The 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?

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? Broadly state their involvement regarding food intake

Answer 3

AgRP (agouti-related peptide)/NPY (neuropeptide Y) = stimulatory (increases food intake)
POMC (proopiomelanocortin) = inhibitory (prevents food intake)

Note that both sets of neurons extend to
other hypothalamic and extrahypothalamic regions

Question 4

Describe how the melanocortin system works. What effect does AgRP have on this pathway?

Answer 4

• Under normal conditions, POMC is broken down to alpha-MSH, which stimulates downstream MC4 receptors (in VMH or PVN) => prevents food intake.
• When you need to eat, there will be an increase in AgRP activity; AgRP will block the MC4 receptor and stimulate an increase in food intake

Question 5

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

Answer 5

POMC deficiency – associated with obesity, red hair and pale skin
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 hypothalamus (via specific receptors), telling it how much fat there is in storage (so plasma concentration correlates with fat mass)

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 regarding the hypothalamus?

Answer 9

Leptin inhibits the activity of orexigenic NPY/AgRP neurons and reduces expression of NPY and AgRP, whilst leptin activates anorectic POMC neurons
Therefore, with high plasma leptin, the anorectic pathways mediated by POMC are switched on => reducing food intake.

Note that leptin receptors are expressed by the subpopulations of neurons in the arcuate nucleus

Question 10

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

Answer 10

They develop leptin resistance

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 (hypogonadism)
This is also the reason why people who are severely underweight get secondary amenorrhoea

Question 12

Describe the central effects of insulin.

Answer 12

Enters CNS via receptor-mediated uptake across the BBB and acts as an anorectic signal => decreases food intake and body weight

Question 13

What is ghrelin and how is it activated?

Answer 13

‘Hunger hormone’/orexigenic factor (28 amino acid peptide) produced and released primarily by the gastric oxyntic cells.

It is activated by Ghrelin-O-acyltransferase (GOAT), which adds an acyl side chain to the 3rd serine residue

Question 14

What central effect(s) does ghrelin have?

Answer 14

• Stimulates Agrp/NPY neurones; Inhibits POMC neurones
• Increases growth hormone (GH) release in the hypothalamus

Although the majority of ghrelin is synthesized in the periphery, ghrelin is also expressed centrally by ghrelin immunoreactive neurons which have terminals on hypothalamic NPY/AgRP and POMC.

Question 15

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

Answer 15

L-cells of the small intestine

Question 16

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

Answer 16

PYY release is post-prandial and is correlated with calorie intake (also depends on macronutrient composition); 2 forms = PYY1-36 and PYY3-36

Has an anorectic effect mediated via the inhibitory Y2 receptor present on arcuate NPY neurons + increased activation of arcuate neurons expressing POMC.
=> reduces food intake, delays gastric emptying, delays pancreatic and gastric secretions

Question 17

What gene encodes GLP-1/how is it formed?

Answer 17

The preproglucagon gene product is widely expressed in the L cells of the small intestine, in the pancreas (and in the brain stem NTS).
Tissue-specific cleavage of proglucagon by the enzymes prohormone convertase 1 and 2 results in different products (so GLP-1 is produced in small intestine)

Question 18

What are the 2 important effects of GLP-1?

Answer 18

1. GLP-1 is a powerful incretin hormone, (potentiating all stages of insulin biosynthesis)
2. Circulating GLP-1 levels are inversely correlated with body mass; GLP-1 acts to inhibit food intake.

Question 19

Describe the degradation of GLP-1. State its half life

Answer 19

It is rapidly broken down by dipeptidyl peptidase-4 (DPP-IV) when unbound to albumin
It has a half-life of around 1 minute (relatively short)

Question 20

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

Answer 20

Saxenda (liraglutide)

Question 21

What is the problem with PYY3-36 as a drug target?

Answer 21

High levels of PYY can cause nausea

There is only a relatively small “sweet spot”, in terms of concentration, that will have beneficial effects

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 evolutionary 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) => specific genes selected for to increase
metabolic efficiency and fat storage.

Question 24

What is the adaptive drift hypothesis?

Answer 24

• Normal distribution of body weight: the fat are eaten, the thin starve
• Humans learned to better defend/evade predators
• Thus obesity not selected against
• Putting on body fat is then a ‘neutral change’ (neither beneficial nor detrimental to the ability of an organism to survive and reproduce)