A Novel Adipocytokine, Visceral Adipose Tissue-derived Serine Protease Inhibitor (Vaspin), and Obesity

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1 The Journal of International Medical Research 2008; 36: A Novel Adipocytokine, Visceral Adipose Tissue-derived Serine Protease Inhibitor (Vaspin), and Obesity Q LI 1,2, R CHEN 2,3, J MORIYA 2, J YAMAKAWA 2, H SUMINO 4, T KANDA 2 AND T TAKAHASHI 2 1 School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2 Department of General Medicine, Kanazawa Medical University, Ishikawa, Japan; 3 Department of Traditional Chinese Medicine, Union Hospital Affiliated to Huazhong University of Science and Technology, Wuhan, China; 4 Department of Nursing, Faculty of Nursing, Takasaki University of Health and Welfare, Gunma, Japan Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an interesting novel adipocytokine with insulin-sensitizing effects. Some studies have suggested that vaspin could play an important role in the development of obesity and metabolic disorders. The induction of vaspin mrna expression could represent a compensatory mechanism associated with obesity, severe insulin resistance and type 2 diabetes mellitus, however it is unclear whether a correlation exists between human vaspin serum levels and markers of insulin sensitivity and glucose or lipid metabolism. Vaspin serum concentrations have been shown to be lower in lean subjects and competitive sportsmen with long-term physical training, but they are increased with weight loss associated with a physical training programme. In conclusion, there is at present no clear proof of a causal link between vaspin and visceral fat accumulation, or insulin resistance. This article reviews the role of vaspin in obesity-associated diseases and its potential as a new biomarker for obesity and impaired insulin sensitivity. KEY WORDS: VISCERAL ADIPOSE TISSUE-DERIVED SERINE PROTEASE INHIBITOR; VASPIN; OBESITY; ADIPOCYTOKINES Introduction Globally, the incidence of obesity is rising rapidly, not only in industrialized nations but also in developing countries. A variety of disorders, e.g. hyperlipidaemia, hyperglycaemia and hypertension, are common in obese individuals. 1,2 Numerous studies conducted this decade have revealed that adipose tissue secretes a variety of bioactive substances that circulate and affect target tissues. 3 These substances, collectively termed adipocytokines, include leptin, 4 adiponectin, 5 resistin, 6 tumour necrosis factor-α, 7 plasminogen activator inhibitor- 1, 8 interleukin-6 (IL-6) 9 and various growth factors. 10 They are currently considered to play a crucial role in interactions between a variety of systems, including the adrenal, 625

2 immune, and central and peripheral nervous systems. 11 Visceral adipose tissuederived serine protease inhibitor (vaspin) has been identified as an adipocytokine with insulin-sensitizing effects in a rat model of type 2 diabetes; 12 however, the association between vaspin and obesity is unclear. This review focuses on the role of vaspin in obesity-associated diseases. Vaspin: a novel adipocytokine Vaspin, a member of the serine protease inhibitor family, is an adipocytokine that has been isolated from the visceral adipose tissue of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. 11 The OLETF rat is an animal model of type 2 diabetes, which is characterized by abdominal obesity, insulin resistance, hypertension and dyslipidaemia. 13 It is likely that vaspin belongs to the serpins. They are a superfamily of proteins characterized by the presence of a core domain consisting of three β-sheets and nine α-helices. There are approximately 500 serpins and a phylogenetic analysis divides them into 16 classes and 10 highly diverged orphans. 14,15 The inhibitory activity of vaspin is unknown, but the presence of a reactive site loop besides β-sheets and α-helices, indicates that vaspin probably belongs to the serpin family. The rat, mouse and human vaspin cdnas have open reading frames of 1236, 1242 and 1245 nucleotides, respectively, and the putative proteins include 412, 414 and 415 amino acids, respectively. 12 Vaspin gene expression in adipose tissue There has been a paradigm shift from the notion that adipose tissue is merely a storage site for energy to one where adipose tissue plays an active role in energy homeostasis and various processes. 16 The predominant type of adipose tissue, commonly called fat in mammals is white adipose tissue. Vaspin mrna expression has been shown to be highly expressed in the white adipose tissue of OLETF rats at the peak of obesity, body weight and insulin resistance, i.e. at 30 weeks, and decreased with worsening diabetes, i.e. at 50 weeks. 12 Administration of pioglitazone significantly up-regulated the levels of vaspin mrna and maintained them until the rats reached 50 weeks of age. Expression of vaspin mrna was absent, however, in 6-week-old lean Long-Evans Tokushima Otsuka (LETO) rats, and in subdermal, brown fatty tissue and other non-adipose tissues from OLETF rats. 12 These observations suggest that vaspin might have an insulin-sensitizing effect, mainly on white adipose tissue. Human vaspin mrna has been detected in both visceral and subcutaneous white adipose tissue in a subpopulation of obese, not lean, normal glucose tolerant subjects. 17 Visceral vaspin expression significantly correlated with body mass index (BMI), percentage body fat and the levels of plasma glucose following 2-h oral glucose tolerance testing. Subcutaneous vaspin mrna expression was significantly correlated with waist-to-hip ratio, fasting plasma insulin concentration and glucose infusion rate during steady state of an euglycaemic hyperinsulinaemic clamp (Table 1). 17 However, multivariate linear regression analysis revealed percentage body fat as the strongest predictor of visceral vaspin and insulin sensitivity as the strongest determinant of subcutaneous vaspin mrna expression. 17 Some studies have postulated that the induction of vaspin mrna expression in human adipose tissue could represent a compensatory mechanism associated with obesity and severe insulin resistance. 17,18 626

