14. Obesity and the endocrine control of food intake Flashcards
What types of input does the hypothalamus receive regarding body weight?
- Ghrelin, PPY and other gut hormones
- Neural input from the periphery and other brain region
- Leptin
Where is the paraventricular nucleus located in relation to the arcuate nucleus?
- Arcuate nucleus sits at the base of the brain, above the median eminence
- 3rd ventricle above the arcuate nucleus
- Paraventricular nucleus above the 3rd ventricle
Describe the function of the arcuate nucleus
• Incomplete BBB allows access to peripheral hormones
• Integrates peripheral and central feeding signals
• 2 neuronal populations
- stimulatory - NPY/Agrp neuron (increases appetite)
- inhibitory - POMC neuron (stimulates MC4R - decreases appetite)
How does NPY affect appetite?
- Binds to Y family receptors
* Downstream from that, appetite and food intake is stimulated
How does POMC affect food intake in the melanocortin system?
- POMC is a precursor for ACTH which is a precursor for α-MSH
- POMC neurones work via α-MSH, which binds to the MC4R receptor to suppress food intake
How does Agrp affect food intake in the melanocortin system?
- Agrp is an endogenous antagonist of MC4R
- (Separate from Agrp) there is a baseline stimulation of MC4R by α-MSH to suppress appetite
- If this signal is taken away, Agrp blocks the suppressing signal - increases appetite
Outline any human CNS mutations affecting appetite
• Haven’t found any NPY or Agrp mutations
• POMC deficiency and MC4R mutations can cause morbid obesity
• POMC deficiency also:
=> loss of ACTH => no longer have hypothalamo-pituitary-adrenal axis (cortisol deficiency)
=> paleness and ginger hair
Which gene in mice can lead to profound obesity, diabetes, infertility and low immune function?
- Ob/ob mouse
- Recessive genetic disorder - misses something coded by the ob gene
- Ob gene codes for leptin
- Thinks it is starving, eats too much, and switches off immune system
Where is leptin released from?
White adipose tissue
What affect does central or peripheral administration of leptin have?
- Decreases food intake
- Increases thermogenesis
- Activates POMC and inhibits NPY/Agrp neurones
Why is leptin ineffective as a weight control drug?
- Most fat human have leptin but don’t respond very well
- Obesity is due to leptin resistance
- Leptin is also an anti-starvation hormone rather than an anti-obesity hormone
- Useful in people with leptin deficiency
What effect does leptin deficiency/absence have?
- Hyperphagia
- Lower expenditure
- Sterility
When is leptin administration used clinically?
- Restore LH pulsatility in leptin deficient children
* Restore LH pulsatility in women with amenorrhoea (driven by stress/low body fat)
What affect does central administration of insulin have on food intake?
Reduces food intake - receptors in the hypothalamus
What is the largest endocrine organ/system
Gastrointestinal tract
What effects do the following have: • Cholecystokinin • Secretin • Ghrelin • Gastrin
- Cholecystokinin - gall bladder contraction, GI motility, pancreatic exocrine
- Secretin - pancreatic exocrine
- Ghrelin - hunger, growth hormone release
- Gastrin - acid secretion
Where is Peptide YY and GLP-1 released?
L cells of the small intestine - enteroendocrine cells
What effect does Peptide YY have?
• Low before a meal
• After eating a meal, peptide YY is released (36aa peptide hormone)
• Released in proportion to calorie intake
• First 2 aa are chopped off to activate it
• Modulates neurones in the arcuate nucleus:
- inhibits NPY
- stimulates POMC
• Decreases appetite
What effect does Glucagon-like peptide (GLP) have?
• Doesn’t bind the glucagon receptor but it’s made by the same gene
• Coded for by the pre-pro glucagon gene, and released post-prandially
• Stimulates glucose-stimulated insulin release
• Reduces food intake
• Glucagon gene product can be chopped up in different ways depending on the tissue present - alpha cells in pancreas (glucagon) or L cells of instestine (GLP-1)
• Can be used as anti-diabetic medication
• Rapid half life - broken down by DPP4
- synthetic drugs are used as long-acting agonists
How does ghrelin work?
• 28 aa peptide hormone
- fatty acid chain at serine at 3 position
• Ghrelin o-acyltransferase (GOAT) activates ghrelin
• Released from stomach
• Fatty acid chain helps access brain where receptor is
• Ghrelin increases before a meal, then drops when full
• Makes you feel hungry if you haven’t eaten for a while
• Modulates neurones in the arcuate nucleus:
- stimulates NPY/Agrp
- inhibits POMC
• Increases appetite
How can injecting gut hormones make you feel and how can you avoid this?
- Nausea
* IV fusion is fine
How much of your BMI is predicted by genes?
60-80%
What is the thrifty gene hypothesis?
- Favourable to increase metabolic efficiency and fat storage - these genes are selected for
- Plentiful food - little exercise - genes predispose their carriers to obesity and diabetes
- Thin humans didn’t survive famines
- Evolutionary sensible to put on weight
- Evidence - populations prone to starvation become larger when exposed to Western diet and sedentary life-style
Why isn’t everyone obese in the obesogenic environement today?
- Adaptive drift (drifty gene) hypothesis
- Years ago, humans learned to defend against predators
- Obesity wasn’t selected against
- Putting on body fat then a neutral change
