Hypothalamus, Leptin Signalling and Resistance

Question 1

What neurons does the melanocortin circuit comprise?

Answer 1

First order neurons:
Neuropeptide Y, AGRP, POMC

Question 2

Roles of leptin in whole body homeostasis

Answer 2

Feeding - eating
Anorexia - starvation
Hedonic feeding - motivation to eat
Energy expenditure - thermoregulation
Glucose homeostasis - insulin sensitivity

Question 3

True or false:
ARC neurons/circuits are crucial for fat (energy) and glucose homeostasis

Answer 3

True

Question 4

What hormones are involved in surveillance of total body energy stores?

Answer 4

Leptin and Insulin by targeting the ARC neurons

Question 5

Leptin and insulin are increased/decreased in the fasted state

Answer 5

Decreased
Leads to activation of NPY/AGRP and inhibits POMC

Question 6

Leptin and insulin are increased/decreased in the fed state

Answer 6

Increased
Leads to inhibition of NPY/AGRP and activates POMC

Question 7

What does ghrelin act in opposition to?

Answer 7

Acts in opposition to leptin/insulin in the ARC

Question 8

What secretes ghrelin?

Answer 8

Endocrine cells lining the stomach

Question 9

What is the enzyme that makes ghrelin active?

Answer 9

GOAT - ghrelin-O-acetyltransferase

Question 10

Are ghrelin levels high before or after a meal?

Answer 10

Before, they rapidly fall after eating.

Question 11

Is ghrelin the direct cause of obesity?

Answer 11

No

Question 12

What are the results of chronic ghrelin infusion to the CNS?

Answer 12

Increased lipogenesis, decreased lipid oxidation
Increases blood glucose and decreases insulin secretion

Question 13

DIO increases/reduces ghrelin secretion, plasma ghrelin, GOAD mRNA and transport across the BBB

Answer 13

Reduces

Question 14

What becomes resistant to ghrelin during obesity?

Answer 14

The hypothalamic circuitry (ARC: NPY/ARGP neurons) that controls food intake

Question 15

True or false:
Ghrelin levels normalise quickly when weight loss is achieved

Answer 15

False
They take a very long time to normalise

Question 16

What is the physiological role of ghrelin?

Answer 16

To defend the body weight and glucose homeostasis during times of food shortage to prevent weight loss

Question 17

What does LEAP2 do?

Answer 17

Blocks the effects of ghrelin in a dose dependent manner

Question 18

Does fasting reduce or increase LEAP2 levels?

Answer 18

Reduces
Re-feeding increases

Question 19

In obesity there is higher/lower LEAP2 and higher/lower ghrelin

Answer 19

There is higher LEAP2 and lower ghrelin

Question 20

Leptin, insulin and ghrelin activate signalling pathways to trigger responses by what?

Answer 20

Transcription of neuropeptides
Electrical activity
Synaptic plasticity

Question 21

Key signalling pathways in energy and glucose homeostasis

Answer 21

JAK-STAT
PI3K-FoxO1
AMPK
Shp-MAPK

Question 22

True or false:
Leptin receptors do not have intrinsic tyrosine kinase

Answer 22

True

Question 23

Describe the structure of leptin receptors

Answer 23

Single transmembrane domain cytokine-like protein
Has to have a dimer
End-terminal domain

Question 24

What happens when leptin binds to the leptin receptor?

Answer 24

You get dimerisation

Question 25

What allows association of JAK2 to leptin?

Answer 25

Leptin binds to LEP-Rb which is a dimer that allows the association of JAK2

Question 26

What does JAK2 do?

Answer 26

Elicits autophosphorylation and transactivation of kinase Rapidly phosphorylates tyrosine residues

Question 27

What does activated JAK2 phosphorylate?

Answer 27

STAT3 which then dissociates from LEP-R

Question 28

What happens when there is CNS specific interruption of STAT3 signalling?

Answer 28

There is induction of hyperphagia, diabetes, obesity and infertility

Question 29

What is the docking site for STAT5?

