Leptin Flashcards

1
Q

How do neurotransmitters/modulators affect LTP?

A

Change either

  • the threshold for LTP
  • magnitude of LTP
  • duration of LTP
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2
Q

What is leptin?

A

A 16 kDa protein that acts as an endocrine hormone

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3
Q

Which gene encodes for leptin?

A

Ob gene

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4
Q

What is leptin mostly made by?

A

White adipose tissue

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5
Q

What is the amount of circulating leptin proportional to?

A

Body weight

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6
Q

What is the main role of leptin?

A

To regulate energy homeostasis

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7
Q

Which gene encodes of the leptin receptor?

A

db gene

diabetes gene

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8
Q

Which receptor superfamily is leptin a member of?

A

Class I cytokine receptor superfamily

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9
Q

Name the leptin receptor (ObR) isoforms

A

ObR a-f

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10
Q

Which is thought to be the most competent signalling ObR isoform?

A

ObR(b)

Has lotsa tyrosine residues

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11
Q

Phosphorylation of WHAT occurs at the C terminal of the leptin receptor?

A

Tyrosine reside phosphorylation by JAK

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12
Q

What occurs after JAK activation?

A

STAT3 activation

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13
Q

What is the main function of the JAK-STAT pathway?

A

Regulate gene transcription

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14
Q

What other pathways does ObR binding activate?

A

RAS > RAF signalling

PI3K

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15
Q

Where are high levels of Ob-R mRNA expressed?

A

Hippocampus
Cerebellum
Brainstem
Amygdala

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16
Q

What is the main route for leptin into the brain?

A

Via a sturable transport system regulated by triglycerides and other factors

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17
Q

Where do shorter ObR isoforms get expressed in the brain?

A

On brain microvessels

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18
Q

Which other route does leptin take into the brain?

A

via CSF

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19
Q

How can we see where leptin is in the hippocampus?

A

Fix and permeablise them then 4% paraformaldehyde and 0.1% Triton X-100

Insert primary Ab and secondary Ab

Visual with laser scanning confocal microscope

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20
Q

Which antibodies are used to in the immunocytochemical determination of leptin location?

A

Primary - polyclonal goat anti-Ob-R

Secondary - Alexa 488 conjugated donkey anti-goat

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21
Q

Where in the hippocampus are leptin receptors highly expressed?

A

At synapses

Shanley et al 2002
O’Malley et al 2007

22
Q

How do we know that Ob-Rs are highly expressed at synapses?

A

Ob-R tagged with green Ab
Synapses with red synapsin-1
Overlap them and see

Shanley et al 2002
O’Malley et al 2007

23
Q

Which excitatory receptor type is most active at CA1 neurons?

A

AMPAR

24
Q

How does the presence of leptin change theta-burst stimulation respnose?

A

Theta burst stimulation causes STP (for approx. 30 mins)
In the presence of 50nM leptin, theta burst stimulation causes potentiation of the cell for at least 90 mins - LTP

Shanley et al 2001

25
Q

What effect does leptin have on NMDAR transmission?

A

Enhancement of NMDA action –> more NMDAR function

(Doesn’t occur in the absence of ObR)

Shanley et al 2001

26
Q

How can we monitor NMDAR function with leptin?

A

Digital epifluoroescence

This picks up changes in intracellular Ca2+ and since NMDAR are Ca2+ permeable, it monitors their function

27
Q

How does Leptin modulate NMDAR function?

A

via PI3K and MAPK

28
Q

Outline the composition of NMDARs

A

At least one NR1 subunit
One or more NR2 subunits
With/without NR3

29
Q

Where are the different types of NR2 subunit expressed?

A

NRA - synaptic

NR2B - extrasynaptic

30
Q

How does leptin affect NMDA trafficking?

A

Increases
Can be seen through immunocytochemical methods again

Harvey et al 2005

31
Q

In which age group does leptin have the most effect on rodent hippocampal functioning?

A

Adults

32
Q

Outline the composition of AMPARs

A

Tetrameric complexes of 4 subunits

GluA1-4

33
Q

Which AMPAR subunits have long C-terminal tails?

A

GluA1 and 4

34
Q

How does leptin affect GluA1 surface expression?

A

Increases it - seen via immunocytochemical techniques

Moult et al 2010

35
Q

What are the most common AMPAR subunits in the hippocampus?

A

GluA1 and 2

36
Q

Which AMPAR subunits are Ca2+ permeable?

A

GluA1

37
Q

How does leptin affect LTP via AMPARs?

A

Increases insertion of GluA2 lacking AMPARs into synapses
Increases GluA1 surface expression

(More Ca2+, more excitation)
Moult et al 2010

38
Q

What does PI3K do?

A

Phosphorylates phosphoinositides on the 3’ position

39
Q

What accompanies leptin-induced GluA1 surface receptor increase?

A

Increase in PIP3

Moul et al 2010

40
Q

How does leptin increase PI3K activity?

A

Increases PI3K activity
This increases conversion of PI(4,5)P3 to PI(3,4,5)3

Also decreases PTEN activity
This reduces the reverse from happening

41
Q

What happens to LTP in leptin insensitive rats? (fa/fa rats)

A

Impaired LTP in hippocampus, basal transmission is fine

42
Q

Which type of memory is impaired in Zucker fa/fa rats?

A

Spatial

43
Q

In which disease may leptin be helpful?

A

AD

44
Q

Why do we think leptin will be helpful in this disease?

A

Circulating leptin low in patients and in transgenic mice
Leptin administration decreases beta-amyloid levels (and they have opposing actions)
Leptin improves memory in mouse models of b-amyloid toxicity

45
Q

Why is leptin implicated in this disease?

A

AD patients have less body weight and imbalance in leptin levels

46
Q

Which study showed that leptin prevents amyloid beta induced internalisation of AMPARs?

A

Doherty et al 2013

47
Q

Which leptin fragment mimics the action of leptin?

A

Leptin 116-130

Malekizadeh et al 2017

48
Q

What is the role of leptin in brain regions outwith the hypothalamus?

A

Unsure

49
Q

What occurs upon leptin binding to shorter isoforms?

A

Internalisation of leptin

50
Q

Inhibition of which compound mimics the action of leptin?

A

PTEN phosphatase

Moult et al 2010