Author(s): Arner P
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 factorand 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 insulinresistant 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 (10–12). 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 Abbreviations: PBEF, Pre-B cell colony enhancing factor; T2DM, type 2 diabetes mellitus.
Referred From: https://www.semanticscholar.org/paper/Editorial%3A-Visfatin%E2%80%94A-True-Or-False-Trail-To-Type-2-Arner/e3cd53a410ba1fa1d64919a3835d05f8105c6211
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