Adiponectin (also known as Acrp30, AdipoQ, Apm1 and GBP28) is an adipocyte-derived hormone discovered almost simultaneously by four different groups using diverse methodological approaches.1,2,3,4 Very early after its discovery, it was found that the adiponectin gene is exclusively expressed in adipose tissue, which, therefore, represents the only source of the circulating protein. However, unlike leptin, its tissue expression and its plasma concentration are decreased (not increased) in obesity and/or type 2 diabetes. Further work provided evidence that adiponectin may prevent atherogenesis by suppressing endothelial adhesion molecules via inhibition of the NF-KappaB signaling pathway.5,6 Last year, Fruebis et al published exciting novel data showing that a proteolytic cleavage product of adiponectin causes increased fatty acid oxidation and weight loss in murine models of dietary induced obesity.7
In the August issue of Nature Medicine, two studies published side-by-side now show that acute treatment of mice with adiponectin dramatically improves insulin sensitivity in both skeletal muscle and liver tissues.8,9 More specifically, in models of obesity and diabetes, adiponectin improved insulin-mediated glucose uptake by the skeletal muscle and insulin-mediated suppression of hepatic glucose production, both mechanisms leading towards normalization of serum glucose concentration. The effect of adiponectin on skeletal muscle in obese or lipoatrophic mice is mediated by increased expression of genes involved in fatty acid transport and  -oxidation and probably of genes increasing energy expenditure (indicated by an increase in rectal temperature).8 Enhanced thermogenesis and fat oxidation then result in decreased muscle triglyceride content and improved glucose uptake and insulin signaling. In the second study, acute injections of adiponectin to wild-type, ob/ob and non-obese diabetic (NOD) mice resulted in a significant drop in serum glucose concentration in these three animal models.9 Adiponectin decreased glucose output from isolated primary hepatocytes, consistent with the hypothesis that this adipocytokine normalizes serum glucose concentration by suppressing hepatic glucose production.
Together with previously published data, these studies strongly suggest that adiponectin may represent a new molecular target for the treatment of different disorders of the metabolic syndrome including obesity, insulin resistance, and atheroscelerosis. Like leptin, adiponectin seems to prevent the deposition of fat in insulin-sensitive tissues by increasing fat oxidation. Unlike leptin (which acts both directly or via CNS mechanisms), adiponectin seems to act exclusively at peripheral tissues, although its effects on the brain have not yet been tested. Therefore, there are at least two hormones secreted by the adipocyte that play a role in counteracting the ectopic fat storage syndrome by increasing fat oxidation. Interestingly, in Yamauchi's study, insulin resistance was almost totally reversed when the two adipocytokines were combined in physiological dose.8
Insulin resistance is clearly recognized to be one¾if not the most¾important predictor of the development of type 2 diabetes. However, even if the molecular mechanisms of insulin resistance are not totally understood, there is evidence that part of the resistance is related to cellular and intracellular molecular defects whereas the other part may be the consequence of impaired transport of insulin to insulin-dependent tissues. Danforth recently proposed that a failure of adipocyte differentiation precipitates type 2 diabetes by causing storage of excess calories in skeletal muscle, liver, pancreas and blood, all precipitating insulin resistance.10 The major culprit in insulin resistance may, therefore, be an ectopic fat storage in tissues not meant to store fat.11 Three lines of evidence support the above hypothesis. First, failure to develop adipose tissue mass in either mice or man¾known as lipodystrophy¾results in severe insulin resistance and diabetes probably because of excess storage of lipids into tissues other than adipose. Secondly, most obese patients shunt part of dietary fat into skeletal muscle and liver, and the degree of their insulin resistance correlates closely with lipid infiltration into these tissues. Thirdly, large fat cells are predictive of the development of type 2 diabetes,12 probably as a consequence of the failure of the adipose tissue to expand (impaired fat cell proliferation/differentiation) and, therefore, to accommodate excess energy intake. As a result, dietary fat is deposited in excess in tissues not designed for fat storage. In support of the 'ectopic fat storage hypothesis,' treatment with thiazolidinediones improves insulin sensitivity in part by activation of PPAR- , which promotes the differentiation and proliferation of new fat cells, therefore increasing the capacity to store the excess dietary fat. As a consequence, less unwanted fat is deposited in insulin-sensitive tissues and insulin sensitivity is improved.
The two new studies on the insulin-sensitizing role of adiponectin leave us now with many unanswered questions regarding the physiological role and importance of adiponectin in health and disease. How is the secretion of adiponectin controlled? What is the importance of post-translational processing of adiponectin for its physiological activity? Through which receptor(s) does adiponectin or its fragments act? How does adiponectin and other adipocyte-derived proteins interact to modulate insulin resistance? What are the post-receptors signaling pathways involved in the insulin-sensitizing effect of adiponectin? What other physiological mechanisms are regulated by adiponectin?
