Burning carbs in the Andes

I am finally back from a very busy semester.  I taught physiology classes at Mills College and UC Berkeley this semester, so I have been interested in new topics in human physiology.  This week’s paper by Schippers et al. came out recently in Current Biology and describes adaptations that mice must make in order to live at high altitude.  They compared the metabolism of mice that live at 4000m above sea level in the Andes where the oxygen content of air is about 13%, to mice at sea level, which contains 21% oxygen.  We all know from experience that we need oxygen to survive and it’s harder to exercise at high altitudes, but why do our bodies actually need oxygen?

Oxygen in cellular respiration

Most all physiology can be explained by the following equation, which describes the process of cellular respiration:

Glucose + 6 Oxygen (O2) --> 6 Carbon dioxide (CO2) + 6 Water (H2O) + 34 ATP

Glucose is a simple carbohydrate (sugar) that we use as a direct energy source.  Glucose, which is 6 carbons long, gets broken down step by step in a series of chemical reactions.  At each step, a little bit of energy is released by the reaction and that is stored in carrier molecules.  These carriers then donate the energy in the form of electrons, which is then harnessed to make another molecule called ATP.  ATP is cellular energy.  The chemical bonds in ATP store high energy and can be used to drive other cellular reactions, like pumping ions, or the process that causes muscle contraction.  Without ATP we die. 

But what does oxygen have to do with this?  Well, the electrons that are donated by the carrier molecules must hop from protein to protein in what is known as the “electron transport chain”.  The final electron acceptor is oxygen (O2), which forms water with that extra electron.  That’s it.  That’s why we breathe, that’s why our heart pumps blood— our tissues need energy (ATP) to perform cellular tasks and in order to get energy from glucose, we need oxygen to accept the final electron.  Carbon dioxide is produced as a byproduct and is removed from the body during exhalation.

Glycolysis is anaerobic respiration and does not use oxygen. Note that oxygen is used as the last step of the electron transport chain to make the majority of the ATP. (www.phschool.com/science/biology_place/biocoach/cellresp)

I should also mention here that the more our tissues are active and working, the more ATP they need and the more O2 needs to get to the cells.  When we exercise our muscles are very active, so that’s why the heart rate and breathing rate increase; our body needs to intake more oxygen and distribute it faster to our muscles.

You can see that oxygen plays a critical role in our cells, so the mice at high altitudes are going to have a harder time getting their cellular energy.  How do they manage to run around when there is so little oxygen?

Energy sources

As I mentioned above, we can make ATP directly from glucose (a carbohydrate).  We can also make ATP by using fats as an energy source.  There are two differences between these two energy sources:

1) When we use fats as an energy source, it always requires oxygen.  Glucose, on the other hand, can make a limited amount of ATP without oxygen, which is called anaerobic respiration.  This is useful during short vigorous activity, but we cannot make enough ATP by anaerobic respiration for sustained exercise.

2) For a given amount of oxygen, more ATP is produced from carbohydrates, like glucose, than from fats.  However, the amount of ATP created from a single fat molecule is greater than from a glucose molecule.  In other words, if you have plenty of oxygen, you should be burning fats.  But once oxygen becomes limiting, either because you’re working so hard, or because you’re at a high altitude, then carbohydrates should be used.

Given this information, the authors hypothesized that the mice at high altitudes will burn more carbohydrates than mice at sea level.  They have a limited amount of oxygen in the air, so they need to use it in the most efficient way to produce the energy they need.

High altitude mice burn more carbohydrates, but fatigue sooner

The authors did all their tests in the same experimental conditions, with the same amount of oxygen in the air for both sets of mice.  Under normal oxygen conditions and when there was low oxygen content, the high altitude mice burned more carbohydrates than the other mice during moderate exercise.  At rest, they also burned more carbohydrates under low oxygen conditions.  The authors found that the activity of enzymes associated with breaking down carbohydrates were greater in the high altitude mice, specifically in the heart muscles.  The heart has to work harder at high altitude to get enough oxygen to the tissues, so it makes sense that these muscles, in particular, would be burning carbohydrates preferentially. 

