The Weaker Vessel
Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard
Medical School
One
of the hottest ideas to hit the cancer world in the last decade is anti-angiogenesis
therapy. Angiogenesis is the process by which new blood vessels are
formed. Tumors can’t keep growing unless their blood supply keeps
pace, so blocking angiogenesis is a logical way to fight cancer. At
least it seemed that way to Judah Folkman, a researcher at Harvard Medical
School, who has achieved iconic status for his contributions in this
area. There are now several anti-angiogenic agents in clinical trials
for different cancers, and fortunes are being made and lost in the biotech
battles to develop ever more potent drugs.
So what does this have to do with obesity and diabetes? Plenty, it
turns out. One of the interesting attributes of fat is that it is the
only normal tissue that can dramatically increase its mass during adult
life. Think about it—you’d be hard pressed to increase the
size of your liver, your lungs, or, sadly, your brain. But large numbers
of Americans are having no trouble expanding their waistlines. In this
way fat is reminiscent of tumor tissue, and like tumor cells, fat cells
would get into trouble quickly if they didn’t increase their blood
supply as they grew.
This sort of thinking led scientists in Folkman’s lab to try
treating obese mice with different anti-angiogenic drugs originally
developed for the fight against cancer. The results were actually quite
impressive; these agents led to significant amounts of weight loss in
all the different models of obesity tested. This slimming effect was
associated with reduced food intake as well as increased energy burning,
although the reasons behind these changes were not clear. The mice appeared
healthy, and it’s important to mention that they didn’t
lose all their adipose tissue. This is critical because the complete
absence of fat, a condition called lipodystrophy, leads to even more
serious health problems than obesity.
One important caveat is that the drugs used in the Folkman study were
general blockers of angiogenesis. That means that they reduced blood
vessel growth throughout the body, not only in fat. While the most obvious
explanation for the weight loss was reduction of angiogenesis in the
fat tissue, other explanations were also technically possible. Furthermore,
you wouldn’t really want to fight obesity with a drug that affects
many different tissues at once.
A new study just published in the journal Nature Medicine puts this
issue to rest. In this study, performed by a group at Baylor University
in Texas, the blood vessels of adipose tissue were specifically targeted
for inhibition. This was made possible by the discovery of a protein
sequence that binds to the blood vessels of adipose tissue, and nowhere
else in the body. By attaching this protein sequence to another protein
that causes cell death, the investigators could target and destroy developing
blood vessels in fat specifically. Consistent with the earlier data
from the Folkman lab, this treatment resulted in significant weight
loss in obese mice.
The Texas group went a step farther, however, by identifying the protein
in the blood vessels of adipose tissue that allowed the specific targeting.
It turns out that this protein, called prohibitin, is known to reside
within all cells in the body, where it serves a variety of poorly understood
functions. Despite its presence inside every cell, it seems (this was
not explicitly proven, mind you) that prohibitin must hang out on the
surface of the blood vessels in fat tissue, where it would be available
for binding.
Lots of important questions remain about the basic biology of the system,
but if these results are confirmed, it would give people a big bulls-eye
to shoot for in the war on obesity. Given where are in that battle,
and where we need to be, any new targets are welcome.
Viewpoint is an editorial column that expresses the opinion of the
specific Medical Director, who is solely responsible for its content.
Viewpoint does not represent the views or opinions of Veritas Medicine
and does not reflect the opinions of other physicians and researchers.
References
Maria A. Rupnick, Dipak Panigrahy, Chen-Yu Zhang, Susan M. Dallabrida,
Bradford B. Lowell, Robert Langer, and M. Judah Folkman. From the Cover:
Adipose tissue mass can be regulated through the vasculature. Proceedings
of the National Academy of Sciences 2002 99: 10730-10735.
Mikhail G Kolonin, Pradip K Saha, Lawrence Chan, Renata Pasqualini,
Wadih Arap. Reversal of obesity by targeted ablation of adipose tissue.
Nature Medicine 10, 625 - 632 (01 Jun 2004).
Written by Evan D. Rosen, M.D., Ph.D.
Content created 6/10/04
This information was last reviewed June 10, 2004.
Read All of Dr. Rosen’s features by clicking here
http://www.diabetesincontrol.com/rosen/index.shtml
