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Editorial |
Karolinska Institutet at the Department of Medicine Karolinska University Hospital SE-141 86 Stockholm, Sweden
Address all correspondence and requests for reprints to: Peter Arner, M.D., Ph.D., Professor, Karolinska Institutet, Department of Medicine, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}ki.se.
It is well established from epidemiological studies that upper body obesity is a risk factor for type 2 diabetes mellitus (T2DM) and other disorders having insulin resistance as a common pathogenic denominator (1). Visceral adipose tissue seems, in this respect, to be more pernicious than the much larger sc adipose tissue. Unlike all other fat depots, visceral adipose tissue is drained by the portal vein; thereby this adipose region has direct contact with the liver. Portal release of products from visceral fat could be of particular importance for inducing T2DM or protecting from this disorder due to effects on the liver. Indeed, removal of abdominal sc adipose tissue from obese insulin-resistant subjects has no metabolic effect, whereas removal of visceral (i.e. omental) fat improves insulin sensitivity in such individuals (2, 3). Furthermore, most (but not all) cross-sectional studies show a better correlation between insulin sensitivity and visceral fat than with sc adipose tissue, although the latter region is by far the body’s largest fat depot (1).
What factor(s) in adipose tissue causes insulin resistance? It was long thought that fatty acids produced by lipolysis in fat cells were the only culprits. Circulating fatty acids are elevated in T2DM and other insulin-resistant conditions, and they interfere with the production, breakdown, and action of insulin, with glucose metabolism, and with the production of lipoproteins by mechanisms that have been discussed (4). Furthermore, adipocyte lipolysis and thereby fatty acid release is more prominent from visceral than from sc adipose tissue (1). However, during the last 15 yr or so it has become increasingly apparent that adipose tissue, besides releasing lipids, is a very active protein-secreting organ (5). The tissue secretes classical hormones such as leptin and adiponectin, cytokines such as tumor necrosis factor-
and interleukins, chemokines such as monocyte attractant protein 1, coagulation factors such as plasminogen activator 1 (PAI-1), and complement factors such as adipsin. Some of these proteins are termed adipokines, meaning that they are produced by the fat cells. Leptin and adiponectin are only produced by adipocytes, whereas most of the other proteins are produced by fat cells as well as by the stromal cells of adipose tissue. Many of the proteins promote insulin resistance because they have direct or indirect adverse effects on glucose and lipid metabolism and on insulin action. The production of these antiinsulin proteins is increased in the adipose tissue of obese subjects. Several of the adipokines also orchestrate an inflammatory state of adipose tissue, which could be a major etiological factor in the link between adipose tissue and T2DM (6).
Not all adipokines are diabetogenic. Some of them may be protective against insulin resistance and T2DM. The best example is adiponectin, which has insulin-like effects in liver and muscle and also acts as an insulin sensitizer (7). The adipocyte production of adiponectin is decreased in insulin-resistant states, and a low circulating adiponectin level is an independent risk factor for T2DM (5, 7).
Recently an adipose-tissue-derived protein termed visfatin was described with putative antidiabetogenic properties (7). Visfatin was reported to be expressed almost exclusively in visceral adipose tissue and has insulin-like metabolic effects (8). It turns out, though, that the molecule was previously identified as a growth factor for early B-lymphocytes termed pre-B cell colony enhancing factor (PBEF) (9). However, the visfatin gene is expressed in adipocytes, where it is subject to regulation (10, 11, 12). Furthermore, in humans the gene is expressed predominantly in visceral as compared with sc human adipose tissue (7). These findings are exiting news and could provide a novel mechanism by which visceral fat accumulation can promote the development of T2DM as discussed in some detail (13). In particular, effects of visfatin on the liver could be of importance for T2DM and other insulin-resistant disorders because of the portal delivery discussed above.
Further support for a role of visfatin in T2DM is presented in this issue by Chen et al. (14). They measured plasma visfatin in 61 T2DM patients and 59 matched control subjects. The concentration was 2-fold elevated in T2DM, and visfatin was found to be associated with T2DM even after statistical adjustment of known biomarkers. However, after adjustment for body mass index and waist-to-hip ratio there was no longer an independent association between visfatin and T2DM. As a matter of fact, the only fully independent repressor for plasma visfatin levels in the study of Chen et al. was waist-to-hip ratio (14). Despite this finding, the authors concluded that visfatin may play a role in the pathogenesis of T2DM.
