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.