The high altitude mice, therefore, have adapted to the low oxygen environment by having more active enzymes to break down carbohydrates rather than fats.  One problem with that, though, is that the carbohydrate storage is less extensive than fat storage.  The researchers found that high altitude mice fatigued more quickly than the sea level mice, which burned more fats.  They suggest that the fast fatigue is a result of using up all the carbohydrate stores.  These mice, though, don’t travel long distances and just need short bursts of speed to escape predators.

I really like how so many physiological processes can be explained through understanding cellular respiration.  It’s so logical that animals at high altitude need to use oxygen more efficiently, so they use carbohydrates more for energy.  It’s simple.

Cellways on temporary hiatus

I will not have time to update this blog this semester since I am teaching four classes plus research.  I'll catch up with you again in the winter.

In the meantime, enjoy this hilarious chemistry comic:

A biological reason for aging weight gain

There is a growing epidemic of obesity in the aging population.  Of course a lot of this has to do with our cultural lifestyle, but could there also be a biological explanation related to the way our bodies age?  One clue comes from the fact that older lab mice have a tendency to become obese, without the added influence of fast food restaurants.  Although there certainly are differences in metabolism as you age, the older mice also intake more food; it’s as if their body isn’t telling them the “I’m full” signal.  Yang et al examine the biological mechanism underlying this age-dependent obesity in the newest edition of Neuron. 

The Hypothalamus

There is a region towards the interior of the brain called the hypothalamus which controls all sorts of basic physiological parameters.  For instance, it sets the body temperature, monitors blood pressure and the water content of the blood, and initiates the feeling of thirst and hunger.  There are a group of neurons in the hypothalamus called POMC neurons, which release a hormone, called a-MSH, which decreases appetite (the feeling of “I’m done eating”).  Could it be that these neurons don’t function properly in older mice, so they aren’t getting enough a-MSH to signal them to stop eating?

Problems with the POMC neurons

The authors find that as the mice get older, their POMC neurons get more negative inside.  Remember that active neurons fire action potentials, which are basically short bursts of positive ions rushing into the cell.  If the POMC neurons are more negative than usual, they will have further to go to fire an action potential and will be less active.  The older POMC neurons are in fact much less active and therefore release less a-MSH.

What makes the older POMC neurons more negative?  The authors find that the neurons are overexpressing a potassium channel (K channel), which will mean there are more open pores in the membrane for K to escape the cell.  As the positive K ions leave the neuron, it will make the inside more negative.  Okay, but why are K channels overexpressed in older neurons?  Turns out this whole cascade is initiated by a key signaling protein called TOR.  Increased TOR levels have been associated with various aspects of aging before, and an inhibitor of TOR (called rapamycin) can increase the life span of mice and other animals.  Check out the diagram below, which puts all these steps together.

Summary: For whatever reason, POMC neurons overexpress TOR, which makes these neurons less active.  They release less of the a-MSH hormone, so the mice don’t get the “stop eating” signal and continue to intake food, leading to obesity.

Two complimentary experiments

To test that this pathway is actually correct, the authors did two complimentary experiments.

1) If TOR is artificially increased in young mice (to mimic older mice), will they intake more food and gain weight?

2) If TOR levels are decreased in older mice (to mimic younger mice), will they lose weight?

For experiment #1, they raised TOR levels in young mice by knocking out an upstream inhibitor of TOR.  TOR levels are normally controlled within a certain range by inhibitors, so if you get rid of that inhibition, there will be more TOR present.  Over many weeks, these mutant mice did in fact get fatter than the controls and their POMC neurons were too negative and didn’t function properly, just like older mice.

For experiment #2, they wanted to decrease TOR in older mice.  This is actually pretty easy to do by injecting the older mice with the drug rapamycin, which inhibits TOR (TOR actually stands for Target Of Rapamycin).  Rapamycin is made by bacteria, which were first discovered in soil samples from Easter Island.  It is currently approved for human use, as an immunosuppressant for organ transplant patients.  When the older mice were injected with rapamycin for a few weeks, the POMC neurons came back to life and fired many action potentials.  The cells weren’t so negative because there were less K channels being expressed.  And yes, rapamycin caused the older mice to eat less and lose a considerable amount of weight.

So there you have it: rapamycin is the wonder drug—it will make you live longer and healthier, but there will be a price to pay with a lowered immune system.  There may be other ways to tap into this dysfunction in the older POMC neurons to help prevent midlife obesity.