Are they right or is visfatin a false trail, as has been the fate for another novel adipose factor termed resistin (15)? The latter protein was originally though to be an adipokine because it is produced by fat cells and causes insulin resistance in rodent models. However, subsequent human studies failed to link resistin to insulin resistance. In addition, the protein is not produced by human fat cells but by some yet-unidentified cell in the stroma of human adipose tissue, which might be the macrophage (16)
A very recent study (17) contradicts several of the findings with visfatin reported in this issue (12) and it also fails to confirm the original findings in human adipose tissue (8). Thus, Berndt et al. (17) found no relationship between plasma visfatin and insulin sensitivity or insulin itself, which differs from what is reported in this issue (14). They also found no difference in visfatin gene expression between sc and visceral adipose tissue in humans and failed to demonstrate an association between visceral fat mass and plasma visfatin, which also contrasts with the original findings (8, 17). Although it is possible to explain some of the discrepancies by differences in methods and in the composition of the study groups, it is reasonable to state that, for the moment, it is unclear whether visfatin is predominantly a visceral fat factor and whether it is related to insulin sensitivity. There is a crux with the study in this issue (12) and with that of Berndt et al. (17). Both reports are "deep-freezer" investigations, meaning that the measures are performed retrospectively on material that has been collected sometime ago for another purpose than to study visfatin. Therefore, we have to await future prospective studies before one can elucidate the true importance of visfatin for T2DM.
Is visfatin a real adipokine? In the original report it was found to be secreted from an artificial mouse fat cell line termed 3T3L1 (8). As pointed out, however, the work on PBEF suggests that the ability of visfatin to be a secreted protein should be interpreted with some caution (18). In cultures of non-adipose cells, PBEF is found predominantly intracellularly (in the nucleus and cytoplasm) and the protein lacks a signal sequence. Therefore, it is necessary to demonstrate significant release of visfatin from true fat cells, in particular human adipocytes, before one can consider this protein as a clinically relevant adipokine. The origin of plasma visfatin remains also to be established. Although the protein may be produced by adipose tissue, it could only be a local factor that is not released into the circulation. This was found to be true for adipose derived TNF- in human adipose tissue (19). Rodent adipose tissue, on the other hand, releases large amounts of TNF- to the circulation (20).
Despite the concerns about the reports on visfatin and PBEF published hitherto, the molecule is a promising model for other insulin mimickers and also for adipogenesis. Visfatin clearly stimulates glucose uptake in adipocytes and myocytes and inhibits glucose release from liver cells (8). Furthermore, it phosphorylates proteins that participate in postreceptor insulin signal transduction (8). Most intriguing, visfatin also binds to the insulin receptor but probably at a different site than the hormone itself (8). The affinities of visfatin and insulin for the insulin receptor are similar, but the circulating visfatin concentration is at least 10 times lower than that of insulin. Furthermore, visfatin is regulated differently than insulin by dietary factors. Taken together, these features of visfatin make the protein per se a less likely candidate for a clinically useful insulin substitute. When, however, visfatin binding sites on the insulin receptor as well as its signal transduction system are better defined, it might be possible to develop therapeutically relevant visfatin analogs.
Besides its metabolic effects, visfatin seems also to regulate adipocyte formation. Overexpression of visfatin in preadipocytes facilitated differentiation of these cells to mature adipocytes and promoted fat deposition in the cells (8). This might also be an insulin-like effect. Clearly, more studies are needed to fully appreciate visfatin stimulation of adipogenesis.
As discussed before (13), the dual effects of visfatin, namely a global insulin-like one and a local adipogenic one, create a therapeutic challenge if visfatin or visfatin analogs are to be used in clinical practice to treat T2DM. On the one hand, they may facilitate glucose control; on the other hand, they may promote the development of obesity.
In summary, visfatin is a promising novel adipose tissue factor, but much remains to be elucidated before its clinical role can be established. For the moment, it cannot be considered as a surrogate marker for visceral fat accumulation despite its name. The labeling of visfatin as a true adipokine is not established. The contribution of adipose tissue to circulating visfatin levels is unknown for the moment. Anyhow, the discovery of visfatin has boosted recent diabetes and obesity research and one is looking forward to knowing more about its mechanism of action, regulation, and clinical relevance. The incidence of T2DM continues to increase dramatically in most parts of the world, and our ways to prevent or cure the disorder are limited despite enormous research efforts. Therefore, novel trails, such as visfatin, are most welcome, even if they are to be proven false.
Footnotes
Abbreviations: PBEF, Pre-B cell colony enhancing factor; T2DM, type 2 diabetes mellitus.
Received November 1, 2005.
Accepted November 11, 2005.
References
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