Resistin and Adiponectin—of Mice and Men
Version of Record online: 6 SEP 2012
2002 North American Association for the Study of Obesity (NAASO)
Volume 10, Issue 11, pages 1197–1199, November 2002
How to Cite
Stumvoll, M. and Häring, H. (2002), Resistin and Adiponectin—of Mice and Men. Obesity Research, 10: 1197–1199. doi: 10.1038/oby.2002.162
- Issue online: 6 SEP 2012
- Version of Record online: 6 SEP 2012
- Received for review July 24, 2002. Accepted for publication in final form July 28, 2002
In recent years, a novel paradigm for the role of adipose tissue in metabolism has emerged. The secretion and release into plasma of biologically active peptides with distant sites of action made the adipocyte an endocrine active cell and adipose tissue an endocrine gland. Peptides as diverse as angiotensin, insulin-like growth factor 1, interleukins, and plasminogen-activator inhibitor 1 were found to be expressed and secreted from adipocytes. Many of these hormone-like peptides became of special interest in explaining the pathophysiology of disorders associated with obesity such as hypertension and atherosclerosis. In the arena of type 2 diabetes research, the adipocytokines resistin, adiponectin, and tumor necrosis factor-α are under discussion as links between obesity and insulin resistance, whereas the role of leptin probably has to be confined to the context of lipotrophic diabetes (1).
Two and one-half years ago, the newly described protein “resistin” caused some excitement in the field and was proclaimed as an important link between obesity and insulin resistance (2). In the original publication, serum resistin concentrations were higher in mouse models of obesity (ob/ob, db/db, diet-induced obesity) and decreased with treatment of thiazolidinediones (3). Intravenous administration of resistin caused glucose intolerance and insulin resistance in mice. However, the excitement about the “resistin concept” slackened considerably when a year later Way et al. (4) presented evidence for reduced expression of resistin in epididymal adipose tissue from four different murine models of obesity including ob/ob and db/db mice. Moreover, after treatment with the thiazolidinedione rosiglitazone, resistin mRNA decreased, shaking the original concept even further.
In general, for any peptide proposed to cause insulin resistance in an endocrine fashion, increased levels in serum of the obese would seem to be a prerequisite. Nevertheless, like with tumor necrosis factor-α paracrine, mechanisms may be operative, and increased interstitial concentrations of the peptide, undetected by measurements in serum, may be present. Moreover, there may be fat-depot-specific differences in expression and/or secretion of the peptide. The study by Milan et al. (5) addressed this question by examining resistin gene expression in different fat depots of fa/fa rats. They demonstrated reduced expression of resistin in visceral adipose tissue of obese compared with lean rats and found no difference for subcutaneous adipose tissue. Moreover, weight loss resulted in a further decrease in resistin mRNA levels in visceral adipose tissue, leaving little ground for a role of resistin as link between obesity and insulin resistance in rodents.
In humans, the metabolic role of resistin is even less clear because circulating concentrations have not been reported. This may have to do with difficulties in developing a specific assay, and more likely, with the disputed and probably minute quantities released into plasma. In human adipocytes, resistin is not expressed at all or only at very low levels (6,7,8), although two recent reports from one group suggest otherwise (9,10). Nevertheless, not even proven absence of resistin mRNA from adipocytes would necessarily preclude expression of resistin in human fat depots, which in addition to adipocytes, contains stromal cells (preadipocytes), vascular cells, and blood cells.
Interestingly, two groups reported resistin expression in human white blood cells (7,8). In this issue of Obesity Research, Milan et al. (5) report significant amounts of resistin mRNA expressed in rat splenocytes, albeit less than in visceral adipose tissue, and unresponsive to weight loss. In view of the insulin-sensitizing effect of neutralizing anti-resistin antibodies in mice in vivo (3), it is possible that resistin mediates insulin resistance of inflammation rather than insulin resistance of obesity. It is of note that resistin is identical to a protein previously identified in association with allergic pulmonary inflammation that was called FIZZ1 (found in inflammatory zone 1) (11). Therefore, resistin may well be involved in subclinical inflammatory processes including those affecting adipose tissue.
In contrast to resistin, the evidence for adiponectin as a link between adipose tissue and insulin resistance seems to be less controversial. With a concentration of around 5μg/mL, adiponectin represents one of the most abundant circulating proteins (0.01% of total protein) in human plasma. In obese humans, plasma adiponectin concentrations are significantly decreased (12,13), and high plasma adiponectin concentrations predicted increased insulin sensitivity (12,14). After interventional weight reduction, plasma adiponectin concentrations increased (15). Consistently, Milan et al. reported reduced adiponectin mRNA levels in obese rats compared with lean control animals, which increased with weight loss (5). Interestingly, in their rodent model of obesity the effects were only present in visceral but not in subcutaneous adipose tissue. This is of particular note in view of the observation that in insulin resistant mice, intravenous administration of recombinant adiponectin restored normal insulin sensitivity (16), most likely due to more efficient suppression of hepatic glucose production (17). Finally, adiponectin knockout mice became insulin resistant at ∼8 weeks of age (18). To summarize, adiponectin clearly demonstrates insulin-sensitizing properties both in men and mice; it is lower in adipose tissue and serum of obese animals and humans and qualifies as link between obesity and insulin resistance.
Genetic studies may permit insight into physiological significance of adipocytokines from a different angle. The human homolog of the murine resistin gene has been identified and mapped to chromosome 19p13.3, a region previously not associated with obesity or type 2 diabetes. A number of variants in the resistin genes have been identified in different populations. Some associations with measures of obesity and insulin sensitivity were reported (19,20). Because these were not replicated in other populations or affected the risk of type 2 diabetes (21,22), the issue clearly needs more studies. The human adiponectin gene resides on chromosome 3q27, which was reported to harbor a susceptibility locus for the metabolic syndrome (23). Association with type 2 diabetes and insulin resistance have been reported (24,25), but, like for resistin, requires independent replication. Because for both genes—resistin and adiponectin—no prevalent mutation in the promoter region seems to exist, the search for genetic variants affecting their expression levels will have to be extended to the transcriptional control machinery that would include the interesting peroxisomal proliferator-activated receptor γ (26).
In conclusion, regardless of an association with obesity or inflammation, regardless of whether it is secreted into the circulation in humans or not, and regardless of differences between mice and men, resistin remains an interesting molecule. More work is needed to characterize its target tissues and its receptor, to define its role in signal transduction especially that of insulin, and to delineate a possible role in insulin resistance of inflammation. But like in Steinbeck's Of Mice and Men, the road ahead is sometimes hazy and the outcome uncertain. Nevertheless, with examples such as adiponectin, which is shaping up to become a true endogenous insulin sensitizer, research devoted to adipocytokines remains exciting.
Dr. Stumvoll is supported by a Heisenberg grant from the Deutsche Forschungsgemeinschaft (Stu 192/3-1).