A Tale of Two Cells
Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine,
Harvard Medical School
If
you’re looking for some exciting reading, you generally don’t
turn to the scientific literature. I mean, no one is going to mistake
the Journal of Clinical Investigation (JCI) for The Da Vinci Code anytime
soon. Having said that, I was absolutely riveted recently by a pair
of recent papers in the JCI. These papers are exciting because they
introduce a surprising hypothesis that could go a long way toward solving
some difficult puzzles in obesity and diabetes research.
In both reports, the authors used a technique called transcriptional
profiling to define the obese state in mice. Transcriptional profiling
is a wildly popular new method that allows scientists to identify which
of an organism’s 30,000 or so genes are turned on or off in a
particular cell type at a particular point in time. Both sets of authors
looked at several different kinds of obese mice. There are a variety
of mouse models of obesity that are similar in that they are all fat,
but different in that they have distinct molecular defects that cause
the weight gain. The idea behind these papers was to look at the genes
that are turned on in the fat tissue of these different animals in order
to identify the set of genes that is affected the same way in all of
them. This defines a core set of "obesity-related genes" in
mouse fat tissue. When this was done, the researchers were surprised
to find that a large part of this core set were genes usually associated
with macrophages, and not fat cells.
Macrophages are cells that participate in the immune response. They
can circulate in the blood or they can take up residence in a variety
of organs like the liver and spleen. Macrophages are phagocytic cells,
which means that they engulf cellular debris and foreign invaders like
microbes and destroy them. As such, they are the garbage men of the
body, and they tend to accumulate in inflamed areas. In fact, they are
not simply bystanders in the inflammatory process, but also release
proteins called cytokines that enhance inflammation. One place where
macrophages play a critical pathological role is in the wall of a diseased
blood vessel. Macrophages migrate into the vessel wall and accumulate
lots of cholesterol, transforming themselves into so-called "foam
cells", which play a central role in the development and progression
of atherosclerosis.
For some time now, people have noticed parallels between macrophages
and adipocytes (fat cells). For one, both cells can 
stockpile
lipids. They also express many (but not all) of the same genes. In the
last few years, papers were written showing that macrophages can express
certain genes that were long held to be close to the essence of "fat
cell-ness", including the transcription factor PPAR-gamma and a
fatty acid binding protein called aP2. Adipocytes, meanwhile, express
scavenger receptors and immune proteins long felt to derive primarily
from macrophages. Pre-adipocytes, which are the cells in fat pads that
are destined to develop into mature adipocytes, have been shown to develop
into macrophage-like cells when tickled in certain ways. So there’s
a lot of overlap between these two cells types.
Even with that degree of overlap, however, the presence of a large number
of macrophage genes in obese fat pads struck these investigators as
odd, especially because they weren’t seen in the fat pads of lean
animals. When they looked closely at the fat pads of the obese mice
with a microscope, they found that there were lots of macrophages nestled
in among the adipocytes. This pattern wasn’t seen in the fat pads
from lean animals, which had relatively few macrophages.
The story got more interesting when the authors looked separately at
which genes were being turned on specifically in the adipocytes and
which were preferentially expressed in the macrophages. The results
showed that several genes that we all thought were made by the adipocytes
themselves, in fact turned out to be derived from macrophages. This
includes tumor necrosis factor-alpha (TNF-alpha) and inducible nitric
oxide synthase (iNOS), which are known to be involved in the insulin
resistance associated with obesity.
TNF-alpha and iNOS gene are expressed in fat pads from obese mice but
not lean ones. Knocking out either of these genes makes mice more insulin
sensitive when they become obese, i.e. they are protected from type
2 diabetes. Despite clear data showing that TNF-alpha and iNOS were
made in fat tissue, it was never obvious that they were actually being
made by the adipocytes themselves. Well, these papers show that they
are actually being made by the macrophages mixed into the fat tissue.
It’s this connection that makes these articles so fascinating
in my opinion. There has been a growing sense in the last five years
or so that biochemical changes reminiscent of chronic inflammation might
be linked to obesity and type 2 diabetes. These papers show for the
first time that the cellular composition of the fat pads changes in
obesity, and that the new cells might well be promoting the inflammatory
state. This opens the possibility that it’s the macrophages and
not the fat cell per se that are the culprits in insulin resistance.
In this scenario, one could imagine treating insulin resistance by blocking
the migration of macrophages into the fat pad. Additionally, the presence
of PPAR-gamma (the molecular target of thiazolidinedione drugs like
Avandia™ and Actos™) in macrophages means that these drugs
might exert their anti-diabetic effects in macrophages rather than fat
cells, as has been believed.
I
hasten to point out that these connections are purely speculative at
this point. Nonetheless, this discovery could add a whole list of new
macrophage targets for anti-diabetic drug development. If the inevitable
next round of studies confirms these findings, especially in humans,
then the inflammation hypothesis of insulin resistance will move a step
closer to wide acceptance.
References
Stuart P. Weisberg, Daniel McCann, Manisha Desai, Michael Rosenbaum,
Rudolph L. Leibel, and Anthony W. Ferrante, Jr. Obesity is associated
with macrophage accumulation in adipose tissue. Journal of Clinical
Investigation 2003 112:1796-1808 .
Haiyan Xu, Glenn T. Barnes, Qing Yang, Guo Tan, Daseng Yang, Chieh J.
Chou, Jason Sole, Andrew Nichols, Jeffrey S. Ross, Louis A. Tartaglia,
and Hong Chen. Chronic inflammation in fat plays a crucial role in the
development of obesity-related insulin resistance. Journal of Clinical
Investigation. 2003 112:1821-1830.
