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8.11 Leptin
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From the lesson
Gene and behavior
Taught By
Chenjian Li
Professor
Donggen Luo
Research Fellow
Yan Zhang
Professor
Okay, then in other experiments, this experiment,
the message is they should tell you what's the feedback
inhibition signal is from the fat tissue.
Fat tissue, they will release this leptin, okay?
[FOREIGN] >> [FOREIGN]
>> [FOREIGN] okay.
This fat tissue are released, this signal.
Because you eat a lot, and then fat tissue then somehow triggered to release leptin.
And this leptin is important signals to control the food consumption, the eating.
Let's take at look how people found this thing.
This is the wild-type animal.
The body size is like this.
Quite interestingly, in the Jackson app [FOREIGN],
Jackson app [FOREIGN] mouse strain.
[FOREIGN], okay.
Somehow this [FOREIGN]
mutation [FOREIGN] okay.
Obese [FOREIGN]
strain [FOREIGN]
strain.
Also, it's kind of a huge body.
That called DB.
DB also is another strain.
But actually, it's different gene mutation, okay?
Let's take a look, okay.
So wild-type is like this.
This is obese animal, very big.
So they did a similar experiment to try to find what's the mechanism here.
To make this wild-type fly and this fly, link it together and see what happen.
This is a change.
And if we use Db fly.
Also, it's like that this is the change.
Db and Ob together, it's the change.
Okay, let's take a look here.
First, take a look at these two fly.
Okay, so this is the Db fly
when you link to another Db sorry [LAUGH].
I'm so used to the fly because [LAUGH] everyday
in the lab I talk about, okay, which [FOREIGN] we need to use or
which fly we should do the recording, I'm sorry, okay.
Db mouse, okay, Db mouse and the wild-type mouse linked together, and
you see, okay, Db mouse.
He grew even larger, right?
And then, this wild-type mouse actually then get thinner and thinner, okay?
And also, here, similar thing.
The Db get larger and larger and
then even this Ob/Ob mouse.
And gets so similar.
It's quite interesting.
So from here, then, how you make
the reasoning to explain these results?
>> [INAUDIBLE] to of the fat.
Lines to the output, which is to
inhibit the nutrition extraction.
>> Okay. >> And maybe the Ob mutant is inhibit
[INAUDIBLE] at the input [INAUDIBLE]
pathway, which means maybe the fat
sensor is disturbed and the- >> So Ob,
you think Ob this is the same cell or Ob is a feedback signal.
>> I think Ob is the sensor.
>> The sensor, okay, why?
>> because since it cause a normal [INAUDIBLE] mouse to [INAUDIBLE]
[FOREIGN]
>> Okay, okay, so to get each,
to get a repeated signal in this case diluted or maybe less inhibition.
Then, these mouse can grow larger, eat more.
[FOREIGN] Now that means this Ob is for what?
>> [INAUDIBLE] >> It's inhibitor signal.
It's not the sensor.
>> [INAUDIBLE] >> So
you think this one controls the leptin release.
>> Yeah.
>> [FOREIGN].
[FOREIGN] Can you explain?
Elaborate.
>> [INAUDIBLE]
>> Right.
>> [INAUDIBLE]
>> Shield it, right?
>> [INAUDIBLE] >> Yeah, okay the concentration.
For the wild-type right now would be diluted a little bit.
They eat more.
Then this wild-type will eat more food right and gain some weight.
[FOREIGN] But for this one is still actually you would have lost some weight.
Because actually, right now,
you get the leptin signal from the wild type, good okay.
Makes sense [FOREIGN].
Okay, so in this case, then that means Db Is the same cell with the leptin receptor.
>> So, I made a mistake.
I think this- >> Okay.
>> Maybe the fat and not the leptin.
>> The fat.
>> Yeah.
>> Okay, leptin is from the fat.
>> [INAUDIBLE] >> Yeah, released by the fat tissue.
Okay, for this one say, there are anybody
volunteer to make a reasoning here, yeah?
>> [INAUDIBLE] >> Okay, good.
>> [INAUDIBLE] to limit
food consumption
[INAUDIBLE] >> Yeah.
>> [INAUDIBLE] will in turn produce more leptin.
>> Good, okay.
So this guy will release more leptin, right, okay.
>> [INAUDIBLE] becomes thinner.
>> Yeah, so this wild-type, they have with the receptive intact.
>> So you have more inhibitor signal and then reject to eat, right.
Okay, good, if everybody follow the same page and
then I guess we understood everything here.
So Db is the leptin receptor and
then Ob is the leptin, the inhibitor signal.
Okay, so indeed, people later mapped these two locations.
And this Ob and the Db, and
found actually corresponding to why is this the leptin?
Why is it the leptin receptor?
All right, so what's the next step, if you got all these data in your hands?
What will we do next?
>> [INAUDIBLE] >> Okay,
the protein leptin is found in the fat tissue, okay, and then?
>> [INAUDIBLE] >> Yeah, clone the receptor, right?
>> Also what others [INAUDIBLE] >> Okay,
good, so the important thing is that right now,
you know all these things then you wanted to know where this receptor is expressed.
Of course, leptin, where does leptin come from?
And then, for the receptor, because we talk about actually the hypothalamus.
If you destroy the hypothalamus and then there was trouble,
like just just so they could see this Ob mouse, right?
And then, indeed, people found the receptor, the leptin receptor
concentrate in the hypothalamus, okay?
The hypothalamus actually just some neurons actually express.
Mainly two types of neurons express the leptin receptor.
For example, there was one group of neuron called AgRP neuron.
And they expressed the leptin receptor, okay?
And people did experiments actually,
they used a virus to transfect the brain
especially for this nucleus.
For tha AgRP, okay, for this neuron.
Express channelrhodopsin.
Channelrhodopsin is right now is kind of fashion in neuroscience.
It's called optical genetics [FOREIGN].
Now, that what's that mean is actually this channelrhodopsin is a light sensor.
The light sensor itself is a channel.
So if you shine light and then this channel can open and
then will excite the neuron express this protein, okay.
So when they express this channelrhodopsin AgRP neuron and
then use a fiber buried in the brain, a optical fiber.
And they use a laser to stimulate the neuron that means you
can excite particularly those leptin receptor neuron and
what they found you can see here.
This is the control fly during
the [INAUDIBLE] and this is the, yeah,
this is for the consumption, yep.
For the consumption, you can see the wild-type fly is okay.
They take some food.
But then, if you have channelrhodopsin expressed in
a stimulant then the mouse will just eat crazy.
It doesn't matter, the mouse is full or not,
you're just eating, okay, continuously.
That means these neurons really control the eating, right?
All right, so later people found actually there are two groups of
neuron in the hypothalamus actually express the leptin receptor.
That is one POMC neuron and one is this AgRP neuron.
And then, the leptin, okay,
the leptin actually will excite this neuron, activated this POMC neuron.
And the POMC unit will release some peptide.
Then a peptide will activate it at downstream neuron here,
express MC4R [INAUDIBLE] receptor, and to inhibit the eating.
Okay, this is this pathway.
And for this pathway thing is different.
This AgRP, AgRP then, apparently when the AgRP
neuron excited then the animal will eat crazy, right.
So that means that this AgRP neuron actually somehow
inhibit this POMC pathway, you see?
The leptin will inhibit this neuron.
This neuron will inhibit this guy and then you have some inhibition.
That means that HRP neuron controls the eating.
And then, POMC neuron inhibit the eating.
This is quite new progress, okay,
is because right now we are in a stage we have these
fancy tools to study, to use for this kind of behavior study.
Okay, I guess this all what I can say about this gene and behavior.
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