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Serum Vaspin Concentrations in Human Obesity and Type 2 Diabetes Byung-Soo Youn 1 2 , Nora Klöting 3 , Jürgen Kratzsch 4 , Namseok Lee 1 , Ji Woo Park 1 , Eun-Sun Song 1 , Karen Ruschke 3 , Andreas Oberbach 3 , Mathias Fasshauer 3 , Michael Stumvoll 3 and Matthias Blüher 3 1 AdipoGen, College of Life Science and Biotechnology, Korea University, Seoul, Korea 2 Immunomodulation Research Center, University of Ulsan, Ulsan, Korea 3 Department of Medicine, University of Leipzig, Leipzig, Germany 4 Institute of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Leipzig, Germany Address correspondence and reprint requests to Matthias Blüher, MD, University of Leipzig, Department of Medicine, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany. E-mail: bluma{at}medizin.uni-leipzig.de ; or Byung S. Youn, PhD, Scientific Director, AdipoGen. E-mail: bsyoun{at}adipogen.com Abstract OBJECTIVE— Vaspin was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose tissue in a rat model of type 2 diabetes. We have recently shown that vaspin mRNA expression in adipose tissue is related to parameters of obesity and glucose metabolism. However, the regulation of vaspin serum concentrations in human obesity and type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS— For the measurement of vaspin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating vaspin in a cross-sectional study of 187 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or type 2 diabetes before and after a 4-week physical training program. RESULTS— Vaspin serum concentrations were significantly higher in female compared with male subjects. There was no difference in circulating vaspin between individuals with NGT and type 2 diabetes. In the normal glucose-tolerant group, circulating vaspin significantly correlated with BMI and insulin sensitivity. Moreover, physical training for 4 weeks resulted in significantly increased circulating vaspin levels. CONCLUSIONS— We found a sexual dimorphism in circulating vaspin. Elevated vaspin serum concentrations 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. Low circulating vaspin correlates with a high fitness level, whereas physical training in untrained individuals causes increased vaspin serum concentrations. ELISA, enzyme-linked immunosorbent assay HEK, human embryonic kidney IGT, impaired glucose tolerance NGT, normal glucose tolerance OGTT, oral glucose tolerance test PAI-1, plasminogen activator inhibitor type 1 Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 8 November 2007. DOI: 10.2337/db07-1045. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1045 . B.-S.Y. and N.K. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 3, 2007. Received July 28, 2007. DIABETES

Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity Matthias Blüher 1 , Stefan Engeli 2 , Nora Klöting 1 , Janin Berndt 1 , Mathias Fasshauer 1 , Sándor Bátkai 3 , Pál Pacher 3 , Michael R. Schön 4 , Jens Jordan 2 and Michael Stumvoll 1 1 Department of Internal Medicine III, University of Leipzig, Leipzig, Germany 2 Franz-Volhard Clinical Research Center, Charité Campus Buch, HELIOS Klinikum Berlin, and Max-Delbrück Center for Molecular Medicine, Berlin, Germany 3 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 4 Department of Surgery, University of Leipzig, Leipzig, Germany Address correspondence and reprint requests to Michael Stumvoll, MD, University of Leipzig, Medical Department III, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany. E-mail: michael.stumvoll{at}medizin.uni-leipzig.de Abstract The endocannabinoid system has been suspected to contribute to the association of visceral fat accumulation with metabolic diseases. We determined whether circulating endocannabinoids are related to visceral adipose tissue mass in lean, subcutaneous obese, and visceral obese subjects (10 men and 10 women in each group). We further measured expression of the cannabinoid type 1 ( CB 1 ) receptor and fatty acid amide hydrolase ( FAAH ) genes in paired samples of subcutaneous and visceral adipose tissue in all 60 subjects. Circulating 2-arachidonoyl glycerol (2-AG) was significantly correlated with body fat ( r = 0.45, P = 0.03), visceral fat mass ( r = 0.44, P = 0.003), and fasting plasma insulin concentrations ( r = 0.41, P = 0.001) but negatively correlated to glucose infusion rate during clamp ( r = 0.39, P = 0.009). In visceral adipose tissue, CB 1 mRNA expression was negatively correlated with visceral fat mass ( r = 0.32, P = 0.01), fasting insulin ( r = 0.48, P < 0.001), and circulating 2-AG ( r = 0.5, P < 0.001), whereas FAAH gene expression was negatively correlated with visceral fat mass ( r = 0.39, P = 0.01) and circulating 2-AG ( r = 0.77, P < 0.001). Our findings suggest that abdominal fat accumulation is a critical correlate of the dysregulation of the peripheral endocannabinoid system in human obesity. Thus, the endocannabinoid system may represent a primary target for the treatment of abdominal obesity and associated metabolic changes. 2-AG, 2-arachidonoyl glycerol OGTT, oral glucose tolerance test SREBP-1c, sterol regulatory element–binding protein 1c Footnotes M.B. and S.E. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 16, 2006. Received June 14, 2006. DIABETES

