This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wake, D. J. Articles by Walker, B. R. Search for Related Content PubMed PubMed Citation Articles by Wake, D. J. Articles by Walker, B. R.

Local and Systemic Impact of Transcriptional Up-Regulation of 11ß-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity

Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital (D.J.W., D.E.W.L., B.R.W.), Edinburgh, Scotland EH4 2XU; and Department of Medicine, Umea University Hospital (E.R., S.S., T.O.), Umea, S-901 85 Sweden

Address all correspondence and requests for reprints to: Prof. Tommy Olsson, Department of Medicine, Umea University Hospital, Umea, Sweden. E-mail: tommy.olsson{at}medicin.umu.se.

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11ß-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized ß coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR- and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 ± 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

This work was supported by the British Heart Foundation, the Swedish Heart and Lung Foundation, the Swedish Medical Research Council, the Medical Faculty of Umea University, the Northern Councils Cooperation Committee (Visare Norr), and the Heart and Lung Association in Kramfors-Solleftea.

Abbreviations: GR, Glucocorticoid receptor 11HSD1, 11ß-hydroxysteroid dehydrogenase type 1; SBC, standardized ß coefficient.

This article has been cited by other articles:

				H. Filipsson and G. Johannsson GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies Eur. J. Endocrinol., November 1, 2009; 161(S1): S85 - S95. [Abstract] [Full Text] [PDF]

				P. Anagnostis, V. G. Athyros, K. Tziomalos, A. Karagiannis, and D. P. Mikhailidis The Pathogenetic Role of Cortisol in the Metabolic Syndrome: A Hypothesis J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 2692 - 2701. [Abstract] [Full Text] [PDF]

				D. E W Livingstone, S. L Grassick, G. L Currie, B. R Walker, and R. Andrew Dysregulation of glucocorticoid metabolism in murine obesity: comparable effects of leptin resistance and deficiency J. Endocrinol., May 1, 2009; 201(2): 211 - 218. [Abstract] [Full Text] [PDF]

				G. Fanciulli, A. Delitala, and G. Delitala Growth hormone, menopause and ageing: no definite evidence for 'rejuvenation' with growth hormone Hum. Reprod. Update, May 1, 2009; 15(3): 341 - 358. [Abstract] [Full Text] [PDF]

				J. Q. Purnell, S. E. Kahn, M. H. Samuels, D. Brandon, D. L. Loriaux, and J. D. Brunzell Enhanced cortisol production rates, free cortisol, and 11{beta}-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E351 - E357. [Abstract] [Full Text] [PDF]

				S. Sai, C. L. Esteves, V. Kelly, Z. Michailidou, K. Anderson, A. P. Coll, Y. Nakagawa, T. Ohzeki, J. R. Seckl, and K. E. Chapman Glucocorticoid Regulation of the Promoter of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Is Indirect and Requires CCAAT/Enhancer-Binding Protein-{beta} Mol. Endocrinol., September 1, 2008; 22(9): 2049 - 2060. [Abstract] [Full Text] [PDF]

				A. Balachandran, H. Guan, M. Sellan, S. van Uum, and K. Yang Insulin and Dexamethasone Dynamically Regulate Adipocyte 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Endocrinology, August 1, 2008; 149(8): 4069 - 4079. [Abstract] [Full Text] [PDF]

				K. Yang, H. Guan, E. Arany, D. J. Hill, and X. Cao Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor FASEB J, July 1, 2008; 22(7): 2452 - 2464. [Abstract] [Full Text] [PDF]

				R. A. De Sousa Peixoto, S. Turban, J. H. Battle, K. E. Chapman, J. R. Seckl, and N. M. Morton Preadipocyte 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Is a Keto-Reductase and Contributes to Diet-Induced Visceral Obesity in Vivo Endocrinology, April 1, 2008; 149(4): 1861 - 1868. [Abstract] [Full Text] [PDF]

				R. H. Stimson, A. M. Johnstone, N. Z. M. Homer, D. J. Wake, N. M. Morton, R. Andrew, G. E. Lobley, and B. R. Walker Dietary Macronutrient Content Alters Cortisol Metabolism Independently of Body Weight Changes in Obese Men J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4480 - 4484. [Abstract] [Full Text] [PDF]

				N. Arai, H. Masuzaki, T. Tanaka, T. Ishii, S. Yasue, N. Kobayashi, T. Tomita, M. Noguchi, T. Kusakabe, J. Fujikura, et al. Ceramide and Adenosine 5'-Monophosphate-Activated Protein Kinase Are Two Novel Regulators of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity in Cultured Preadipocytes Endocrinology, November 1, 2007; 148(11): 5268 - 5277. [Abstract] [Full Text] [PDF]

