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.
