Biology concepts – obesity, brown adipose tissue,
agonist/antagonist, protective hypothermia, hyperthermia, reactive oxygen
species, ischemia, hypoxia
When The Wizard of Oz was
released in 1939, it just barely turned a profit. The '39 version was
the third attempt at filming the children’s classic, and the first two efforts
had not fared much better.
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I
don’t see how people didn’t take to the Wizard of Oz right away.
It
had new technology for the movies, a good villain, and all those
little
people. The tin man on the left was played by Jack Haley, but
originally
it was supposed to Buddy Ebsen (Jed from the Beverly
Hillbillies).
Unfortunately, the lead metal in the makeup almost
killed him
during the makeup/costume tests. Glenda the good witch
(Billie
Burke) had that squeaky voice. She only began acting
after
her husband, Flo Ziegfeld, Jr. (son of the Ziegfeld Follies
creator),
went belly up on Black Monday in 1929.
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It’s smart to hang on to useless things and knowledge, something might
change. For Oz – it was television. For some reason, this film translated
better to TV than it did the big screen. The Library of Congress now rates it
as the most viewed film ever. And it wasn’t even shown on TV until 1956. The
weird part – very few people in 1956 owned a color television, so Dorothy’s
entrance into the land of Oz was no big deal for most folks until the late
1960’s.
Why am I telling you this story? Because the same thing
happens in biology and medicine. Problems can become assets if the right
environment is created or the proper setting is found. We've been discussing
the capsaicin receptor, TRPV1, for some weeks, and this is where I find a
negative being turned into a positive.
As you know, the TRPV1 capsaicin receptor is primarily a heat sensing receptor for thermoregulation of the body. If activated by noxious
(painful) high temperatures, it generates a pain signal and initiates a cooling
program for the body, including sweating.
In an effort to block TRPV1 to create analgesia (no pain),
the problem has been that blockers also stop thermoregulation and the
patient overheats. This prevents most TRPV1 antagonists (substances that bind the receptor but
don’t allow function) from being used as analgesics. But what about in other
situations?
I was wondering if TRPV1 antagonists might be helpful in
obesity, by helping burn off some fat through increased cooling
activity. If they are indeed helpful, nobody knows about it yet. I couldn’t find
even one paper that studied TRPV1 antagonists as a way to induce increased energy
expenditure and weight loss. In fact, I learned just the opposite. Capsaicin
and other TRPV1 agonists might help
with weight loss.
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On
the left is brown fat and white fat. You can see that brown fat
actually
looks browner because of all the mitochondria that it
contains.
White fat contains a lot more lipid. The right cartoon
shows
that a cold challenge initiates uncoupled fat metabolism in
brown
fat, creating heat. But the cold also releases more fatty acids
from white
fat, which can then be burned by the brown fat. The
involvement
of bone comes from bone breakdown. Breakdown
releases
a protein that stimulate white fat to release fatty acids,
this
would provide energy for the brown fat.
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The heat induced by cold comes from increased activity of
brown adipse tissue (BAT) – brown fat. We have talked about BAT before, how it
is especially important for infants because they lose heat so easily. Brown fat
has lots of mitochondria, but they don’t make ATP. They convert all the energy
they burn into heat.
New research is showing that BAT can be important to adults
as well. Those people that have more BAT tend to have less white fat, the kind
that makes you bigger. What is more, a 2013 paper shows that cold temperature
exposure can help create more BAT, and this effect is mimicked by capsaicin and
other TRPV1 agonists.
If you expose adults to mildly cold temperatures for six
hours a day, they start to make more BAT and this means they burn more energy
for heat; therefore less energy is left to be stored as white fat. But the
study also showed that giving the people capsaicin for weeks in a row generated
the same increase in BAT and stopped white fat accumulation.
One mechanism involved is that TRPV1 agonists stimulate an increase in uncoupling protein (UCP) expression in BAT. This is
the protein that permits the BAT mitochondria to produce lots of heat instead of
lots of ATP and a little heat. The uncoupling protein activity in BAT uses excess
calories to produce heat, so those calories are not available to make fat.
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Here
is how a stem cell becomes a fat cell (adipocyte).
The
mesenchymal cell can go two directions, one
toward
fat and one toward muscle. But notice you can
get
to a brown fat cell through the pathway meant for
muscle
cells. PG stands for prostaglandins; different
profiles
of prostaglandins lead to a decision to become
a
brown fat cell or a white fat cell. We know this picture
is
incomplete now, because we have evidence that
TRPV1
agonists can drive the decision between
brown
fat and white fat.
