Getting AMP’ed
Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine,
Harvard Medical School
A
few months ago I wrote a Viewpoint about an enzyme called AMP Kinase
(AMPK), which has been getting a lot of attention because of its involvement
in fat burning and insulin sensitivity. AMPK is found in many organs,
including "energetic" tissues like fat, liver, and muscle.
AMPK is an ancient enzyme, meaning that some version of it can be found
in organisms as diverse as yeast, worms, plants, and humans.
In lower organisms, AMPK-like proteins act as a sort of 'fuel gauge',
detecting when energy levels are low and altering biochemical pathways
inside cells to generate more. This general effect also occurs in mammals
like us. AMPK activation leads to increased sugar uptake in muscle and
the burning of fatty acids in liver, among other things.
These actions would be predicted to have a beneficial effect in obesity
and diabetes, by reducing blood sugar levels and by burning triglycerides
that can interfere with insulin signaling pathways in muscle and liver.
Two of the most popular oral agents for type 2 diabetes, metformin and
the thiazolidinediones, stimulate AMPK, which may account for some of
their therapeutic actions. As you might imagine, there is enormous interest
among pharmaceutical companies to produce newer and more powerful drugs
that activate AMPK for use in obesity and diabetes.
Two new studies have just appeared that put a new wrinkle into the AMPK
story. These papers show that AMPK is expressed in the areas of the
brain that control appetite and food intake. As you might predict from
a protein that acts as a sensor for low energy levels, activation of
AMPK in the brain (specifically, in parts of the hypothalamus) induces
food-seeking behavior. In fact, hormones or proteins that are known
to increase hunger, like ghrelin and AGRP, induce AMPK activity. Conversely,
agents that diminish appetite, like leptin and MC4 receptor agonists,
decrease AMPK activity in the hypothalamus. Furthermore, adding a supercharged
version of AMPK to the brain of a mouse causes the animal to eat more
and gain weight, while a so-called "dominant negative" enzyme
(which not only doesn’t work well by itself but also messes up
any normal copies of the enzyme that are hanging around) causes mice
to eat less and lose weight.
The implication of these studies is that drugs that activate AMPK might
have beneficial effects on insulin sensitivity in peripheral tissues
like liver and muscle, but paradoxically, this benefit might be negated
by increased food intake and body weight. Similarly, drugs that antagonize
the effects of AMPK in the brain would be expected to cause people to
lose weight, but might also promote insulin resistance in liver and
muscle. This conundrum will spur research into tissue-specific modulators
of AMPK, which might simultaneously reduce AMPK activity in the hypothalamus,
while stimulating the enzyme in muscle and liver. It may be a lot to
ask, but hey, a guy can dream….
References
Ulrika Andersson, Karin Filipsson, Caroline R. Abbott, Angela Woods,
Kirsty Smith, Stephen R. Bloom, David Carling, and Caroline J. Small.
AMP-activated Protein Kinase Plays a Role in the Control of Food Intake.
Journal of Biological Chemistry, Mar 2004; 279: 12005 - 12008.
Read All of Dr. Rosen’s features by clicking here
http://www.diabetesincontrol.com/rosen/index.shtml
