14 - Obesity and the endocrine control of food intake

Question 1

What are the inputs to the thalamus that involve the relation of food intake?

Answer 1

• Ghrelin, PPY and other gut hormones
• neural input from the periphery and other brain regions
• leptin

Question 2

What 2 hypothalamic nuclei are involved in the regulation of food intake and where are they located?

Answer 2

arcuate nucleus
- (at the base of the brain) sits above the median eminence
paraventricular nucleus
- sits above the third ventricle

Question 3

Which nucleus in the hypothalamus is the key brain are involved in regulation of food intake?

Answer 3

arcuate nucleus

Question 4

What feature of the arcuate nucleus allows it to integrate central and peripheral inputs?

Answer 4

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 (sits above the median eminence)

Question 5

What are the two neuronal populations in the arcuate nucleus and what effect do they have on food intake?

Answer 5

Agrp/NPY = stimulatory (increases food intake)
POMC = inhibitory (prevents food intake)

Question 6

Describe how the melanocortin system works.

Answer 6

Under normal conditions, POMC is broken down to alpha-MSH, which stimulates the MC4R receptor and prevents food intake

When you need to eat, Agrp activity will increase.
Agrp will block the MC4R receptor and stimulate an increase in food intake

Question 7

State some CNS mutations that affect this system and can cause obesity.

Answer 7

POMC deficiency – associated with obesity, red hair and pale skin (and cortisol deficient)
MC4R mutation – associated with obesity
There are NO known Agrp or NPY mutations

Question 8

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

Answer 8

• Infertility
• Stunted linear growth
• Decreased immune function
• Obesity
• Diabetes
• Decreased energy expenditure
• Decreased body temperature

NOTE: top 3 are less obvious

Question 9

What does the ob gene code for?

Answer 9

leptin

Question 10

What is leptin?

Answer 10

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
(the amount produced is proportional to the amount of adipose tissue that you have)

Question 11

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

Answer 11

Decreases food intake

Increases thermogenesis

Question 12

State the effects of leptin have on the melanocortin system

Answer 12

Inhibits Agrp/NPY neurones
Stimulates POMC

Result = decrease in energy expenditure

Question 13

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

Answer 13

Circulating leptin is usually proportional to body fat mass

A lot of obese people are leptin resistant (rather then leptin deficient)

Question 14

Describe the role of insulin in food intake

Answer 14

Insulin has a similar effect to leptin as it reduces food intake
circulates at levels proportional to body fat

central administration of insulin will reduce food intake

Question 15

What hormones are involved in short term regulation of food intake?

Answer 15

peptide-YY
Glucagon-like peptide 1
ghrelin

Question 16

Where are peptide YY and GLP-1 released from?

Answer 16

L cells of the small intestine

Question 17

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

Answer 17

PYY stimulates POMC neurones and inhibits NPY neurones

It is released post-prandially

Question 18

Describe the levels of PPY in the body throughout the day

Answer 18

low before a meal, high once you have had a meal

Question 19

What is GLP-1 and what gene encodes it?

Answer 19

Glucagon-Like Peptide 1

Encoded by pre-proglucagon gene

Question 20

What are the effects of GLP-1?

Answer 20

Important role in the incretin effect (glucose-stimulated insulin release)
Decreases food intake

Question 21

Describe the degradation of GLP-1.

Answer 21

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

It has a half-life of around 1 minute

Question 22

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

Answer 22

Saxenda

Question 23

What is ghrelin and how is it activated?

Answer 23

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 24

Describe the levels of ghrelin in the body throughout the day

Answer 24

high in the morning

drops after every meal and then slowly rises again

Question 25

What effect does ghrelin have on the melanocortin system (in the arcuate nucleus)?

Answer 25

Stimulates Agrp/NPY neurones
Inhibits POMC neurones
Result = increase in food intake

Question 26

Compare the levels of PPY and ghrelin before and after a meal

Answer 26

ghrelin increases before a meal and drops after

PPY is the opposite - surpasses hunger after a meal

Question 27

What is the problem with using gut hormones (e.g.PYY 3-36) as a drug target?

Answer 27

Get a very high spike in the hormones, which causes nausea

Question 28

State some comorbidities associated with obesity.

Answer 28

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

Question 29

What is the thrifty gene hypothesis?

Answer 29

(natural selection)
thin people didn’t survive or pass on their genes.
those putting on extra weight were at an evolutionary advantage because it meant that we could survive the times when food was scarce
hence, it is evolutionary sensible to put on weight

Question 30

What is the adaptive drift hypothesis?

Answer 30

There used to be normal distribution of body weights
Predators would kill the fat people
But then we got better at evading predators so increased body weight because a neutral change