14. Obesity and the endocrine control of food intake

Question 1

What types of input does the hypothalamus receive regarding body weight?

Answer 1

• Ghrelin, PPY and other gut hormones
• Neural input from the periphery and other brain region
• Leptin

Question 2

Where is the paraventricular nucleus located in relation to the arcuate nucleus?

Answer 2

• 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

Question 3

Describe the function of the arcuate nucleus

Answer 3

• 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)

Question 4

How does NPY affect appetite?

Answer 4

• Binds to Y family receptors

* Downstream from that, appetite and food intake is stimulated

Question 5

How does POMC affect food intake in the melanocortin system?

Answer 5

• 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

Question 6

How does Agrp affect food intake in the melanocortin system?

Answer 6

• 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

Question 7

Outline any human CNS mutations affecting appetite

Answer 7

• 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

Question 8

Which gene in mice can lead to profound obesity, diabetes, infertility and low immune function?

Answer 8

• 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

Question 9

Where is leptin released from?

Answer 9

White adipose tissue

Question 10

What affect does central or peripheral administration of leptin have?

Answer 10

• Decreases food intake
• Increases thermogenesis
• Activates POMC and inhibits NPY/Agrp neurones

Question 11

Why is leptin ineffective as a weight control drug?

Answer 11

• 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

Question 12

What effect does leptin deficiency/absence have?

Answer 12

• Hyperphagia
• Lower expenditure
• Sterility

Question 13

When is leptin administration used clinically?

Answer 13

• Restore LH pulsatility in leptin deficient children

* Restore LH pulsatility in women with amenorrhoea (driven by stress/low body fat)

Question 14

What affect does central administration of insulin have on food intake?

Answer 14

Reduces food intake - receptors in the hypothalamus

Question 15

What is the largest endocrine organ/system

Answer 15

Gastrointestinal tract

Question 16

What effects do the following have:
• Cholecystokinin
• Secretin
• Ghrelin
• Gastrin

Answer 16

• Cholecystokinin - gall bladder contraction, GI motility, pancreatic exocrine
• Secretin - pancreatic exocrine
• Ghrelin - hunger, growth hormone release
• Gastrin - acid secretion

Question 17

Where is Peptide YY and GLP-1 released?

Answer 17

L cells of the small intestine - enteroendocrine cells

Question 18

What effect does Peptide YY have?

Answer 18

• 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

Question 19

What effect does Glucagon-like peptide (GLP) have?

Answer 19

• 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

Question 20

How does ghrelin work?

Answer 20

• 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

Question 21

How can injecting gut hormones make you feel and how can you avoid this?

Answer 21

• Nausea

* IV fusion is fine

Question 22

How much of your BMI is predicted by genes?

Answer 22

60-80%

Question 23

What is the thrifty gene hypothesis?

Answer 23

• 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

Question 24

Why isn’t everyone obese in the obesogenic environement today?

Answer 24

• 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