Leptin Flashcards
Where is leptin made?
Primarily made and secreted by white adipose tissue
What is the function of leptin?
Regulates energy homeostasis via its actions in the hypothalamus
What gene produces the leptin receptor?
The diabetes (db) gene
What receptor family does leptin belong to?
Class I cytokine receptor family
Where in the brain is leptin receptor expression high?
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
How does leptin get into the brain?
Via a saturable transport system Leptin also reaches the brain via the CSF
Where are short OB-R isoforms expressed in the brain?
On brain microvessels These isoforms bind and internalise leptin
What does leptin do to hippocampal synaptic plasticity?
It causes LTP (instead of STP without the presence of leptin)
What does leptin do to NMDA receptors?
Enhances them which mediates synaptic transmission
What effect does leptin have on NMDA induced calcium influx?
Leptin increases the NMDA induced calcium influx
What is the function of NR2 subunits?
They determine biophysics and pharmacology of NMDAR
Which NMDA receptor subunits predominate in the hippocampus?
NR2A and NR2B
Where are NR2A and NR2B expressed respectively?
NR2A is synaptic whereas NR2B is expressed extrasynaptically
Leptin has the capacity to enhance NMDA receptor mediated currents but what is required for this to occur?
Leptin receptors are required
Which substances are involved in leptin modulation of NMDAR function?
PI3-kinase and MAPK
What do specific C-terminal regions determine in AMPAR complexes?
They determine the trafficking properties of AMPAR complexes
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?
GluA1 and 4 have long tails, GluA2 and 3 have short tails
What effect does leptin have on GluA1 surface expression?
Increases GluA1 surface expression
Which AMPA receptor subunits are predominant in the hippocampus?
GluA1 and GluA2
What is the difference between GluA1 and GluA2 in terms of calcium permeability?
GluA1 = calcium permeable GluA2 = calcium impermeable
What does this diagram show?
Leptin promotes GluA1 trafficking to synapses - increased GluA1 with leptin treatment compared to control image
What is the function of PI3K?
It converts PIP2 to PIP3 which then activates downstream targets
Leptin activates a kinase and inhibits a phosphatase. What kinase and what phosphatase does leptin act upon?
Leptin activates PI3 kinase and inhibits PTEN
What effect does leptin have on BpV?
Leptin occludes the effects of BpV on synaptic strength
How does leptin increase GluA1 expression and PIP3 levels?
Via inhibition of PTEN
How does leptin increase excitatory synaptic strength?
By increasing GluA1 surface expression
How does leptin facilitate hippocampal LTP?
By enhancing NMDAR function
What underlies trafficking of GluR1 to CA1 synapses in the hippocampus?
Leptin inhibition of PTEN underlies trafficking of GluR1 to CA1 synapses
What does leptin insensitivity do to LTP and LTD in rodent models?
Leptin insensitive rodents display impaired hippocampal LTP and LTD
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
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
What effect does amyloid beta have on AMPAR internalisation?
Amyloid beta promotes AMPAR internalisation
What effect does leptin have on amyloid beta induced AMPAR internalisation?
Leptin prevents amyloid beta induced internalisation of AMPA receptors
