In last month’s Viewpoint I wrote about
the endocannabinoids—molecules that look
like the active component of marijuana and stimulate
receptors in the brain to promote appetite. The
relevance to obesity and type 2 diabetes is obvious—find
a drug that blocks the endocannabinoids from working,
and you might have a pretty good appetite suppressant.
The story has gotten even more interesting in
the short time since I wrote that piece. In an
attempt to find new members of the endocannabinoid
family, a group of researchers identified a molecule
called oleylethanolamide, or OEA. OEA is made
by cells in the small intestine in response to
food. This makes it different than most endocannabinoids,
which are primarily made in the brain. There are
other critical differences as well, but none more
important than the fact that OEA actually inhibits
food intake, an effect completely opposite to
that of other known endocannabinoids. In addition,
it was recently shown that OEA does not work by
binding the known endocannabinoid receptors, and
it has been unclear which receptor OEA does bind
and activate. More on that in a moment.
OEA is also interesting because it is made in
the small intestine. How does the OEA signal get
to the brain to tell it to stop eating? Well,
it appears that OEA activates nerves in the wall
of the intestine, sending a direct signal to the
parts of the brain that control food intake. This
is in sharp contrast to most other molecules that
affect appetite, such as leptin or ghrelin, which
exert their effects by circulating in the blood
until they hit the brain. In fact, one of the
hallmarks of leptin, ghrelin, and other such molecules
is that they work just as well if injected directly
into the brain as they do when injected into the
blood. OEA, on the other hand, works only if injected
in the intestine; injection into the brain has
no effect whatsoever. It turns out this is because
the OEA receptor, unlike the leptin or ghrelin
receptors, is located outside the brain.
As I alluded to earlier, one of the big mysteries
about OEA has been the identity of its receptor.
In new work published in the journal Nature, the
same team of researchers that discovered the anti-appetite
activity of OEA has solved this puzzle, and I
believe the answer will have a profound impact
on the field of diabetes and obesity out of proportion
to the importance of OEA per se. I say this because
the OEA receptor turns out to be a protein called
PPAR-alpha, and PPAR-alpha is already well known
to be intricately involved in the handling of
fats in the blood and liver.
PPAR-alpha is the target of drugs called fibrates,
such as gemfibrozil (Lopid™) and fenofibrate
(Tricor™). These agents are used to lower
triglyceride levels in blood, and have beneficial
effects on cholesterol as well. These drugs do
not appear to affect appetite, however, probably
because their interactions with PPAR-alpha are
relatively weak. In fact, the new study shows
that stronger PPAR-alpha agonists now being developed
by drug companies to lower blood lipids do, in
fact, reduce appetite in rodents, as would be
predicted from the OEA work. The most impressive
data linking OEA to PPAR-alpha, however, were
from studies performed in mice genetically engineered
to lack PPAR-alpha. These mice are immune to the
effects of OEA, proving conclusively the requirement
for PPAR-alpha in mediating OEA’s effects
on satiety.
Perhaps the most important aspect of the story
lies outside the role of OEA in appetite suppression,
and has more to do with the identity of OEA as
a natural PPAR activator. For years, drug companies
and academic laboratories have invested millions
of dollars in the hunt for the natural compounds
that activate all three forms of the PPAR molecule:
PPAR-alpha, PPAR-delta, and PPAR-gamma. Some candidates
have been identified, but none of them satisfy
all the criteria for a bona fide PPAR activator.
OEA, on the other hand, does meet these criteria.
It is produced in high concentrations in the very
cells that contain PPAR-alpha, it binds to the
receptor with high affinity, it does not bind
to any appreciable degree with the other two forms
of PPAR, and its effects are not seen when the
receptor is not present. The discovery of OEA
as a true PPAR-alpha activator will surely spur
the hunt for similar molecules that might bind
PPAR-delta and PPAR-gamma as well. PPAR-gamma
is of particular interest, since it is the protein
activated by the thiazolidinedione anti-diabetic
drugs Avandia™ and Actos™. The discovery
of a natural PPAR-gamma activator would teach
us an awful lot about what goes wrong in type
2 diabetes, and could lead to the development
of new and more powerful insulin-sensitizing agents.
So the story can be summed up as follows: researchers
note that marijuana smoking increases appetite,
which leads to the discovery of endocannabinoids,
natural compounds that induce food intake. A new
endocannabinoid-like molecule is discovered (OEA)
which unexpectedly blocks appetite. Furthermore,
the effects of OEA are found to be carried by
nerves in the gut, and not by receptors in the
brain. Finally, OEA is discovered to work by binding
and activating PPAR-alpha, providing scientists
with their first look at a true, high-affinity
specific ligand for a PPAR protein.
What this will ultimately mean for patients is
not altogether clear, but I would predict rapid
advancement in the development of drugs that work
on all three forms of PPAR, with benefits on appetite
reduction, lipid lowering, and, probably, new
oral anti-diabetics as well.
References:
F. Rodríguez de Fonseca, M. Navarro, R.
Gómez, L. Escuredo, F. Nava, J. Fu, E.
Murillo-Rodríguez, A. Giuffrida, J. LoVerme,
S. Gaetani, S. Kathuria, C. Gall, D. Piomelli.
An anorexic lipid mediator regulated by feeding.
Nature 414, 209 - 212 (08 Nov 2001).
Jin Fu, Silvana Gaetani, Fariba Oveisi, Jesse
Lo Verme, Antonia Serrano, Fernando Rodríguez
de Fonseca, Anja Rosengarth, Hartmut Luecke, Barbara
Di Giacomo, Giorgio Tarzia, Daniele Piomelli.
Oleylethanolamide regulates feeding and body weight
through activation of the nuclear receptor PPAR-
alpha. Nature 425, 90 - 93 (04 Sep 2003).
This information was last reviewed October 10,
2003.
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