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CVDM > Hypothalamus, Leptin Signalling and Resistance > Flashcards

Hypothalamus, Leptin Signalling and Resistance Flashcards

1
Q

What neurons does the melanocortin circuit comprise?

A

First order neurons:
Neuropeptide Y, AGRP, POMC

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2
Q

Roles of leptin in whole body homeostasis

A

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

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3
Q

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

A

True

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4
Q

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

A

Leptin and Insulin by targeting the ARC neurons

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5
Q

Leptin and insulin are increased/decreased in the fasted state

A

Decreased
Leads to activation of NPY/AGRP and inhibits POMC

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6
Q

Leptin and insulin are increased/decreased in the fed state

A

Increased
Leads to inhibition of NPY/AGRP and activates POMC

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7
Q

What does ghrelin act in opposition to?

A

Acts in opposition to leptin/insulin in the ARC

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8
Q

What secretes ghrelin?

A

Endocrine cells lining the stomach

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9
Q

What is the enzyme that makes ghrelin active?

A

GOAT - ghrelin-O-acetyltransferase

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10
Q

Are ghrelin levels high before or after a meal?

A

Before, they rapidly fall after eating.

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11
Q

Is ghrelin the direct cause of obesity?

A

No

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12
Q

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

A

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

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13
Q

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

A

Reduces

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14
Q

What becomes resistant to ghrelin during obesity?

A

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

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15
Q

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

A

False
They take a very long time to normalise

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16
Q

What is the physiological role of ghrelin?

A

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

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17
Q

What does LEAP2 do?

A

Blocks the effects of ghrelin in a dose dependent manner

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18
Q

Does fasting reduce or increase LEAP2 levels?

A

Reduces
Re-feeding increases

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19
Q

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

A

There is higher LEAP2 and lower ghrelin

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20
Q

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

A

Transcription of neuropeptides
Electrical activity
Synaptic plasticity

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21
Q

Key signalling pathways in energy and glucose homeostasis

A

JAK-STAT
PI3K-FoxO1
AMPK
Shp-MAPK

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22
Q

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

A

True

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23
Q

Describe the structure of leptin receptors

A

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

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24
Q

What happens when leptin binds to the leptin receptor?

A

You get dimerisation

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25
Q

What allows association of JAK2 to leptin?

A

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

26
Q

What does JAK2 do?

A

Elicits autophosphorylation and transactivation of kinase
Rapidly phosphorylates tyrosine residues

27
Q

What does activated JAK2 phosphorylate?

A

STAT3 which then dissociates from LEP-R

28
Q

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

A

There is induction of hyperphagia, diabetes, obesity and infertility

29
Q

What is the docking site for STAT5?

A

pY1077

30
Q

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

A

No, it plays a minor role

31
Q

By what system does insulin activate downstream signalling kinases?

A

PI3 kinase sytem

32
Q

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

A

Leptin

33
Q

What does FOX-O1 do?

A

Mediates many of the metabolic actions of insulin

34
Q

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

A

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

35
Q

True or false:
Monogenic causes of obesity are common

A

False - monogenic causes are rare

36
Q

True or false:
Humans without detectable leptin exist

A

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

37
Q

Genes associated with obesity

A

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

38
Q

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

A

Bidirectional

39
Q

What signals control meal size?

A

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

40
Q

What 3 factors underlie regulation of food intake?

A

Satiety signalling
Adiposity negative feedback signalling
Food reward

41
Q

What is satiation?

A

Sense of fullness generated during a meal

42
Q

What is satiety?

A

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

43
Q

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

A

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

44
Q

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

A

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

45
Q

Where does OXM come from and what does it do?

A

Comes from oxyntic cells in stomach and suppresses appetite

46
Q

How is leptin transported into the brain?

A

Via the BBB

47
Q

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

A

The more leptin you have

48
Q

Fasting increases/decreases plasma leptin?

A

Decreases

49
Q

CNS/PNS is the main leptin target?

A

CNS

50
Q

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

A

Decreases food intake

51
Q

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

A

That leptin stops working

52
Q

What is lipodystrophy?

A

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

53
Q

Is lipodystrophy congenital or acquired?

A

Can be either

54
Q

Patients with what virus are more prone to lipodystrophy?

A

HIV

55
Q

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

A

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

56
Q

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

A

For the changes in the synapses to occur

57
Q

What does deletion of the brain insulin receptor result in?

A

An obese state

58
Q

What is the effect on injected or infused insulin icv?

A

Inhibits food intake and reduces body weight

59
Q

Effects of insulin delivery to the hypothalamus

A

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

60
Q

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

A

Lower ratio

61
Q

How does insulin reduce hepatic glucose production?

A

By acting in the ARC to inhibit gluconeogenesis

CVDM (16 decks)

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