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. 2008 Jul 18;13(4):599–613. doi: 10.2478/s11658-008-0025-6

Regulation of human aldoketoreductase 1C3 (AKR1C3) gene expression in the adipose tissue

Per-arne Svensson 1, Britt G Gabrielsson 1, Margareta Jernås 1, Anders Gummesson 1, Kajsa Sjöholm 1,✉
PMCID: PMC6275867  PMID: 18641923

Abstract

Aldoketoreductase 1C3 (AKR1C3) is a functional prostaglandin F synthase and a negative modulator of the availability of ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ). AKR1C3 expression is known to be associated with adiposity, one of the components of the metabolic syndrome. The aim of this study was to characterize the expression of AKR1C3 in the adipose tissue and adipocytes and to investigate its potential role in the metabolic syndrome. Using microarray analysis and realtime PCR, we studied the expression of AKR1C3 in adipose tissue samples from obese subjects with or without metabolic complications, during very low calorie diet-induced weight loss, and its expression in isolated human adipocytes of different sizes. The adipose tissue AKR1C3 expression levels were marginally lower in obese subjects with the metabolic syndrome compared with the levels in healthy obese subjects when analyzed using microarray (p = 0.078) and realtime PCR (p < 0.05), suggesting a secondary or compensatory effect. The adipose tissue mRNA levels of AKR1C3 were reduced during and after dietinduced weight-loss compared to the levels before the start of the diet (p < 0.001 at all time-points). The gene expression of AKR1C3 correlated with both adipose tissue mRNA levels and serum levels of leptin before the start of the diet (p < 0.05 and p < 0.01, respectively). Furthermore, large adipocytes displayed a higher expression of AKR1C3 than small adipocytes (1.5-fold, p < 0.01). In conclusion, adipose tissue AKR1C3 expression may be affected by metabolic disease, and its levels are significantly reduced in response to dietinduced weight loss and correlate with leptin levels.

Key words: Metabolic syndrome; Adipose tissue; Adipocytes; Diet-induced weight loss; Aldoketoreductase 1C3; 15-deoxy-12,14-prostaglandin J2

