Abstract
Objective:
Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance.
Design, subjects and methods:
Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively.
Results:
In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P<0.0001) being also higher in mature adipocytes compared with stromo-vascular cells (P<0.0001). However, OM PEDF relative gene expression was decreased in morbidly obese subjects (P=0.01). Both OM PEDF and OM PEDF receptor (PEDFR) correlated positively with lipogenic and lipolytic genes, and with genes implicated in the lipid vacuole formation. Circulating PEDF levels were not associated with fat PEDF gene expression. In the second cohort, SC PEDF was decreased in subjects with type 2 diabetes and did not change significantly after weight loss. We next explored circulating PEDF in association with markers of liver-related insulin resistance injury (alanine aminotransferase, r=0.59, P=0.001). Interestingly, liver PEDF gene expression increased with obesity and insulin resistance in men, being significantly associated with fasting glucose and glycated hemoglobin in two independent cohorts. In fact, high glucose led to increased PEDF in HepG2 cells, while inflammatory stimuli present in the adipose tissue environment downregulated PEDF.
Conclusion:
Liver, but not adipose tissue, might be the source of increased circulating PEDF linked to insulin resistance.
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References
Tilg H, Moschen AR . Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–783.
Shoelson SE, Herrero L, Naaz A . Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132: 2169–2180.
Tombran-Tink J, Chader GJ, Johnson LV . PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res 1991; 53: 411–414.
Steele FR, Chader GL, Johnson LV, Tombran-Tink J . Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci USA 1993; 90: 1526–1530.
Becerra SP, Sagasti A, Spinella P, Notario V . Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop. J Biol Chem 1995; 270: 25992–25999.
Zvonic S, Lefevre M, Kilroy G, Floyd ZE, DeLany JP, Kheterpal I et al. Secretome of primary cultures of human adipose-derived stem cells (ASCs): modulation of serpins by adipogenesis. Mol Cell Proteomics 2007; 6: 18–28.
Chiellini C, Cochet O, Negroni L, Samson M, Poggi M, Ailhaud G et al. Characterization of human mesenchymal stem cell secretome at early steps of adipocyte and osteoblast differentiation. BMC Mol Biol 2008; 9: 26.
Crowe S, Wu LE, Economou C, Turpin SM, Matzaris M, Hoehn KL et al. Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab 2009; 10: 40–47.
Sabater M, Moreno-Navarrete JM, Ortega FJ, Pardo G, Salvador J, Ricart W et al. Circulating pigment epithelium-derived factor levels are associated with insulin resistance and decrease after weight loss. J Clin Endocrinol Metab 2010; 95: 4720–4728.
Tombran-Tink J, Mazuruk K, Rodriguez IR, Chung D, Linker T, Englander E et al. Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium derived factor, a unique neurotrophic serpin. Mol Vis 1996; 2: 11.
Ponsuksili S, Murani E, Schellander K, Schwerin M, Wimmers K . Identification of functional candidate genes for body composition by expression analyses and evidencing impact by association analysis and mapping. Biochim Biophys Acta 2005; 1730: 31–40.
Jenkins A, Zhang SX, Gosmanova A, Aston C, Dashti A, Baker MZ et al. Increased serum pigment epithelium derived factor levels in Type 2 diabetes patients. Diabetes Res Clin Pract 2008; 82: 5–7.
Chen HB, Jia WP, Lu JX, Bao YQ, Li Q, Lu FD et al. Change and significance of serum pigment epithelium-derived factor in type 2 diabetic nephropathy. Zhonghua Yi Xue Za Zhi 2007; 87: 1230–1233.
Ogata N, Matsuoka M, Matsuyama K, Shima C, Tajika A, Nishiyama T et al. Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy. J Clin Endocrinol Metab 2007; 92: 1176–1179.
Yamagishi S, Adachi H, Abe A, Yashiro T, Enomoto M, Furuki K et al. Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab 2006; 91: 2447–2450.
Yamagishi S, Inagaki Y, Nakamura K, Abe R, Shimizu T, Yoshimura A et al. Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. J Mol Cell Cardiol 2004; 37: 497–506.
