Friday, August 10, 2012

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.