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Abbreviations used

15d-PGJ2

15-deoxy-12,14-prostaglandin J2

AKR1C3

aldoketoreductase 1C3

BMI

body mass index

HDL

high density lipoprotein

hs-CRP

high sensitivity C-reactive protein

LDL

low density lipoprotein

om

omental

PPARγ

peroxisome proliferator-activated receptor-gamma

sc

subcutaneous

VLCD

very low calorie diet

WHR

waist-to-hip ratio

Footnotes

These authors contributed equally to this study

References

  • 1.Goldstein D.J. Beneficial health effects of modest weight loss. Int. J. Obes. Relat. Metab. Disord. 1992;16:397–415. [PubMed] [Google Scholar]
  • 2.Sjöström L., Narbro K., Sjöström C.D., Karason K., Larsson B., Wedel H., Lystig T., Sullivan M., Bouchard C., Carlsson B., Bengtsson C., Dahlgren S., Gummesson A., Jacobson P., Karlsson J., Lindroos A.K., Lönroth H., Näslund I., Olbers T., Stenlöf K., Torgerson J., ågren G., Carlsson L.M. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 2007;357:741–752. doi: 10.1056/NEJMoa066254. [DOI] [PubMed] [Google Scholar]
  • 3.Rajala M.W., Scherer P.E. Minireview: The adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144:3765–3773. doi: 10.1210/en.2003-0580. [DOI] [PubMed] [Google Scholar]
  • 4.Björntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991;14:1132–1143. doi: 10.2337/diacare.14.12.1132. [DOI] [PubMed] [Google Scholar]
  • 5.Despres J.P., Moorjani S., Lupien P.J., Tremblay A., Nadeau A., Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis. 1990;10:497–511. doi: 10.1161/01.atv.10.4.497. [DOI] [PubMed] [Google Scholar]
  • 6.Kissebah A.H. Intra-abdominal fat: is it a major factor in developing diabetes and coronary artery disease? Diabetes Res. Clin. Pract. 1996;30(Suppl):25–30. doi: 10.1016/s0168-8227(96)80035-0. [DOI] [PubMed] [Google Scholar]
  • 7.Pouliot M.C., Despres J.P., Nadeau A., Moorjani S., Prud’Homme D., Lupien P.J., Tremblay A., Bouchard C. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992;41:826–834. doi: 10.2337/diabetes.41.7.826. [DOI] [PubMed] [Google Scholar]
  • 8.Montague C.T., O’Rahilly S. The perils of portliness: causes and consequences of visceral adiposity. Diabetes. 2000;49:883–888. doi: 10.2337/diabetes.49.6.883. [DOI] [PubMed] [Google Scholar]
  • 9.Gabrielsson B.G., Johansson J.M., Jennische E., Jernås M., Itoh Y., Peltonen M., Olbers T., Lönn L., Lönroth H., Sjöström L., Carlsson B., Carlsson L.M., Lönn M. Depot-specific expression of fibroblast growth factors in human adipose tissue. Obes. Res. 2002;10:608–616. doi: 10.1038/oby.2002.83. [DOI] [PubMed] [Google Scholar]
  • 10.Gabrielsson B.G., Johansson J.M., Lönn M., Jernås M., Olbers T., Peltonen M., Larsson I., Lönn L., Sjöström L., Carlsson B., Carlsson L.M. High expression of complement components in omental adipose tissue in obese men. Obes. Res. 2003;11:699–708. doi: 10.1038/oby.2003.100. [DOI] [PubMed] [Google Scholar]
  • 11.Vidal H. Gene expression in visceral and subcutaneous adipose tissues. Ann. Med. 2001;33:547–555. doi: 10.3109/07853890108995965. [DOI] [PubMed] [Google Scholar]
  • 12.Blouin K., Richard C., Belanger C., Dupont P., Daris M., Laberge P., Luu-The V., Tchernof A. Local androgen inactivation in abdominal visceral adipose tissue. J. Clin. Endocrinol. Metab. 2003;88:5944–5950. doi: 10.1210/jc.2003-030535. [DOI] [PubMed] [Google Scholar]
  • 13.Blouin K., Richard C., Brochu G., Hould F.S., Lebel S., Marceau S., Biron S., Luu-The V., Tchernof A. Androgen inactivation and steroidconverting enzyme expression in abdominal adipose tissue in men. J. Endocrinol. 2006;191:637–649. doi: 10.1677/joe.1.06365. [DOI] [PubMed] [Google Scholar]
  • 14.Quinkler M., Bujalska I.J., Tomlinson J.W., Smith D.M., Stewart P.M. Depot-specific prostaglandin synthesis in human adipose tissue: a novel possible mechanism of adipogenesis. Gene. 2006;380:137–143. doi: 10.1016/j.gene.2006.05.026. [DOI] [PubMed] [Google Scholar]
  • 15.Quinkler M., Sinha B., Tomlinson J.W., Bujalska I.J., Stewart P.M., Arlt W. Androgen generation in adipose tissue in women with simple obesity—a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. J. Endocrinol. 2004;183:331–342. doi: 10.1677/joe.1.05762. [DOI] [PubMed] [Google Scholar]
  • 16.Lin H.K., Jez J.M., Schlegel B.P., Peehl D.M., Pachter J.A., Penning T.M. Expression and characterization of recombinant type 2 3 alphahydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution. Mol. Endocrinol. 1997;11:1971–1984. doi: 10.1210/me.11.13.1971. [DOI] [PubMed] [Google Scholar]
  • 17.Penning T.M., Burczynski M.E., Jez J.M., Lin H.K., Ma H., Moore M., Ratnam K., Palackal N. Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) Mol. Cell Endocrinol. 2001;171:137–149. doi: 10.1016/S0303-7207(00)00426-3. [DOI] [PubMed] [Google Scholar]
  • 18.Desmond J.C., Mountford J.C., Drayson M.T., Walker E.A., Hewison M., Ride J.P., Luong Q.T., Hayden R.E., Vanin E.F., Bunce C.M. The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. Cancer Res. 2003;63:505–512. [PubMed] [Google Scholar]
  • 19.Spiegelman B.M. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–514. doi: 10.2337/diabetes.47.4.507. [DOI] [PubMed] [Google Scholar]