The inverse correlation between plasma adiponectin and body fat is most intriguing.13 Why do animals or individuals with larger adipose depots secrete less of a protein made by the adipose tissue itself? Such observations may argue in favor of an autocrine or paracrine effect of adipocytes inhibiting their own production and secretion of the hormone. An initial clue towards the regulation of adiponectin secretion is provided by the increased production of the protein in white adipocytes (and 3T3L1 adipocytes grown in vitro) and increased serum concentration in response to treatment with an insulin sensitizing PPAR- activator such as rosiglitazone.8 Furthermore, high-fat feeding of mice caused a reduction in adiponectin mRNA and circulating levels, whereas caloric restriction increased the level of the protein. Thus, adiponectin expression and secretion correlate with insulin sensitivity and these preliminary data indicate that hormones such as leptin and/or insulin may down-regulate its production. However, adiponectin levels seem relatively constant in humans and do not change after a meal, which seems to exclude insulin as a regulator of its production.13 Another issue to be resolved is what part of the adiponectin protein is biologically active? Adiponectin is a 247-amino acid protein consisting of an N-terminal collagenous domain and a C-terminal globular domain.7 Intriguingly, crystallography studies revealed that the globular domain of adiponectin has significant homology with the tumor-necrosis factor family,14 other cytokines involved in insulin resistance. It is unclear whether the whole protein is necessary for the insulin-sensitizing effect since, in some studies, only the intact protein caused biological effects,9 whereas in others the globular domain was sufficient.7 It is conceivable that different post-translational modifications (multimerization, proteolytic processing events) may be required for different biological activities in different tissues. In a genome-wide scan for the discovery of genetic loci underlying the susceptibility to traits of the metabolic syndrome, Kissebah et al identified a 'hot' area on chromosome 3q27 overlapping the region where adiponectin maps on the human genome. More intriguingly, another 'hot' locus (LOD = 5.0) was found on 17p12 working in an epistatic way with the chromosome 3 locus to determine the susceptibility to the development of the metabolic syndrome.15 The locus on chromosome 17 harbors a gene for the receptor protein known to bind the globular 'heads' of the complement factor C1q. This receptor is highly expressed in endothelium, smooth muscle and hepatocytes. Since the globular domain of adiponectin shares significant homology with the globular domain of C1q, it is conceivable that the C1q receptor may be the, or one of the receptors for adiponectin or its biologically active fragment. It is likely that many research groups are actively working on the identification of the adiponectin receptor(s).
Our notion of the adipocyte as being a storage tank for fat has undergone a dramatic change over the past 6 or 7 years.16 It is now well accepted that the adipose tissue plays a complex role as an endocrine organ releasing many important hormones in response to acute or chronic changes in metabolic status. Figure 1 presents many of the hormones and proteins secreted by the adipose tissue including some of the key players for the link between obesity and insulin resistance such as leptin, TNF- , resistin and adiponectin. Now, the challenging task is to understand at the physiological and molecular levels the interaction between these messengers of the obese state and the insulin resistance so common in obesity. Some or all of these hormones seem to play a role in important biological functions such as feeding behavior, energy and fat balance, insulin sensitivity, and atherogenesis. Dynamic interactions between these proteins probably dictate the fine-tuning of the above mechanisms. The two recent papers on the role of adiponectin in insulin sensitivity represent an important step towards an understanding of the regulation of such important survival mechanisms and may shed some light on why the prevalence of disorders of the metabolic syndrome is so high in our 'obesigenic' environment. Most of the work remains to be done to elucidate what part of the insulin signaling cascade is influenced by the activity of these new adipocytokines.
The findings on adiponectin are still preliminary; we need to fully understand the importance of this hormone in health and disease. However, with only preliminary data, there is credence to the idea that adiponectin and its receptor(s) may represent an exciting target for the development of drugs to treat facets of the metabolic syndrome. First, the protein itself or an analog (or a fragment of it) can be used to target insulin resistance in type 2 diabetic patients. These patients will probably be sensitive to the action of adiponectin since their body is relatively depleted in this hormone. This is in marked contrast to the use of leptin, which has been proven mostly inefficacious in obese patients because of resistance to its action. If the biology continues to support the importance of adiponectin in the etiology of traits of the metabolic syndrome, pharmaceutical companies will identify small molecules as oral drugs. Such molecules may act at different steps of the adiponectin pathway, ie to increase the synthesis and secretion of the hormone, to mimic its activity at the level of the receptor or, finally, to enhance in an allosteric manner the activity of the endogenous hormone. New breakthroughs in our under- standing of the regulation of the hormone may also lead to intervention and prevention strategies (such as diet) to improve its production and secretion.
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, interleukins, leptin, resistin and adiponectin play an important role in whole-body carbohydrate metabolism and therefore insulin sensitivity. Adiponectin seems to play a role as an insulin sensitizer, both at the level of the skeletal muscle tissue and the liver. More specifically, it improves muscle insulin sensitivity by increasing fat oxidation and, therefore, decreasing muscle triglyceride, a major inhibitor of insulin signaling. The picture is not so clear at the hepatic level, but the new data discussed in this comment show that adiponectin may have a direct effect on the hepatocyte to suppress glucose production (in vitro data) or indirectly via a lowering of plasma free-fatty acids. The new exciting data about the importance of adiponectin in the development of insulin resistance now raise many questions. How is adiponectin secretion controlled? What is the importance of post-translational processing for adiponectin biological activity? How do adiponectin and other adipocyte-derived proteins interact to modulate insulin resistance? What are the post-receptor(s) signaling pathways involved in the insulin sensitizing effect of adiponectin? What other physiological mechanisms are regulated by adiponectin? All these questions are likely to be at least partially answered within the next year or so.