Endocrine Control of Food Intake

Question 1

Which key area of the hypothalamus is involved in the regulation of food intake?

Answer 1

Arcuate nucleus

Question 2

What feature of this area allows it to integrate central and peripheral inputs?
(Arcuate nucleus)

Answer 2

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

Question 3

What are the two neuronal populations in the arcuate nucleus?

Answer 3

Agrp/NPY = stimulatory (increases food intake)

POMC = inhibitory (prevents food intake)

Question 4

Describe how the melanocortin system works.

Answer 4

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

Question 5

State some CNS mutations that affect this system and can cause obesity. (POMC/Agrp/NPY/MC4R system)

Answer 5

POMC deficiency – associated with obesity, red hair and pale skin (No MSH)

MC4R mutation – associated with obesity

There are NO known Agrp or NPY mutations

Question 6

What are the features of the leptin deficiency ob/ob mouse?

Answer 6

Obesity

Diabetes

Decreased energy expenditure

Decreased body temperature

Infertility

Stunted linear growth

Decreased immune function

Question 7

What is leptin?

Answer 7

It is a 167 amino acid hormone

It is produced by adipocytes and signals to the brain, telling it how much fat there is in storage

Question 8

What effect does centrally administered leptin have on leptin deficient individuals?

Answer 8

Decreases food intake

Increases thermogenesis

Question 9

What effect does leptin have on the melanocortin system?

Answer 9

Inhibits Agrp/NPY neurones

Stimulates POMC

Result = decrease in energy expenditure

Question 10

What issue do obese people without leptin deficiency have, whichmeans that leptin treatment is not effective as an anti-obesity drug?

Answer 10

Circulating leptin is usually proportional to body fat mass

So a lot of obese people are leptin resistant

Question 11

Why won’t people with leptin deficiency go through puberty?

Answer 11

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

Question 12

Describe the central effects of insulin.

Answer 12

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

Question 13

What is ghrelin and how is it activated?

Answer 13

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

Question 14

What effect does ghrelin have on the melanocortin system?

Answer 14

Stimulates Agrp/NPY neurones

Inhibits POMC neurones

Result = increase in food intake

Question 15

Which cells of the GI tract release PYY and GLP-1?

Answer 15

L-cells

Question 16

What are the effects of PYY and when is it released?

Answer 16

PYY stimulates POMC neurones and inhibits NPY neurones

It is released post-prandially

Question 17

What is GLP-1 and what gene encodes it?

Answer 17

Glucagon-Like Peptide 1

Encoded by pre-proglucagon gene

Question 18

What are the effects of GLP-1?

Answer 18

Important role in the incretin (glucose stimulated insulin release) effect

Decreases food intake

Question 19

Describe the degradation of GLP-1.

Answer 19

It is rapidly broken down by dipeptidyl peptidase-4 (DP-IV)

It has a half-life of around 1 minute

Question 20

State a long-acting GLP-1 receptor agonist that is used for diabetes and obesity.

Answer 20

Saxenda

Question 21

What is the problem with PYY 3-36 as a drug target?

Answer 21

High levels of PYY can cause nausea

There is only a relatively small sweetspot, in terms of concentration, that will have beneficial effects (ie narrow therapeutic window)

Question 22

State some comorbidities associated with obesity.

Answer 22

Stroke, MI, cancer, diabetes, hypertension, osteoarthritis etc.

Question 23

What is the thrifty gene hypothesis?

Answer 23

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)

Question 24

What is the adaptive drift hypothesis?

Answer 24

There use to be a normal distribution in terms of body weight

Predators would kill the fat people

But then we got better at evading predators so increased body weight because a neutral change