Yamagishi S, Nakamura K, Ueda S, Kato S, Imaizumi T . Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF. Cell Tissue Res 2005; 320: 437–445.
Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O et al. Design and validation of a histological score system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313–1321.
Moreno-Navarrete JM, Ortega FJ, Ricart W, Fernandez-Real JM . Lactoferrin increases (172Thr)AMPK phosphorylation and insulin-induced (p473Ser)AKT while impairing adipocyte differentiation. Int J Obes (Lond) 2009; 33: 991–1000.
Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C . Adipose-derived stem cells: isolation, expansion and differentiation. Methods 2008; 45: 115–120.
Famulla S, Lamers D, Hartwig S, Passlack W, Horrighs A, Cramer A et al. Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells. Int J Obes (Lond) 2011; 35: 762–772.
Wedemeyer H, Hofmann WP, Lueth S, Malinski P, Thimme R, Tacke F et al. ALT screening for chronic liver diseases: scrutinizing the evidence. Z Gastroenterol 2010; 48: 46–55.
Sogawa K, Kodera Y, Satoh M, Kawashima Y, Umemura H, Maruyama K et al. Increased serum levels of pigment epithelium-derived factor by excessive alcohol consumptions–Detection and identification by a three-step serum proteome analysis. Alcohol Clin Exp Res 2011; 35: 211–217.
Gaemers IC, Stallen JM, Kunne C, Wallner C, van Werven J, Nederveen A et al. Lipotoxicity and steatohepatitis in an overfed mouse model for non-alcoholic fatty liver disease. Biochim Biophys Acta 2011; 1812: 447–458.
García-Ruiz I, Solís-Muñoz P, Gómez-Izquierdo E, Muñoz-Yagüe MT, Valverde AM, Solís-Herruzo JA . Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice. J Biol Chem 2012; 287: 19564–19573.
Luo Z, Zhang Y, Li F, He J, Ding H, Yan L et al. Resistin induces insulin resistance by both AMPK-dependent and AMPK-independent mechanisms in HepG2 cells. Endocrine 2009; 36: 60–69.
Yamagishi S, Matsui T, Adachi H, Takeuchi M . Positive association of circulating levels of advanced glycation end products (AGEs) with pigment epithelium-derived factor (PEDF) in a general population. Pharmacol Res 2010; 61: 103–107.
Nakamura K, Yamagishi S, Yoshida T, Matsui T, Imaizumi T, Inoue H et al. Hydrogen peroxide stimulates pigment epithelium-derived factor gene and protein expression in the human hepatocyte cell line OUMS-29. J Int Med Res 2007; 35: 427–432.
Yamagishi S, Matsui T, Nakamura K, Ueda S, Noda Y, Imaizumi T . Pigment epithelium-derived factor (PEDF): its potential therapeutic implication in diabetic vascular complications. Curr Drug Targets 2008; 9: 1025–1029.
Diraison F, Dusserre E, Vidal H, Sothier M, Beylot M . Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. Am J Physiol Endocrinol Metab 2002; 282: E46–E51.
Chung C, Doll JA, Gattu AK, Shugrue C, Cornwell M, Fitchev P et al. Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol 2008; 48: 471–478.
Rydén M, Arner P . Tumour necrosis factor-alpha in human adipose tissue – from signaling mechanisms to clinical implications. J Intern Med 2007; 262: 431–438.
Acknowledgements
This work was partially supported by research grants from the Ministerio de Educación y Ciencia (SAF2008-0273). The Prague substudy was supported by research grants from the Ministry of Health of the Czech Republic and General University Hospital in Prague (IGA 10024-4 and MZOVFN2005).
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Moreno-Navarrete, J., Touskova, V., Sabater, M. et al. Liver, but not adipose tissue PEDF gene expression is associated with insulin resistance. Int J Obes 37, 1230–1237 (2013). https://doi.org/10.1038/ijo.2012.223
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DOI: https://doi.org/10.1038/ijo.2012.223
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