Answer 29

pY1077

Question 30

Does Y1077-STAT5 play a major role in food intake and energy expenditure?

Answer 30

No, it plays a minor role

Question 31

By what system does insulin activate downstream signalling kinases?

Answer 31

PI3 kinase sytem

Question 32

As well as insulin, what other hormone couples to the PI3K system?

Answer 32

Leptin

Question 33

What does FOX-O1 do?

Answer 33

Mediates many of the metabolic actions of insulin

Question 34

Increased/reduced FOX-O1 activity in POMC neurons and hypothalamus increases food intake and body weight

Answer 34

Increased activity increases food intake and body weight, reduced activity reduces food intake and body weight

Question 35

True or false: Monogenic causes of obesity are common

Answer 35

False - monogenic causes are rare

Question 36

True or false: Humans without detectable leptin exist

Answer 36

True, although it is more common to have individuals with reduced leptin levels

Question 37

Genes associated with obesity

Answer 37

Mutations in MC4-R and POMC Rare mutations in leptin signalling

Question 38

Is the flow of information between the brain and the body unidirectional or bidirectional

Answer 38

Bidirectional

Question 39

What signals control meal size?

Answer 39

Satiety signals - information from upper GI tract via vagus and sympathetic afferents

Question 40

What 3 factors underlie regulation of food intake?

Answer 40

Satiety signalling Adiposity negative feedback signalling Food reward

Question 41

What is satiation?

Answer 41

Sense of fullness generated during a meal

Question 42

What is satiety?

Answer 42

The period of time between termination of one meal and the start of the next

Question 43

What are PYY3-36 produced from and what do they do?

Answer 43

Produced from L-cells of gut Inhibits gastric motility and reduces food intake

Question 44

What is GLP-1 released from and what is its function?

Answer 44

Released from L-cells Inhibits gastric emptying and reduces food intake

Question 45

Where does OXM come from and what does it do?

Answer 45

Comes from oxyntic cells in stomach and suppresses appetite

Question 46

How is leptin transported into the brain?

Answer 46

Via the BBB

Question 47

The more fat you have, the more/less leptin you have

Answer 47

The more leptin you have

Question 48

Fasting increases/decreases plasma leptin?

Answer 48

Decreases

Question 49

CNS/PNS is the main leptin target?

Answer 49

CNS

Question 50

If you inject leptin intracerebrovascularly what is the effect on food intake?

Answer 50

Decreases food intake

Question 51

Obese humans have high levels of leptin, what does this tell us about leptin?

Answer 51

That leptin stops working

Question 52

What is lipodystrophy?

Answer 52

Rare disorder in which individuals have few or no fat cells and store lipids elsewhere, and have high levels of lipids in the blood

Question 53

Is lipodystrophy congenital or acquired?

Answer 53

Can be either

Question 54

Patients with what virus are more prone to lipodystrophy?

Answer 54

HIV

Question 55

Fasting increases what neuronal mRNAs and decreases what neuronal mRNAs? Why is this?

Answer 55

Increases NPY/AgRP mRNA and decreases POMC/CART mRNA You want the drive to eat to be increased and the drive to stop eating to be decreased

Question 56

Why do you need to stick to a diet for a period of time for it to work?

Answer 56

For the changes in the synapses to occur

Question 57

What does deletion of the brain insulin receptor result in?

Answer 57

An obese state

Question 58

What is the effect on injected or infused insulin icv?

Answer 58

Inhibits food intake and reduces body weight

Question 59

Effects of insulin delivery to the hypothalamus

Answer 59

Modulates hypothalamic neuronal activity Improves whole body insulin sensitivity Promotes lipogenesis and peripheral fat accumulation Increases adaptive theromogenesis

Question 60

Insulin resistant individuals have a lower/higher CSF:plasma insulin ratio compared to insulin sensitive subjects?

Answer 60

Lower ratio

Question 61

How does insulin reduce hepatic glucose production?

Answer 61

By acting in the ARC to inhibit gluconeogenesis