Agrp neurones
- inhibits POMC neurones
- increases appetite
what are the components of ghrelin?
ghrelin o-acyltransferase (GOAT) attaches the fatty acid group and activates ghrelin
the fatty acid chain helps ghrelin access the brain where its receptor is
what can injecting gut hormones result in?
nausea
which comorbidities are associated with obesity?
- sleep apnoea
- depression
- bowel cancer
- osteoarthritis
- gout
- stroke
- MI
- hypertension
- diabetes
what % of the BMI is predicted by your genes?
60-80%
what is the thrifty gene hypothesis?
- specific genes selected for to increase metabolic efficiency and fat storage
- it is evolutionarily sensible to put on weight (in case of famine and for insulation)
- in modern society where there is enough food and little exercise the genes predispose carriers to obesity and diabetes
what is the adaptive drift (drifty gene) hypothesis?
- normal distribution of body weight because the fat are eaten (can’t escape predation) while the thin starve in the cold
- however as humans learnt to defend against predators obesity was not selected against
- there was genetic drift towards putting on more weight