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This all sounds fine, but the proof is in the pudding, so to
speak. Capsaicin and other TRPV1 agonists have been shown to reduce white fat and total body mass in rabbits fed a high-fat/1% capsaicin diet, in mice fed a high sucrose diet, and in human patients kept cold or fed hot. Tomorrow I’m going to
start eating hot peppers in a cold house – I’ll shrink away before your eyes.
What about on the other end of the thermometer? People
freeze to death when they get too cold, and TRPV1 agonists will cool you off
when too warm. No TRPV1 activity causes a reactive hyperthermia, and too much TRPV1 activity will induce a reactive hypothermia. But is there a time when
inducing cold in a body with capsaicin would be a good thing?
Would we be talking about it if there weren’t an exception? It's called protective hypothermia,
and it has become a very important treatment adjunct during stroke and some
over conditions.
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Ischemia
(left) is often associated with coronary (heart) arteries.
Ischemia
means a reduction in blood flow to a tissue or the whole
body.
With less blood flow comes less oxygen, so tissue cells suffer.
Several
mechanisms can lead to a lessening of blood flow. On the
right
is hypoxia, which is often used when referring to the brain or
specific
organs. Hypoxia is a reduction in oxygen to the tissues,
whether
it comes from a reduction in blood flow or some other
reason,
like fewer red blood cells, lower oxygen in the air, etc.
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Getting used to it would include down-regulating the systems that would
normally combat the damage that could be caused by reactive oxygen species
(ROS). Whenever oxygen is being used in tissues, ROS are an unfortunate
by-product. Their name tells you that they’re reactive, which means they can
react with many molecules in the cell and they will do significant damage.
When normal blood flow or oxygen perfusion is re-established,
the sudden increase in O2 causes a spike in ROS (reperfusion injury) – until the cell
can ramp up its antioxidant capabilities again. What medicine needs to do is
find a way to increase the O2 without increasing the ROS damage.
Cold seems to do the trick. Reducing the temperature of the
body reduces cell death and ROS after cardiac arrest, stroke, neonatal
encephalopathy, or traumatic spinal/brain injury. Why? There have been a few
ideas why.
The old hypothesis was that the lower temperature would
reduce cellular metabolism, so that there is less need for O2. This would
imply that the lower the temperature, the better. But very low temperatures
might lead to injury or damage on their own. Also, extended cold could bring
pneumonia or promote sepsis. Maybe colder isn’t always better.
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There
are many ways to get a perfusion injury when
oxygenation
of the tissues is reestablished after hypoxia.
We
talked about the free radicals (ROS) in the post. The
other
injuries are a bit less obvious. We mentioned the
problems
with membranes and the increase in apoptosis.
The
other two are related to spasm of the muscle cells in
the
vessels which would again reduce oxygen levels, and
a
nonspecific activation of coagulation and cell killing that
would
lead to damage as well.
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Even a small decrease in temperature can stabilize the cell
membrane independent of ATP levels. This makes sense; membranes are mostly
lipid, and lower temperatures make fats stiffer – like cold butter. This
will decrease ion movement across the membrane and reduce cell damage.
Lastly, decreased body temperature brings less reperfusion
injury. In this case, maybe the old hypothesis was correct. Colder tissues
metabolize less, so less oxygen will be needed and less ROS will be produced.
So cold is helpful, but how do you do it? You can lower the body temperature by using cooled IV fluid,
cold mist in the nose, or even wrapping specific body parts in cooled blankets.
But perhaps TRPV1 agonists could help cool the body from the inside.
As of early 2014, the evidence for TRPV1 agonists is only in
mouse models, but it’s looking good. A study in 2011 showed the an injection of
capsaicin into the abdominal cavity three hours before inducing hypoxia reduced
the volume of dead tissue and the amount of apoptosis in the brains of the
mice.
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This
is the fruit of the Evodia rutaecarpa
Bentham plant. It has been
used in Chinese herbal medicine for hundreds of years. We are
starting
to learn why it does what it does. It
has been shown to be
an
anti-cancer, anti-obesity, anti-vomiting, anti-hypertension
anti-ulcer,
anti-pain drug. Five thousand years of
culture
leads to good drugs like this.
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The other study from 2013 showed that capsaicin also helps in reperfusion injury. Mice were given strokes by blocking an artery in the
brain and then unblocking it to replenish the blood and oxygen. Injecting capsaicin within
90 minutes of the re-establishment of blood flow produced a mild hypothermia,
reduced the volume of dead tissue in the brain, and increased neural function.
This didn’t occur in mice without TRPV1, so we know the capsaicin receptor was
responsible. Sounds like emergency rooms are going to start stocking hot
peppers.
Today we discussed interesting uses for capsaicin and its
receptor in temperature-related functions. Next week, some weird functions for
TRPV1 that have little or nothing to do with temperature.
For
more information or classroom activities, see:
Brown
adipose tissue –
Protective
hypothermia -
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