3 TABLE 1: Correlation between anthropometric and biochemical parameters, and vaspin mrna expression and vaspin serum concentration in humans 17,19 Vaspin mrna gene expression 17 Vaspin serum concentration 19 Subcutaneous Visceral tissue tissue NGT group T2D group Gender No correlation No correlation Female > male No correlation BMI Positive correlation No correlation Positive correlation No correlation Percentage body fat Positive correlation No correlation ND ND WHR No correlation Negative correlation ND ND FPG Negative correlation No correlation ND ND FPI No correlation Negative correlation ND ND GIR No correlation Negative correlation Negative correlation No correlation NGT, normal glucose tolerance; T2D, type 2 diabetes; BMI, body mass index; WHR, waist-to-hip ratio; FPG, fasting plasma glucose; FPI, fasting plasma insulin; GIR, glucose infusion rate during the steady state of an euglycaemic hyperinsulinaemic clamp; ND, no data. Serum concentrations of vaspin and pathological status Vaspin has been detected in the sera of OLETF and LETO rats, with serum levels being higher in OLETF rats compared with 30-week-old LETO rats, i.e. during the period of insulin resistance. 12 Levels were markedly reduced in OLETF rats when they developed severe hyperglycaemia at 50 weeks, however insulin and pioglitazone treatments seemed to increase the vaspin serum levels of OLETF rats at 50 weeks of age. 12 In studies involving humans, the correlation between vaspin serum levels and markers of insulin sensitivity and glucose metabolism is unclear. Youn et al. 19 developed an enzyme-linked immunosorbent assay for the measurement of human vaspin serum concentration and found sexual dimorphism in the levels of circulating vaspin (Table 1). Elevated serum concentrations of vaspin are associated with obesity and impaired insulin sensitivity, whereas type 2 diabetes seems to abrogate the correlation between increased circulating vaspin, higher body weight and decreased insulin sensitivity (Table 1). 19 Similarly, Seeger et al. 20 found that vaspin levels were significantly higher in women and that gender was an independent predictor of circulating vaspin in the study population. Gender-dependent regulation has also been demonstrated for adiponectin 21 and leptin. 22,23 Surprisingly, the serum concentrations of vaspin have been found to be lower in lean subjects and competitive sportsmen with long-term physical training, but increased with the weight loss associated with a physical training programme (Table 2). 19 The explanation of Youn et al. 19 for this paradox was that the serum concentration of vaspin was differentially regulated in the resting state and after exercise. This is similar to another adipocytokine, IL-6, which is increased during and after exercise whereas, in the resting state, elevated levels correlate with increased BMI and decreased insulin sensitivity