Magneto... yes??

A few months ago I wrote about an article that disputed the claim that pigeons have iron-rich cells in their beaks that sense the earth’s magnetic field.  A new paper by Eder et al. in Proceedings of the National Academy of Sciences describes their discovery of magnetic cells in the trout nose.

The way they discovered these cells was pretty ingenious.  The authors took tissue from the trout olfactory epithelium, which is where chemical odors are sensed, and also where magnetic sensing probably occurs.  They dissociated the cells, which means they separated them from each other, so they were free to move about in the liquid culture.  Then they applied an external magnetic field and rotated it around the dish while they looked at the cells in the microscope.  Out of every 10,000 cells, they observed 1-5 cells that rotated in sync with the magnetic field.  Wow!  I can imagine the excitement in the lab when they first saw a spinning cell.  It’s no wonder that other labs were not able to isolate the magnetic-sensitive cells, since they are so sparse. 

They noticed that each of these rotating cells had a dark chunk inside them that could reflect the microscope light.  Upon closer inspection, this “inclusion” was located right next to the membrane just inside the cell.  They analyzed the elemental composition of the inclusions and a major component was iron, the only biological atom that is magnetic.  The authors suspect that the iron is in the form of magnetite (Fe3O4), which has been found in some bacteria. 

The magnetic inclusions must be attached to the membrane, because the cells move at the same rate as the external magnetic field.  If the magnetite were not tethered to the membrane, then it would spin freely in the intracellular liquid without affecting the rest of the cell.

The cell on the left has unattached magnetite (Fe), whereas on the right it is attached to the membrane.

How do spinning cells tell the rest of the trout about the location of the magnetic field?  We don’t know, but when the cells are in the olfactory epithelium in the trout, I’m sure they will not be able to rotate so freely.  What happens most likely is that changes to the magnetic field will cause the magnetite to change positions slightly, which will tug on the membrane and cause mechanoreceptors to open.  These are ion channels that open or close when there are mechanical deformations of the membrane (like stretching or pushing).  Once ion channels are involved, they can “activate” the cell and send signals to cells in the nervous system, which will relay this information to the brain.  Of course, there's no evidence that these particular rotating cells will do that in vivo, but it certainly is a tantalizing start.

Here is another blogger's take on this same article, but from a physics point of view.

The cunning (and conning) cuttlefish

“The old adage that cheaters never prosper is far from applicable in the animal kingdom.”  That’s the first sentence of a new paper by Brown et al. that was published this week in the journal Biology Letters.  There are numerous examples of animals deceiving other members of their own species and social group.  For instance, one animal could give a false predator alert signal to its group, so it can have a resource all to itself.  However, these cheaters run the risk of being discovered and beat up or otherwise punished (humans do this too but we usually put our cheaters in jail).  The authors investigated this process of deception in the world of cuttlefish.

Cuttlefish are cephalopods like the octopus. They can change the pattern and texture of their skin very rapidly, and different patterns act as signals to their fellow cuttlefish.  Females have one specific display towards rival males ("go away"), whereas males have another pattern when trying to court a female.  Males are often competing for receptive females and interrupting each other’s courtship attempts (that’s not cool).  So wouldn’t it be really beneficial for a male if he could change his display so as not to attract another male rival during courtship.

The authors witnessed an amazing act of signal deception: a male that is interested in courting a female to his left would show the courtship pattern on the left side of his body, while simultaneously showing the female signal to his right side.  A rival male coming up on his right side would see the female display saying “get out of here”, so he wouldn’t try to interrupt the courtship process. 

From Brown et al., 2012, Biology Letters

Just look at this image here; the male has stripes on the side facing the female (“come on baby”) and spots on the side facing a rival male (“not interested”).  And the amazing thing is that they only witnessed this particular type of patterning on males in the company of a receptive female and a rival male.  There’s no sense in cheating if there’s no male around and if there is more than one rival, chances are the trick will be discovered and the cheater will get punished.

Molecularly this is blowing my mind -- how can they create such intricate patterns so quickly?  Behaviorally this is also incredible – it’s such an intelligent form of cheating and it will really pay off if it means he can have a successful mating and pass on his genetic material to the next generation.