  • 20.Palming J., Sjöholm K., Jernås M., Lystig T.C., Gummesson A., Romeo S., Lönn L., Lönn M., Carlsson B., Carlsson L.M. The expression of NAD(P)H:quinone oxidoreductase 1 is high in human adipose tissue, reduced by weight loss, and correlates with adiposity, insulin sensitivity, and markers of liver dysfunction. J. Clin. Endocrinol. Metab. 2007;92:2346–2352. doi: 10.1210/jc.2006-2476. [DOI] [PubMed] [Google Scholar]
  • 21.Gummesson A., Jernås M., Svensson P.A., Larsson I., Glad C.A., Schele E., Gripeteg L., Sjöholm K., Lystig T.C., Sjöström L., Carlsson B., Fagerberg B., Carlsson L.M. Relations of Adipose Tissue CIDEA Gene Expression to Basal Metabolic Rate, Energy Restriction, and Obesity: Population-Based and Dietary Intervention Studies. J. Clin. Endocrinol. Metab. 2007;92:4759–4765. doi: 10.1210/jc.2007-1136. [DOI] [PubMed] [Google Scholar]
  • 22.Behre C.J., Gummesson A., Jernås M., Lystig T.C., Fagerberg B., Carlsson B., Carlsson L.M. Dissociation between adipose tissue expression and serum levels of adiponectin during and after diet-induced weight loss in obese subjects with and without the metabolic syndrome. Metabolism. 2007;56:1022–1028. doi: 10.1016/j.metabol.2007.03.010. [DOI] [PubMed] [Google Scholar]
  • 23.WHO . Part 1: Diagnosis and classification of diabetes mellitus. Geneva: World Health Organization; 1999. Definition, diagnosis and classification of diabetes mellitus and its complications. [Google Scholar]
  • 24.Torgerson J.S., Lindroos A.K., Sjöström C.D., Olsson R., Lissner L., Sjöström L. Are elevated aminotransferases and decreased bilirubin additional characteristics of the metabolic syndrome? Obes. Res. 1997;5:105–114. doi: 10.1002/j.1550-8528.1997.tb00650.x. [DOI] [PubMed] [Google Scholar]
  • 25.Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 1987;162:156–159. doi: 10.1016/0003-2697(87)90021-2. [DOI] [PubMed] [Google Scholar]
  • 26.Brazma A., Hingamp P., Quackenbush J., Sherlock G., Spellman P., Stoeckert C., Aach J., Ansorge W., Ball C.A., Causton H.C., Gaasterland T., Glenisson P., Holstege F.C., Kim I.F., Markowitz V., Matese J.C., Parkinson H., Robinson A., Sarkans U., Schulze-Kremer S., Stewart J., Taylor R., Vilo J., Vingron M. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat. Genet. 2001;29:365–371. doi: 10.1038/ng1201-365. [DOI] [PubMed] [Google Scholar]
  • 27.Karason K., Jernås M., Hägg D.A., Svensson P.A. Evaluation of CXCL9 and CXCL10 as circulating biomarkers of human cardiac allograft rejection. BMC Cardiovasc. Disord. 2006;6:29. doi: 10.1186/1471-2261-6-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Jernås M., Palming J., Sjöholm K., Jennische E., Svensson P.A., Gabrielsson B.G., Levin M., Sjögren A., Rudemo M., Lystig T.C., Carlsson B., Carlsson L.M., Lönn M. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. Faseb J. 2006;20:1540–1542. doi: 10.1096/fj.05-5678fje. [DOI] [PubMed] [Google Scholar]
  • 29.Gabrielsson B.G., Olofsson L.E., Sjögren A., Jernås M., Elander A., Lönn M., Rudemo M., Carlsson L.M. Evaluation of reference genes for studies of gene expression in human adipose tissue. Obes. Res. 2005;13:649–652. doi: 10.1038/oby.2005.72. [DOI] [PubMed] [Google Scholar]
  • 30.Weyer C., Foley J.E., Bogardus C., Tataranni P.A., Pratley R.E. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000;43:1498–1506. doi: 10.1007/s001250051560. [DOI] [PubMed] [Google Scholar]
  • 31.Wake D.J., Strand M., Rask E., Westerbacka J., Livingstone D.E., Soderberg S., Andrew R., Yki-Jarvinen H., Olsson T., Walker B.R. Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin. Endocrinol. (Oxf) 2007;66:440–446. doi: 10.1111/j.1365-2265.2007.02755.x. [DOI] [PubMed] [Google Scholar]
  • 32.Reginato M.J., Krakow S.L., Bailey S.T., Lazar M.A. Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor gamma. J. Biol. Chem. 1998;273:1855–1858. doi: 10.1074/jbc.273.4.1855. [DOI] [PubMed] [Google Scholar]
  • 33.Barrett-Connor E. Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann. Intern. Med. 1992;117:807–811. doi: 10.7326/0003-4819-117-10-807. [DOI] [PubMed] [Google Scholar]
  • 34.Haffner S.M., Valdez R.A., Stern M.P., Katz M.S. Obesity, body fat distribution and sex hormones in men. Int. J. Obes. Relat. Metab. Disord. 1993;17:643–649. [PubMed] [Google Scholar]
  • 35.Day C. Metabolic syndrome, or What you will: definitions and epidemiology. Diab. Vasc. Dis. Res. 2007;4:32–38. doi: 10.3132/dvdr.2007.003. [DOI] [PubMed] [Google Scholar]
  • 36.Peeraully M.R., Sievert H., Bullo M., Wang B., Trayhurn P. Prostaglandin D2 and J2-series (PGJ2, Delta12-PGJ2) prostaglandins stimulate IL-6 and MCP-1, but inhibit leptin, expression and secretion by 3T3-L1 adipocytes. Pflugers Arch. 2006;453:177–187. doi: 10.1007/s00424-006-0118-x. [DOI] [PubMed] [Google Scholar]
  • 37.Lundgren M., Svensson M., Lindmark S., Renström F., Ruge T., Eriksson J.W. Fat cell enlargement is an independent marker of insulin resistance and’ hyperleptinaemia’. Diabetologia. 2007;50:625–633. doi: 10.1007/s00125-006-0572-1. [DOI] [PubMed] [Google Scholar]
  • 38.McLaughlin T., Sherman A., Tsao P., Gonzalez O., Yee G., Lamendola C., Reaven G.M., Cushman S.W. Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis. Diabetologia. 2007;50:1707–1715. doi: 10.1007/s00125-007-0708-y. [DOI] [PubMed] [Google Scholar]

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