The cytokine is at the center of a retraction dispute
By Kelly Rae Chi | June 22, 2007
Scientists continue to debate the validity of a highly-cited, controversial 2004 Science paper about a new fat cell protein with insulin-mimetic properties.
Last week, Osaka University, which hosted the research, demanded that the researchers retract the paper.
In the contested study, Iichiro Shimomura and colleagues at Osaka University Graduate School of Medicine identified a new protein, visfatin, in fat cells and reported that it had insulin-mimetic properties. They found that visfatin lowered blood glucose in vivo in mice and promoted glucose uptake in vitro.
Visfatin, the researchers found, is present in visceral adipose tissue, and circulating levels of the protein correlated with fat mass in humans, which raised the possibility of this protein as a potential drug target for type 2 diabetes and other metabolic disorders, the authors wrote.
But further research in humans has cast doubt on visfatin as a potential therapy.
In the 2004 article, Shimomura and colleagues note that visfatin is genetically identical to a known growth factor for early-stage B-cells. The factor, called pre-B cell colony-enhancing factor (PBEF), is found in bone marrow, liver and muscle. Since 2004, studies have found visfatin/PBEF to be identical to yet another protein, nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in cellular redox reactions.
How visfatin mediates its effects is unclear. In a recent review article, Shin-ichiro Imai, who also works on the same protein, at the Washington University School of Medicine in St. Louis, Mo., and colleagues proposed that the multiple effects of the protein, including its insulin-like properties, can be explained entirely by its ability to catalyze the biosynthesis of nicotinamide adenine dinucleotide (NAD), a classic coenzyme in cellular redox reactions.
Imai's group is testing this proposal, and he declined to talk about unpublished results, but said he believes Shimomura's findings "absolutely" are no longer valid. Imai said it is unclear whether visfatin truly mimics insulin, "but we have made up our mind to deal with this issue purely scientifically," he told The Scientist in an Email.
Using two human subjects, Shimomura's team did not find visfatin mRNA in subcutaneous tissue, but a 2005 Diabetes study found visfatin mRNA in both visceral and subcutaneous adipose tissues. That study did not find a link between plasma concentration of visfatin and insulin sensitivity.
Herbert Tilg, of Innsbruck Medical University in Austria, said "Of course I don't know [whether Shimomura's findings still stand], but the only thing that we can say is that visfatin has been detected repeatedly now in adipose tissue, in visceral adipose tissue and in subcutaneous tissue," he added.
In June 2006, a committee was formed by Osaka University to investigate the findings when "an accuser started to insist existence of fraud, like fabrication or falsification, in the papers of our group," Shimomura wrote to The Scientist in an Email. There was no evidence of fraud, according to Shimomura.
Shimomura wrote that the University raised "several criticisms", though he did not elaborate on what they were. "We authors responded to each of them sincerely. In some aspects, the committee showed different opinions from us," he wrote.
According to Science, the school has not accused the authors of misconduct, but raised "numerous questions" about the paper, including leaving out data that affected the conclusions.
One criticism, according to Science, was the exclusion of data from female knockout mice. The group had made mice heterozygous for a mutation in the visfatin gene and reported that male knockout mice had higher levels of plasma glucose relative to wild-types. The heterozygous female knockouts were left out because they were poor models, according to Shimomura.
"Maybe there is something that I missed, but I don't think that is a real problem," said Claudio Pagano of the University of Padua in Italy. "When you make knockout mice, usually it's not news that you have different phenotypes in males and females."
Shimomura said the group is preparing "adequate action" against the Osaka University. A representative from Osaka University declined to comment on the investigation.
According to Donald Kennedy, editor-in-chief of Science, the journal is taking the investigation very seriously. "We are aware that an investigation of scientific misconduct has been underway at the University of Osaka, and our editors have been in contact with the investigating committee. We have not yet been informed about whether the investigation has been fully concluded. We await the investigation's results and will take appropriate actions once that process has been completed," he said in a statement.
Tilg said it's possible Shimomura's group is wrong about visfatin's potential as a therapeutic target, but in general "he has been considered a high profile scientist. He has made major contributions."
The 2004 findings in Science have been cited 158 times, according to Web of Science.
Shimomura retracted other findings, published in Nature Medicine in 2005, after his group was unable to reproduce data published in the paper. The paper, cited 13 times, found that that reducing activity of an enzyme (different from visfatin) could lead to weight loss and lower blood sugar levels in mice.
What do you think about the 2004 Science paper's data and conclusions? Tell us here.
Kelly Rae Chi
Links within this article:
A. Fukuhara, et al., "Visfatin: a protein secreted by visceral fat that mimics the effects of insulin," Science, published online Dec. 16, 2004.
G. Flores, "Insulin mimic found in fat," The Scientist, Dec. 17, 2004.
J. Stephens & A.J. Vidal-Puig, "An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity," Curr Opin Lipidol, April 2006.
J. Revollo et. al., "The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltranferase regulates Sir2 activity in mammalian cells," J Biol Chem, Dec. 3, 2004.
J. Revollo et al., "The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals," Curr Opin Gastroenterol, March 2007.
J. Berndt et al., "Plasma visfatin concentrations and fat depot-specific mRNA expression in humans," Diabetes, Oct. 2005.
D. Normile, "Osaka University researchers reject demand to retract Science paper," Science magazine, June 22, 2007.
C. Pagano et al., "Reduced plasma visfatin/pre-B cell colony-enhancing factor in obesity is not related to insulin resistance in humans," J Clin Endocrinol Metab, Aug. 2006.
N. Komazawa et al., "Retraction: Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice," Nature Medicine, June 2005.
N. Komazawa et al., "Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice," Nature Medicine, published online Oct. 17, 2004.