4 TABLE 2: Vaspin serum concentration and anthropometric and biochemical parameters after a 4-week intensive physical training programme in different groups of subjects 19 Parameters NGT group IGT group T2D group BMI Decrease Decrease Decrease WHR Decrease Decrease Decrease Percentage body fat Decrease Decrease Decrease GIR Increase Increase Increase VO 2 max Increase Increase Increase Vaspin concentration Increase Increase Increase NGT, normal glucose tolerance; IGT, impaired glucose tolerance; T2D, type 2 diabetes; BMI, body mass index; WHR, waist-to-hip ratio; GIR, glucose infusion rate during the steady state of an euglycaemic hyperinsulinaemic clamp; VO 2 max, the maximal oxygen uptake. Vaspin: causative or protective molecule? Vaspin production decreased as diabetes worsened and body weight fell in untreated OLETF rats, but serum vaspin levels were maintained by treatment with insulin or pioglitazone. 12 This suggests that the upregulation of vaspin may have a defensive action against insulin resistance. It is not known whether the role of vaspin is causative or protective in the development of obesity and metabolic disorders. The study by Hida et al. 12 showed, however, that the administration of recombinant human vaspin significantly improved insulin sensitivity and glucose tolerance, and reversed the expression of genes that may promote insulin resistance in dietinduced obese mice. It is, therefore, reasonable to speculate that the production of vaspin may antagonize the action of unknown proteases that impair the action of insulin. Such a protective or ameliorative relationship is well known in other systems, e.g. α 1 -antitrypsin and neutrophil elastase. 25 Youn et al. 19 have suggested, however, that the elevated vaspin concentration seen after 4 weeks of intensive physical training might represent a transient adaptation mechanism, and that vaspin might play a causative role in the development of obesity and metabolic disorders or, at least, be a biomarker for these diseases. The potential mechanisms require further investigation with more sophisticated methods. Conclusion Adipocytokines are cytokines, predominately or exclusively expressed by adipose tissue, that circulate and affect target tissues. 3 They are thought to play a crucial role in interactions between a variety of systems, including the adrenal, immune, and central and peripheral nervous systems. 11 Although several issues are currently somewhat hazy, it is clear that vaspin, a visceral adipose tissue-derived factor with antiprotease activity, represents a potential new biomarker for obesity and impaired insulin sensitivity. Further studies are needed to determine whether vaspin plays a causal role with respect to the aetiology of obesity and type 2 diabetes. Acknowledgement This study was supported in part by a research grant from Grant-in-Aid for Scientific Research (C), the Ministry of 628

5 Education, Culture, Sports, Science and Technology of Japan (No , to Dr T Kanda, in ). Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 28 February 2008 Accepted subject to revision 3 March 2008 Revised accepted 2 June 2008 Copyright 2008 Field House Publishing LLP References 1 Kaplan NM: The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989; 149: Reaven GM: Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 1993; 44: Ahima RS, Osei SY: Adipokines in obesity. Front Horm Res 2008; 36: Van Harmelen V, Reynisdottir S, Eriksson P, et al: Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes 1998; 47: Berg AH, Combs TP, Scherer PE: ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 2002; 13: Steppan CM, Bailey ST, Bhat S, et al: The hormone resistin links obesity to diabetes. Nature 2001; 409: Moller DE: Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000; 11: Alessi MC, Peiretti F, Morange P, et al: Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46: Fried SK, Bunkin DA, Greenberg AS: Omental and subcutaneous adipose tissue of obese subjects release interleukin 6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998; 83: Muise ES, Azzolina B, Kuo DW, et al: Adipose fibroblast growth factor 21 is up-regulated by PPAR and altered metabolic states. Mol Pharmacol 8 May 2008; DOI /mol [Epub ahead of print]. 11 Lago F, Dieguez C, Gómez-Reino J, et al: The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev 2007; 18: Hida K, Wada J, Eguchi J, et al: Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci USA 2005; 102: Kawano K, Hirashima T, Mori S, et al: Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992; 41: Silverman GA, Bird PI, Carrell RW, et al: The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 2001; 276: Gettins PG: Serpin structure, mechanism, and function. Chem Rev 2002; 102: Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116: Klöting N, Berndt J, Kralisch S, et al: Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem Biophys Res Commun 2006; 339: Zvonic S, Lefevre M, Kilroy G, et al: Secretome of primary cultures of human adipose-derived stem cells. Mol Cell Proteomics 2007; 6: Youn BS, Klöting N, Kratzsch J, et al: Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes 2008; 57: Seeger J, Ziegelmeier M, Bachmann A, et al: Serum levels of the adipokine vaspin in relation to metabolic and renal parameters. J Clin Endocrinol Metab 2008; 93: Nishizawa H, Shimomura I, Kishida K, et al: Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 2002; 51: Horn R, Geldszus R, Potter E, et al: Radioimmunoassay for the detection of leptin in human serum. Exp Clin Endocrinol Diabetes 1996; 104: Ma Z, Gingerich RL, Santiago JV, et al: Radioimmunoassay of leptin in human plasma. Clin Chem 1996; 42: Febbraio MA, Steensberg A, Starkie RL, et al: Skeletal muscle interleukin-6 and tumor necrosis factor-α release in healthy subjects and patients with type 2 diabetes at rest and during exercise. Metabolism 2003; 52: Gettins PG: Serpin structure, mechanism, and function. Chem Rev 2002; 102: Author s address for correspondence Dr T Takahashi Department of General Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa , Japan. taka2si@kanazawa-med.ac.jp 629

Changes and clinical significance of serum vaspin levels in patients with type 2 diabetes

Changes and clinical significance of serum vaspin levels in patients with type 2 diabetes L. Yang*, S.J. Chen*, G.Y. Yuan, D. Wang and J.J. Chen Department of Endocrinology, Affiliated Hospital of Jiangsu