Leptin Flashcards

(33 cards)

1
Q

Where is leptin made?

A

Primarily made and secreted by white adipose tissue

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2
Q

What is the function of leptin?

A

Regulates energy homeostasis via its actions in the hypothalamus

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3
Q

What gene produces the leptin receptor?

A

The diabetes (db) gene

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4
Q

What receptor family does leptin belong to?

A

Class I cytokine receptor family

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5
Q

Where in the brain is leptin receptor expression high?

A

High levels of OB-Rb expressed in specific hypothalamic nuclei High levels of OB-Rb mRNA/protein also expressed in cerebellum, hippocampus, brain stem and amygdala

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6
Q

How does leptin get into the brain?

A

Via a saturable transport system Leptin also reaches the brain via the CSF

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7
Q

Where are short OB-R isoforms expressed in the brain?

A

On brain microvessels These isoforms bind and internalise leptin

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8
Q

What does leptin do to hippocampal synaptic plasticity?

A

It causes LTP (instead of STP without the presence of leptin)

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9
Q

What does leptin do to NMDA receptors?

A

Enhances them which mediates synaptic transmission

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10
Q

What effect does leptin have on NMDA induced calcium influx?

A

Leptin increases the NMDA induced calcium influx

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11
Q

What is the function of NR2 subunits?

A

They determine biophysics and pharmacology of NMDAR

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12
Q

Which NMDA receptor subunits predominate in the hippocampus?

A

NR2A and NR2B

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13
Q

Where are NR2A and NR2B expressed respectively?

A

NR2A is synaptic whereas NR2B is expressed extrasynaptically

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14
Q

Leptin has the capacity to enhance NMDA receptor mediated currents but what is required for this to occur?

A

Leptin receptors are required

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15
Q

Which substances are involved in leptin modulation of NMDAR function?

A

PI3-kinase and MAPK

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16
Q

What do specific C-terminal regions determine in AMPAR complexes?

A

They determine the trafficking properties of AMPAR complexes

17
Q

Cytoplasmic C-terminal tails are key for regulating AMPAR function. What is the difference in tails between GluA1 and 4 compared to GluA2 and 3?

A

GluA1 and 4 have long tails, GluA2 and 3 have short tails

18
Q

What effect does leptin have on GluA1 surface expression?

A

Increases GluA1 surface expression

19
Q

Which AMPA receptor subunits are predominant in the hippocampus?

A

GluA1 and GluA2

20
Q

What is the difference between GluA1 and GluA2 in terms of calcium permeability?

A

GluA1 = calcium permeable GluA2 = calcium impermeable

21
Q

What does this diagram show?

A

Leptin promotes GluA1 trafficking to synapses - increased GluA1 with leptin treatment compared to control image

22
Q

What is the function of PI3K?

A

It converts PIP2 to PIP3 which then activates downstream targets

23
Q

Leptin activates a kinase and inhibits a phosphatase. What kinase and what phosphatase does leptin act upon?

A

Leptin activates PI3 kinase and inhibits PTEN

24
Q

What effect does leptin have on BpV?

A

Leptin occludes the effects of BpV on synaptic strength

25
How does leptin increase GluA1 expression and PIP3 levels?
Via inhibition of PTEN
26
How does leptin increase excitatory synaptic strength?
By increasing GluA1 surface expression
27
How does leptin facilitate hippocampal LTP?
By enhancing NMDAR function
28
What underlies trafficking of GluR1 to CA1 synapses in the hippocampus?
Leptin inhibition of PTEN underlies trafficking of GluR1 to CA1 synapses
29
What does leptin insensitivity do to LTP and LTD in rodent models?
Leptin insensitive rodents display impaired hippocampal LTP and LTD
30
Diabetics often display cognitive impairments, why might this be?
Obesity is a common risk factor for type 2 diabetes Obesity involves leptin resistance so type 2 diabetics may be potentially leptin insensitive which impairs LTP and LTD, leading to cognitive decline such as Alzheimer's
31
What evidence is there to back up the use of leptin as a therapeutic target in AD?
Circulating leptin levels are lower in AD patients Leptin decreases amyloid beta levels in transgenic mice with elevated beta amyloid levels Leptin improves memory in a mouse model of beta amyloid toxicity
32
What effect does amyloid beta have on AMPAR internalisation?
Amyloid beta promotes AMPAR internalisation
33
What effect does leptin have on amyloid beta induced AMPAR internalisation?
Leptin prevents amyloid beta induced internalisation of AMPA receptors