Aims/hypothesis Obesity is frequently associated with low-grade inflammation of adipose tissue (AT), and the increase in adipose tissue macrophages (ATMs) is linked to an increased risk of type 2 diabetes. Macrophages have been regarded as post-mitotic, but recent observations have challenged this view. In this study, we tested the hypothesis that macrophages proliferate within AT in diet-induced obesity in mice and humans. Methods We studied the expression of proliferation markers by immunofluorescence, PCR and flow cytometry in three different models of mouse obesity as well as in humans ( n  = 239). The cell fate of dividing macrophages was assessed by live imaging of AT explants. Results We show that ATMs undergo mitosis within AT, predominantly within crown-like structures (CLS). We found a time-dependent increase in ATM proliferation when mice were fed a high-fat diet. Upregulation of CD206 and CD301 in proliferating ATMs indicated preferential M2 polarisation. Live imaging within AT explants from mice revealed that macrophages emigrate out of the CLS to become resident in the interstitium. In humans, we confirmed the increased expression of proliferation markers of CD68 + macrophages in CLS and demonstrated a higher mRNA expression of the proliferation marker Ki67 in AT from obese patients. Conclusions/interpretation Local proliferation contributes to the increase in M2 macrophages in AT. Our data confirm CLS as the primary site of proliferation and a new source of ATMs and support a model of different recruitment mechanisms for classically activated (M1) and alternatively activated (M2) macrophages in obesity.

Plasma Visfatin Concentrations and Fat Depot–Specific mRNA Expression in Humans Janin Berndt 1 , Nora Klöting 2 , Susan Kralisch 2 , Peter Kovacs 2 , Mathias Fasshauer 2 , Michael R. Schön 3 , Michael Stumvoll 2 and Matthias Blüher 1 2 1 Junior Research Group, University of Leipzig, Leipzig, Germany 2 Department of Internal Medicine, University of Leipzig, Leipzig, Germany 3 Department of Surgery, University of Leipzig, Leipzig, Germany Address correspondence and reprint requests to Michael Stumvoll, MD, University of Leipzig, Medical Department III, Ph.-Rosenthal-Str. 27, D-04103, Leipzig, Germany. E-mail: michael.stumvoll{at}medizin.uni-leipzig.de Abstract Visceral and subcutaneous adipose tissue display important metabolic differences that underlie the association of visceral obesity with obesity-related cardiovascular and metabolic alterations. Recently, visfatin was identified as an adipokine, which is predominantly secreted from visceral adipose tissue both in humans and mice. In this study, we examined whether visfatin plasma concentrations (using enzyme immunosorbent assay) and mRNA expression (using RT-PCR) in visceral and subcutaneous fat correlates with anthropometric and metabolic parameters in 189 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. Visfatin plasma concentration correlates positively with the visceral visfatin mRNA expression ( r 2 = 0.17, P < 0.0001), BMI ( r 2 = 0.062, P = 0.004), percent body fat ( r 2 = 0.048, P = 0.01), and negatively with subcutaneous visfatin mRNA expression ( r 2 = 0.18, P < 0.0001). However, in a subgroup of 73 individuals, in which visceral fat mass was calculated from computed tomography scans, there was no correlation between plasma visfatin concentrations and visceral fat mass. We found no significant correlation between visfatin plasma concentrations and parameters of insulin sensitivity, including fasting insulin, fasting plasma glucose concentrations, and the glucose infusion rate during the steady state of an euglycemic-hyperinsulinemic clamp independent of percent body fat. Visfatin gene expression was not different between visceral and subcutaneous adipose tissue in the entire study group nor in selected subgroups. We found a significant correlation between visceral visfatin gene expression and BMI ( r 2 = 0.06, P = 0.001) and percent body fat (measured using dual-energy X-ray absorptiometry) ( r 2 = 0.044, P = 0.004), whereas no significant association between BMI or percent body fat and subcutaneous visfatin mRNA expression existed (both P >0.5). In conclusion, visfatin plasma concentrations and visceral visfatin mRNA expression correlated with measures of obesity but not with visceral fat mass or waist-to-hip ratio. In addition, we did not find differences in visfatin mRNA expression between visceral and subcutaneous adipose tissue in humans. OGTT, oral glucose tolerance test WHR, waist-to-hip ratio Footnotes Accepted June 28, 2005. Received March 30, 2005. DIABETES

Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisomeproliferator-activated receptor gamma (PPARγ), and PPARγ coactivators PGC1α and PGC1β only in the absence of antioxidants (P< 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

Background/ObjectivesPeople with metabolically healthy obesity (MHO) may still have an increased risk for cardiovascular mortality compared to metabolically healthy lean (MHL) individuals. However, the mechanisms linking obesity to cardiovascular diseases are not entirely understood. We therefore tested the hypothesis that circulating cell adhesion molecules (CAMs) are higher in MHO compared to MHL individuals.Subjects/MethodsSerum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin and P-selectin were measured in age- and sex-matched groups of MHL (n = 32), MHO categorized into BMI-matched insulin sensitive (IS, n = 32) or insulin resistant (IR) obesity (n = 32) and people with metabolically unhealthy obesity (MUO, n = 32).ResultsIndeed, individuals with MHO have significantly higher sICAM-1, E-selectin, and P-selectin serum concentrations compared to MHL people. However, these CAMs are still significantly lower in IS compared to IR MHO. There was no difference between the groups in sVCAM-1 serum concentrations. Compared to all other groups, circulating adhesion molecules were significantly higher in individuals with MUO.ConclusionsThese findings suggest that obesity-related increased cardiovascular risk is reflected and may be mediated by significantly higher CAMs. The mechanisms causing elevated adhesion molecules even in the absence of overt cardio-metabolic risk factors and whether circulating CAMs could predict cardiovascular events need to be explored.

Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth Nora Klöting 1 , Linda Koch 2 , Thomas Wunderlich 2 , Matthias Kern 1 , Karen Ruschke 1 , Wilhelm Krone 3 , Jens C. Brüning 2 and Matthias Blüher 1 3 4 1 Department of Medicine, University of Leipzig, Leipzig, Germany 2 Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne, Cologne, Germany 3 Department of Internal Medicine II, University of Cologne and Center of Molecular Medicine Cologne, Cologne, Germany 4 Interdisciplinary Center for Clinical Research (IZKF), Leipzig, Germany Corresponding authors: Jens C. Brüning, jens.bruening{at}uni-koeln.de ; Matthias Blüher, bluma{at}medizin.uni-leipzig.de Abstract OBJECTIVE— IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro. RESEARCH DESIGN AND METHODS— To investigate the role of IGF-1 receptor in vivo, we have inactivated the Igf-1r gene in adipose tissue (IGF-1R aP2Cre mice) using conditional gene targeting strategies. RESULTS— Conditional IGF-1R inactivation resulted in increased adipose tissue mass with a predominantly increased lipid accumulation in epigonadal fat pads. However, insulin-stimulated glucose uptake into adipocytes was unaffected by the deletion of the IGF-1R. Surprisingly, IGF-1R aP2Cre mice exhibited markedly increased somatic growth in the presence of elevated IGF-1 serum concentrations, and IGF-1 mRNA expression was significantly increased in liver and adipose tissue. IGF-1 stimulation of wild-type adipocytes significantly decreased IGF-1 mRNA expression, whereas the opposite effect was observed in IGF-1R–deficient adipocytes. CONCLUSIONS— IGF-1R signaling in adipocytes does not appear to be crucial for the development and differentiation of adipose tissue in vivo, but we identified a negative IGF-1R–mediated feedback mechanism of IGF-1 on its own gene expression in adipocytes, indicating an unexpected role for adipose tissue IGF-1 signaling in the regulation of IGF-1 serum concentrations in control of somatic growth. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 28 April 2008. N.K. and L.K. contributed equally to this work. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 22, 2008. Received October 29, 2007. DIABETES

