So today what I'm going to talk to you about is some work in my
lab, some fairly recent work on adipose metabolism.
I am a metabolic biochemist, so
that big chart you see I actually look at it and
I see the big holes in it and I presume that most of you have
fallen asleep in some sort of class that I might have taught.
So today I'm gonna talk to you about something you probably
heard about in the popular press.
And it's certainly getting a lot of play lately
in the scientific press.
And that is brown adipose tissue, and the ability for
us to all become incredibly thin by activating our brown or
beige adipose sites.
And that would be wonderful.
But let's see what the evidence suggests.
So classically,
there's been really two types of adipose tissue.
The one I usually think about and the one that drives
me the craziest is white adipose tissues.
So white adipose tissue you can see on me and
probably yourselves in great excess, and
its role is really as a storage organ.
So it stores triglyceride for times when we don't have food,
so we can lipolysize, we can mobilize that fat and
use it in other tissues.
And this has been thought to be one of the central components of
diabetes.
Diabetes, some hypotheses would suggest, begin there with
a chronic inflammation that's driven by a high calorie intake.
They don't expend a lot of energy.
It's mainly a huge lipid droplet.
They just store fat in there and there's very little cytoplasm or
anything else within that cell.
Now, in contrast,
there's this other type of fat called brown adipose tissue.
We call it brown adipose tissue because it actually looks brown.
And so this tissue has really had a revolution lately,
because it's thought if we could harness this tissue
which does not store fat but burns fat in a futile cycle,
that we could just burn fat, we could eat as much as we want and
we would be both literally and figuratively hot.
And so this has garnered a lot of attention through
the National Institutes of Health and
like I say within the press.
And oops okay, so we've known for
a long time that if you induce thermogenesis,
if you make the body utilize energy in a futile cycle,
that it is a great weight loss drug.
And we've known this since turn of the 19th century,
that we could uncouple respiration.
Basically we can make feudalcyclene occur
within an organism, within a human and
we can induce a lot of weight loss.
The problem with that is it kills like half the people
who take it and it was one of the first drugs that were
outlawed by the federal Food and Drug Administration.
But because we live in modern times and we have the Internet,
we can get anything over the Internet and
we still see patients in the That have taken
these uncoupling agents, these thermogenic drugs.
And this individual just recently in 2015 died, and
if you read the quote, she was burning from the inside.
So this is an effective weight loss drug, but
it is incompatible with a therapy.
But what the thought is,
if we could harness the natural ability of the body,
natural ability of the brown adipose tissue to burn fat, we
can eat as many calories as we want, particularly fat because
it's a fat burning machine, that we could all be thin.
And like I say this has garnered quite a bit of attention.
And we won't go into the biochemistry.
If you're really interested in it I'd be happy to tell you
about how this happens.
It's a little complicated.
Anyway, so we thought, well, there's a lot of
circumstantial evidence to suggest that we can do this.
There are circumstances, there are drugs that we know that we
use in the clinic that can give you more brown adipose tissue,
and in fact if you do a correlative study you can find
that obese animals have less, lean animals have more.
But we wanted to ask that direct question is if
we remove the ability
of that adipose tissue to burn fat do we get obese mice?
We did this genetically, so
we were able to generate a mouse where we can,
in a cell specific fashion, remove the ability to burn fat.
We did this in adipose tissue, so
we have mice that in their adipose tissue cannot burn fat.
And so, the expectation then, is that they would not be able to
regulate their body temperature and they would be obese.
So in fact when we did this,
we got mice that were cold intolerant.
The normal temperature, at 21° or room at temperature.
But then when we put them in the refrigerator, or
let's say we modeled them going out on a cold day.
>> [LAUGH].
>> Control mice can do this very well.
So, if we look at their core body temperature,
we put a normal mouse in the refrigerator,
then they are able to maintain body temperature.
Their core body temperature stays the same.
No matter where you go, mainly your core body temperature stays
within a very tight range.
But these mice, they dropped like a rock.
And in fact, we have to remove them from the experiment or
it would be lethal.
So it is absolutely required in an autonomous manner for
thermogenesis.
And you can see the control brown adipose tissue is brown.
But when we remove the ability to burn fat, it becomes
this milky white color because it's packed with lipid.
It's packed with fatty acids because it can't burn them.
So now, the expectation is, we've moved this ability of
adipose tissue to burn fat that we would get obese mice.
So we put them on low-fat and high-fat diets, and
it's irrelevant.
It's irrelevant at 21 degrees
that we've lost this ability to burn fat in adipose tissue.
That probably doesn't make me particularly popular.
This is not a hard experiment, it takes gravity and time.
But there does not seem to be at least in our heads a large
component at room temperature.
And in fact, the mice are not less diabetic, they don't seem
to have any improvement in some of the co-morbidities
that are associated with increased weight gain.
So this is actually reminiscent of something that we had
known for quite some time.
So years ago researchers have removed the ability
of this brown adipose tissue to burn fat in other ways and
more systemically.
