Insulin mimic found in fat

Visfatin activates insulin receptor and lowers insulin levels in vivo and in vitro

Dec 17, 2004
Graciela Flores(

A newly discovered metabolic factor produced predominantly by visceral fat mimics the effects of insulin, according to a report published in this week's Science. The factor, called visfatin, lowered insulin levels in vivo and in vitro and activated the insulin receptor, although in a manner different from that of insulin.

In recent decades, it has become apparent that adipose tissue is not a mere repository of triglycerides, but an extensive endocrine organ that secrets numerous adipocytokines—hormones with key roles in regulating metabolism. "Visfatin should shed new light on the mechanism of insulin resistance and metabolic syndrome [a collection of disorders that includes high insulin and cholesterol levels, and excess body weight] and should help develop a new therapy," senior author Iichiro Shimomura of Osaka University told The Scientist in an email.

Mitchell Lazar of the University of Pennsylvania, who was not involved in the study, was pleased with the "new player from adipose tissue." According to Lazar, adipocytokines can be split into two groups: "insulin resistance factors" (which decrease insulin action) include resistin, tumor necrosis factor alpha, and interleukin 6, while "insulin sensitivity factors" (which improve insulin action) include leptin, adiponectin, "and now visfatin—which actually mimics insulin."

Other hormones, such as the appetite-regulating ghrelin, don't belong to this list because they are not secreted by fat, but are nonetheless important pieces of the network of metabolic regulators. "Once we understand more of the players, we can start modeling [the process]. It's quite interesting," Lazar said.

Shimomura's team came across a protein that is produced by visceral fat—and to a significantly lesser degree by subcutaneous fat—whose plasma levels increased during the development of obesity. The protein turned out to be a known growth factor for early stage B lymphocytes; the authors renamed it "visfatin." "We confirmed that visfatin has a glucose-lowering effect that mimics that of insulin," wrote Shimomura, who assumes that visfatin, like insulin, is involved in maintaining blood glucose levels.

Morris Birnbaum, of Howard Hughes Medical Institute and the University of Pennsylvania, who did not participate in the study, said he found the data "very convincing" but was puzzled by some unexplained results, such as the positive relationship observed between visfatin and insulin sensitivity. "The paper shows that the more visceral fat they had, the more visfatin the fat produced, and that the increase in visfatin improved the sensitivity to insulin," said Birnbaum. "But visceral fat correlates with insulin resistance, not with insulin sensitivity. I found it very difficult to figure a way out of that."

Lazar spotted the same problem, which he called a paradox. "The most intriguing aspect of this paper is that there doesn't seem to be a cause-and-effect relationship [between visfatin and metabolic syndrome]." Lazar speculated that the normal function of visfatin might be to act locally on the adipose tissue where it is secreted. "Visfatin's insulin-like effects would be to make more fat, which would release even more visfatin. So you might get to a vicious loop, and that might help to explain why you have an increase in visceral fat and a worsening of metabolic syndrome."

Birnbaum found this explanation plausible, but he said he is concerned that Lazar's model invokes a lot of elements for which there is no evidence and that it is very different from the model that the authors propose. "In the paper, they talk about circulating visfatin," he said.

Shimomura acknowledged the importance of the paradox. "Most diabetic patients have higher plasma insulin levels because they are insulin resistant," he said. "Chronic hyperinsulinemia due to excess calories induces insulin resistance, leading to the development of diabetes. In this sense, chronic high levels of visfatin in abdominal visceral fat may also be causing insulin resistance by continuously stimulating the insulin receptor."

Regardless of the unexplained results, Birnbaum said that Shimomura's group discovered a protein that improves insulin sensitivity in animals. Much work has to be done, but "it could potentially lead to a new therapeutic," he said. "If you could make a small molecule that mimics visfatin, you'd have a new way of lowering blood glucose in diabetes."