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A FORUM FOR COMMENTARIES ON RECENT PUBLICATIONS |
Department of Physiology, University of Texas Health Science Center, San Antonio.
IN the January 24, 2003, issue of Science, Blüher and colleagues (1) published a provocative study of mice with a knockout of the insulin receptor specifically in the adipose tissue, referred to by the authors as the "FIRKO mouse." Compared to the wild-type mouse, the FIRKO mouse exhibits a markedly decreased body fat content, a 12% increase in median length of life, and an approximately 14% increase in maximum life span.
Two of the findings are particularly exciting. First is the surprise that elimination of the insulin receptor specifically in the adipose tissue prolongs life. This was unexpected because in Caenorhabditis elegans, a loss-of-function mutation in the insulin-signaling system of the nervous system extends the life span, but a similar mutation in the muscle or intestine does not (2). Second, this FIRKO mouse study and the Holzenberger and colleagues (3) study of heterozygous insulin-like growth factor 1 (IGF-1) receptor knockout mice (also published in January of 2003) are the first to provide clear evidence for manipulations that extend the life span of rodents without decreasing food intake on a per animal basis.
Unfortunately, the authors have interpreted their findings in a questionable and misleading way, epitomized by the penultimate sentence of the paper: "In summary, the results of our studies with the FIRKO mice are consistent with the view that leanness, not food restriction, is a key contributor to extended longevity." This interpretation probably stems from their reason for doing the study, in that the authors state "... it is difficult to separate the beneficial effect of caloric restriction from that of leanness," explaining that the aim of their study was to investigate this question.
They briefly note, and apparently dismiss, the findings in the literature that disassociate caloric restriction's reduction in fat mass and its effect on the longevity of rats and mice (4,5). In ad libitum-fed male F344 rats with body fat content ranging from 15% to 25% of body weight, Bertrand and colleagues (4) found no correlation between body fat content and longevity, and a positive correlation in a study of leaner, caloric-restricted rats. Harrison and colleagues (5) compared obese ob/ob mice with lean mice that were congenic except for the ob/ob locus. They found the ad libitum-fed ob/ob mice to be shorter lived than the ad libitum-fed lean mice, but that the caloric-restricted ob/ob mice (48% adult body fat) were longer lived than ad libitum-fed lean mice (22% adult body fat). In fact, the caloric-restricted ob/ob mice were as long lived as the caloric-restricted lean mice, which were very lean, indeed (13% adult body fat). Certainly, given the recent evidence that visceral fat depots are particularly harmful (6), it is important that these two early studies be followed up with research utilizing modern imaging technology, which permits individual fat depots to be monitored in a longitudinal study. Such studies would determine whether the mass of a particular fat depot is negatively associated with the length of life in rodent populations.
In contrast, the study of the FIRKO mouse model by Blüher and colleagues provides no information on the question of the relative importance of reduced fat mass versus reduced caloric intake in the life-extending action of caloric restriction-nor does it provide strong evidence that reduction in fat mass plays a role in the extension of life span in the FIRKO mouse. It is to be expected that the elimination of the insulin receptor in the adipose tissue would cause marked changes in the metabolism of an organism. Indeed, in an earlier communication, Blüher and colleagues (7) reported that the FIRKO mouse differs metabolically from the wild-type mouse in several ways. It has lower plasma levels of triglyceride, 30 kDa adipocyte complement-related protein, and glucose (the last in fasted animals). The usual age-associated decrease in glucose tolerance and increase in insulin resistance did not occur in the FIRKO mouse. Also, these mutant mice did not show the usual relationship between plasma leptin levels and adipose mass. Indeed, it is likely that future studies will show that the FIRKO mouse differs from the wild-type mouse in many other metabolic parameters. Although an increase in life span is one result of the knockout of the adipose tissue insulin receptor and a reduction in fat mass is another, the research on the FIRKO mouse, at least thus far, does not define the relationship, if any, between the two.
Of concern is that the January 24, 2003, Science article of Blüher and colleagues may mislead those readers not intimately familiar with this subject area. This has already occurred, as seen in a reference to the FIRKO mouse in an article in an August 2003 issue of the Journal of Biological Chemistry by Okamoto and Accili (8). To quote: "These data support the notion that a decreased fat mass can affect lifespan independently of caloric restriction ..." It is certainly understandable that authors wedded to a concept, such as "fat is bad," may unwittingly misinterpret their findings. Thus, it is important that the review process of all journals and premier journals, in particular, provide authors with the guidance needed to prevent this from occurring.
Acknowledgments
Address correspondence to Edward J. Masoro, PhD, 21
Legare Street, Charleston, SC 29401. E-mail: masoro{at}aol.com
Footnotes
Decision Editor: James R. Smith, PhD
Received August 11, 2003
Accepted August 11, 2003
REFERENCES
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