Something old, Something new?
A new function for a molecule that is already known
Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical
To an endocrinologist,
there is nothing quite as exciting as the discovery of a new hormone. Hormones
from "classical" endocrine organs like the pituitary and adrenal glands
were described early in the last century. New discoveries have come mainly from
tissues not traditionally considered to be part of the endocrine system. One
such tissue is—believe it or not—fat. Leptin, adiponectin, and resistin
are all fat-derived hormones that have been described in the past ten years.
All of these newly described hormones play important roles in regulating the
It’s been known for a long time that abdominal (or "visceral")
fat is worse for your health than subcutaneous fat. This is the basis for the
distinction between people with "apple" shapes (big bellies, lots
of visceral fat) vs. those with “pear” shapes (big butts, lots of
subcutaneous fat). The apple shapes definitely have it worse than the pears
when it comes to the risk of insulin resistance, type 2 diabetes, and cardiovascular
disease. This has led several groups to try to understand what it is about visceral
fat that makes it so dangerous. Adipose tissue is known to secrete a variety
of factors that can induce insulin resistance, but these seem to be produced
equally by both subcutaneous and visceral fat. In a recent issue of the leading
medical journal Science, however, a group from Osaka, Japan has identified a
protein that is produced in much greater amounts by visceral fat, and it was
thus named visfatin.
Visfatin, it turns out, had already been discovered in a completely different
context. It was found a few years back as a factor that enhances the development
of B cells, which are the cells of the immune system that produce antibodies.
In that context, the factor was named PBEF. PBEF was also found in bone marrow,
liver, and a few other places, but no one ever bothered to look in fat—until
What’s really interesting is that visfatin does not have the properties
that were predicted for a substance made by visceral fat. In fact, the exact
opposite is true. Recall that visceral fat makes you more prone to insulin resistance
and type 2 diabetes. The prediction was that visfatin would increase blood sugar
levels. But when the researchers injected visfatin into mice, blood sugars dropped
substantially. This was true in obese mice that are used as a model of human
type 2 diabetes, as well as in a strain of mice treated with a drug that makes
them more similar to type 1 diabetes.
This led to further experiments that showed that visfatin actually acts as an
insulin mimic—it seems to have all the same biological actions as insulin
itself. In fact, visfatin seems to bind directly to the insulin receptor, albeit
in a different place than insulin. Despite the slightly altered binding position,
visfatin triggers the same cellular responses as insulin, including the induction
of glucose uptake in fat and muscle and the suppression of glucose production
by the liver.
Visfatin circulates at concentrations that are roughly one-tenth those of insulin,
and doesn’t seem to rise and fall in response to eating. This makes it
unlikely that visfatin plays a significant role in the minute-to-minute regulation
of blood sugar levels. It might be useful therapeutically, however, if it can
be delivered more efficiently or conveniently than insulin, or if it enhances
insulin’s action. It is interesting to note that a team from Merck published
a paper several years ago identifying a synthetic drug that could activate the
insulin receptor by binding to a different spot than insulin itself. The existence
of visfatin proves that Mother Nature thought of this idea first.
The discovery of visfatin, or the re-discovery of PBEF if you’re a stickler
for scientific priority, does not explain the detrimental behavior of visceral
fat, and in fact confounds that problem even further. If visceral fat makes
so much visfatin, why isn’t visceral fat healthier for us than subcutaneous
fat? This is still an open and perplexing question, despite the discovery of
a new piece of the metabolic puzzle.
Fukuhara et al. Visfatin: A Protein Secreted by Visceral Fat That Mimics the
Effects of Insulin. Science 307: 430 (2005).