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the \"Gli-code\" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond. The liver is one of the main organs responsible for processing everything that mammals eat and drink. Nutrients absorbed by the gut like sugars and lipids (fats) are processed by the liver and are stored or distributed to provide energy to other organs. Sometimes these metabolic processes become unbalanced. This can lead to lipids accumulating in the liver – a process known as steatosis, which is a feature of human non-alcoholic fatty liver disease. In organs like the liver, cells are instructed how to behave via signaling pathways. A protein outside the cell signals to specific proteins inside, which switch on a set of target genes. One such pathway is the Hedgehog pathway, which primarily regulates tissue regeneration and the development of embryos. A component of this pathway is the Smoothened gene, which indirectly switches on proteins called GLI factors that regulate metabolic genes, including those involved in lipid metabolism. The Hedgehog pathway has been found to control the metabolism of lipids in fat tissue but it is not known whether it is important for lipid metabolism in the liver. Matz-Soja et al. investigated this possible role of the Hedgehog pathway in the liver using mice with a Smoothened gene that could be deleted specifically in that organ. This deletion disrupted Hedgehog signaling and led to lipids accumulating in the liver and eventually to steatosis. These changes were associated with an increase in the amounts and activityof several enzymes (and the proteins that regulate these enzymes) that help to synthesize lipids. Steatosis was also associated with low amounts of two of the three GLI factors; indeed, this seems to be key for triggering problems with lipid metabolism. Human livers with steatosis showed the same changes in levels of the GLI factors. Increasing the amount of GLI factors in liver cells taken from mice with steatosis reduced the accumulation of lipids and brought lipid metabolism back to its normal balance. A focus of future studies will be to understand how the Hedgehog signaling pathway interacts with other signaling pathways known to regulate liver lipid metabolism, such as insulin signaling. This knowledge will help clinicians to design new treatments for lipid-associated diseases like non-alcoholic fatty liver disease.

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue Byung-Soo Youn 1 , Sa-Ik Bang 2 , Nora Klöting 3 , Ji Woo Park 1 , Namseok Lee 1 , Ji-Eun Oh 1 , Kyung-Bae Pi 1 , Tae Hee Lee 4 , Karen Ruschke 3 , Mathias Fasshauer 3 , Michael Stumvoll 3 and Matthias Blüher 3 1 AdipoGen, College of Life Science and Biotechnology, Korea University, Seoul, Korea 2 Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Medicine, University of Leipzig, Leipzig, Germany 4 Formulae Pharmacology Department, Oriental Medical School, Kyungwon University, Seong Nam City, Kyunggi-Do, Korea Corresponding authors: Matthias Blüher, bluma{at}medizin.uni-leipzig.de , and Byung-Soo Youn, bsyoun{at}adipogen.com Abstract OBJECTIVE— Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS— For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays. RESULTS— Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Gα. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels. CONCLUSIONS— Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 3 December 2008. B.-S.Y. and S.-I.B. contributed equally to this study. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 19, 2008. Received August 22, 2008. DIABETES

The differential associations of adipose depots with metabolic risk during obesity have been proposed to be controlled by environmental and genetic factors. We evaluated the regional differences in transcriptome signatures between abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) in obese black South African women and tested the hypothesis that 12-week exercise training alters gene expression patterns in a depot-specific manner. Twelve young women performed 12-weeks of supervised aerobic and resistance training. Pre- and post-intervention measurements included peak oxygen consumption (VO 2peak ), whole-body composition and unbiased gene expression analysis of SAT depots. VO 2peak increased, body weight decreased, and body fat distribution improved with exercise training (p < 0.05). The expression of 15 genes, mainly associated with embryonic development, differed between SAT depots at baseline, whereas 318 genes were differentially expressed post-training (p < 0.05). Four developmental genes were differentially expressed between these depots at both time points ( HOXA5, DMRT2 , DMRT3 and CSN1S1 ). Exercise training induced changes in the expression of genes associated with immune and inflammatory responses, and lipid metabolism in gSAT, and muscle-associated processes in aSAT. This study showed differences in developmental processes regulating SAT distribution and expandability of distinct depots, and depot-specific adaptation to exercise training in black South African women with obesity.