But what they ended up finding was
they get a very similar phenotype.
The put the mice on a high fat diet and
they don't see much of an improvement in weight gain.
And so it really killed the field for a long time,
it really diminished the enthusiasm until another paper,
actually several independent things happened.
One is that we had thought of humans as
only having brown adipose tissue when they're born.
So there's an interscapular area that newborns have
particularly to keep them warm, but as adults,
we've somewhat lost this ability.
But it had been rediscovered in adult humans that there is
a small amount of brown adipose tissue in your core.
And the thought is that if we can modulate that and
improve upon that, improve upon how much there is,
that this could, Improve body weight regulation.
But the other thing that came out was that,
well maybe we're doing all of our experiments wrong.
And the wrongness of it is that mice don't have clothes on,
but we do.
So we don't go to the animal room without clothes on, and
in fact, no one wants to see that.
>> [LAUGH] >> But
if you then take these mice and put them at the temperature that
they want to be at, which is 30 degrees Celsius,
then they can start revealing some of these phenotypes.
And now you can get these same mice that are whole body
knockouts of thermogenic proteins, to now gain weight.
Maybe this is more closely matched to humans.
And in fact there's a lot of interesting physiology that
happens when we house mice at different temperatures.
And so if we just look at UCP1,
which is a thermogenic protein, which
it regulates the amount of heat that brown adipose can make.
It's regulated by temperature, so
if you put the mice a little bit of cold,
a little bit of hot its expression changes.
And what's interesting, there's a lot of interesting
physiology that goes on because the inside of the mouse,
of course, stays the same temperature, but
they have to react to their outside environment.
So, when they're cold, when they're mildly cold stressed,
at our normal working room temperature
they have to eat more food and they have to expend more energy
because they have to maintain their body temperature.
And in fact there's a whole host of interesting physiology that's
going on, even so much as when mice are housed at
thermoneutrality they can get rid of tumors much easier.
So it's actually kind of driven some thought that maybe
being in a hot tub might be good for well, a lot of things,
but including cancer therapy.
>> [LAUGH] >> So what we had
been kind of forced to ask is, well, if we put these
mice at different temperatures so they can't burn fat
in an autonomous manner, are they able to now become obese.
So we were able to monitor their energy expenditure over time.
And again, this is really interesting physiology.
So if you're at 30 degrees,
their energy expenditure is quite low.
And of course you can see the up and down of
energy expenditure because most of them are active at night.
And then when we change the temperature acutely you get
a huge spike in energy expenditure, and
another huge increase in energy expenditure upon
even going a little bit lower.
However, even though these mice are thermogenically incompetent
in brown adipose tissue,
these types of changes they're able to adapt quite normally.
So, but what was also interesting,
was that we put these mice at thermoneutrality and
we fed them a high fat diet, and the first thing we saw was
we couldn't find any brown adipose tissue anymore.
So by putting our knock outs, the ones that cannot
oxidize fatty acids, can't burn fatty acids and adipose tissue,
they completely eliminate brown adipose tissue.
It's actually quite amazing, my graduate student has dissected
thousands of these mice, I probably shouldn't say that,
anyway, and she can't find it.
She knows what she's doing and it's just not there.
Even histologically it's hard to find.
So now the expectation is, now we have mice that have it, and
we have mice that do not have this tissue,
this thermogenic tissue, that now they're gonna be obese.
And they're not.
So we don't find any evidence that in an autonomous manner
that we can burn our fat away, or
at least not from a therapeutic standpoint but
from a basic science standpoint.
So this is somewhat against, I think, the very strong
push that the field is putting on, as to whether brown adipose
tissue is really playing a role in regulating our body weight.
In fact, these mice are not more diabetic.
They really are very similar to their litter mates.
And so, I just want to leave you with, well,
we really have not found a lot of evidence to suggest that
this is going to be a viable therapeutic target.
It's obviously very important for cold induced thermogenesis.
Mice cannot survive in the cold without it.
But we don't see a change in body
temperature at any ambient temperature.
It's just a remarkable metabolic and physiological adaptation
where the mice are able to maintain normal body weight
even though they can't do this very highly energetic process.
And so one of the things that we really like to ask is really,
does brown adipose tissue really play a role in obesity, but
can we use it now as a therapy?
So we know a couple of ways that we can modify
how much brown adipose tissue a mouse has.
And so here the other remarkable thing that I thing that I didn't
have time to tell you about is that in our mice that can't burn
fat in their adipose tissue.
They also can't make new brown fat.
Their brown fat it doesn't work normally anyway, but
then we can't induce more of it.
So it's a really great model I think moving forward,
is that we can take a control mouse,
and we can take most of their subcutaneous adipose tissue,
white adipose tissue, and turn it into this brown,
thermogenic adipose tissue, in several different ways.
These are not proprietary drugs.
We know how these work.
But our mice do not do this process.
So now what we wanna ask, is there a real therapeutic
potential, or are we barking up the wrong tree?
And that's what I'll leave you with today,
cuz we're just starting those experiments.
So thank you.