Something old, Something new? A new function for a molecule that is already kno

Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical School

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 body’s metabolism

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 now.

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.

Reference:
Fukuhara et al. Visfatin: A Protein Secreted by Visceral Fat That Mimics the Effects of Insulin. Science 307: 430 (2005).