Wednesday, April 23, 2014

Chili Peppers Run Hot And Cold

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.

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.
Over time, what was first considered bad has become a classic. In what many people consider the best year ever in film, The Wizard of Oz is now a favorite among favorites, more than Goodbye Mr. Chips, Mr. Smith Goes to Washington, Stagecoach, or even Gone With the Wind – all produced in 1939.

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.

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.
We have discussed how TRPV1 activation by noxious heat helps to cool the body, but it turns out that noxious cold leads to TRPV1 activation as well, but in these cases, it brings an increase in heat production. So TRPV1 can cool you down or warm you up as needed. Pretty cool. You'll have to wait a few weeks to find out how a heat receptor senses noxious cold.

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.

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.
But there may also be another mechanism at work. A 2014 study in laboratory petri dishes shows that cells destined to become white fat cells can be stopped from changing by capsaicin. In cells called preadipocytes, capsaicin stopped their proliferation (dividing to become more cells) and their differentiation (changing) to become full-fledged adipocytes (fat cells). Another study (2012) showed that in liver, capsaicin could prevent the accumulation of white fat build up (called fatty liver) and could actually induce UCP protein expression in some fat cells, turning them into liver BAT. Amazing.

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 hotTomorrow 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.

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.
Protective hypothermia is an induced cold that is used to protect tissues from post-ischemic injury. When there is a reduction in blood (ischemia) or oxygen (hypoxia) to a tissue or organ, the cells are starved for oxygen and then become starved for ATP (you need oxygen to make ATP). With lower oxygen over time, either from low oxygen or reduced blood flow, the tissues get used to having lower oxygen levels.

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.

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.
Now scientists think protective hypothermia works in a couple of different ways. Colder temperatures bring a neuroprotective effect by preventing apoptosis (programmed cell death). Less O2 means less ATP being made, and a decrease in ATP usually means that the mechanisms for maintaining proper ion movements in and out of the cell are hampered. Increased ion flux triggers apoptosis. So lower temperature brings less ion flux, less damage, and less cellular suicide.

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.

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.
Two 2013 studies added strength to the 2012 study. One experiment used a Chinese herbal medicine that contained a chemical called evodiamine. It had been known that evodiamine helped in stroke victims, but we didn’t know why. Evodiamine was shown to be a TRPV1 agonist in 2012, and the 2013 study showed that after a stroke, the agonist increased cell survival mechanisms and reduced apoptosis.

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.

Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, & Saito M (2013). Recruited brown adipose tissue as an antiobesity agent in humans. The Journal of clinical investigation, 123 (8), 3404-8 PMID: 23867622

Feng Z, Hai-Ning Y, Xiao-Man C, Zun-Chen W, Sheng-Rong S, & Das UN (2014). Effect of yellow capsicum extract on proliferation and differentiation of 3T3-L1 preadipocytes. Nutrition (Burbank, Los Angeles County, Calif.), 30 (3), 319-25 PMID: 24296036

Yoneshiro T, & Saito M (2013). Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Current opinion in clinical nutrition and metabolic care, 16 (6), 625-31 PMID: 24100669

Muzzi M, Felici R, Cavone L, Gerace E, Minassi A, Appendino G, Moroni F, & Chiarugi A (2012). Ischemic neuroprotection by TRPV1 receptor-induced hypothermia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32 (6), 978-82 PMID: 22434066

Cao Z, Balasubramanian A, & Marrelli SP (2014). Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion. American journal of physiology. Regulatory, integrative and comparative physiology, 306 (2) PMID: 24305062

For more information or classroom activities, see:

Brown adipose tissue –

Protective hypothermia -


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