				P. Barat, D. E. W. Livingstone, C. M. C. Elferink, C. R. McDonnell, B. R. Walker, and R. Andrew Effects of Gonadectomy on Glucocorticoid Metabolism in Obese Zucker Rats Endocrinology, October 1, 2007; 148(10): 4836 - 4843. [Abstract] [Full Text] [PDF]

				J. Buren, S.-A. Bergstrom, E. Loh, I. Soderstrom, T. Olsson, and C. Mattsson Hippocampal 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression Has a Diurnal Variability that Is Lost in the Obese Zucker Rat Endocrinology, June 1, 2007; 148(6): 2716 - 2722. [Abstract] [Full Text] [PDF]

				B. Mariniello, V. Ronconi, S. Rilli, P. Bernante, M. Boscaro, F. Mantero, and G. Giacchetti Adipose tissue 11{beta}-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing's syndrome Eur. J. Endocrinol., September 1, 2006; 155(3): 435 - 441. [Abstract] [Full Text] [PDF]

				S. K. Paulsen, S. B. Pedersen, J. O. L. Jorgensen, S. Fisker, J. S. Christiansen, A. Flyvbjerg, and B. Richelsen Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1093 - 1098. [Abstract] [Full Text] [PDF]

				H. A Sigurjonsdottir, J. Koranyi, M. Axelson, B.-A. Bengtsson, and G. Johannsson GH effect on enzyme activity of 11{beta}HSD in abdominal obesity is dependent on treatment duration Eur. J. Endocrinol., January 1, 2006; 154(1): 69 - 74. [Abstract] [Full Text] [PDF]

				M. G. Gnanalingham, A. Mostyn, R. Webb, D. H. Keisler, N. Raver, M. C. Alves-Guerra, C. Pecqueur, B. Miroux, M. E. Symonds, and T. Stephenson Differential effects of leptin administration on the abundance of UCP2 and glucocorticoid action during neonatal development Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1093 - E1100. [Abstract] [Full Text] [PDF]

				R. Basu, R. J. Singh, A. Basu, E. G. Chittilapilly, M. C. Johnson, G. Toffolo, C. Cobelli, and R. A. Rizza Obesity and Type 2 Diabetes Do Not Alter Splanchnic Cortisol Production in Humans J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3919 - 3926. [Abstract] [Full Text] [PDF]

				I. J Bujalska, N. Draper, Z. Michailidou, J. W Tomlinson, P. C White, K. E Chapman, E. A Walker, and P. M Stewart Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11{beta}-hydroxysteroid dehydrogenase type 1 J. Mol. Endocrinol., June 1, 2005; 34(3): 675 - 684. [Abstract] [Full Text] [PDF]

				E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, and J. S. Flier Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity Diabetes, April 1, 2005; 54(4): 1023 - 1031. [Abstract] [Full Text] [PDF]

				K. H. Pietilainen, A. Rissanen, J. Kaprio, S. Makimattila, A.-M. Hakkinen, J. Westerbacka, J. Sutinen, S. Vehkavaara, and H. Yki-Jarvinen Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E768 - E774. [Abstract] [Full Text] [PDF]

				A. J. Drake, D. E. W. Livingstone, R. Andrew, J. R. Seckl, N. M. Morton, and B. R. Walker Reduced Adipose Glucocorticoid Reactivation and Increased Hepatic Glucocorticoid Clearance as an Early Adaptation to High-Fat Feeding in Wistar Rats Endocrinology, February 1, 2005; 146(2): 913 - 919. [Abstract] [Full Text] [PDF]

				S. Boullu-Ciocca, A. Dutour, V. Guillaume, V. Achard, C. Oliver, and M. Grino Postnatal Diet-Induced Obesity in Rats Upregulates Systemic and Adipose Tissue Glucocorticoid Metabolism During Development and in Adulthood: Its Relationship With the Metabolic Syndrome Diabetes, January 1, 2005; 54(1): 197 - 203. [Abstract] [Full Text] [PDF]

				P. W. Franks, W. C. Knowler, S. Nair, J. Koska, Y.-H. Lee, R. S. Lindsay, B. R. Walker, H. C. Looker, P. A. Permana, P. A. Tataranni, et al. Interaction Between an 11{beta}HSD1 Gene Variant and Birth Era Modifies the Risk of Hypertension in Pima Indians Hypertension, November 1, 2004; 44(5): 681 - 688. [Abstract] [Full Text] [PDF]

				J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart 11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response Endocr. Rev., October 1, 2004; 25(5): 831 - 866. [Abstract] [Full Text] [PDF]

				K. Kannisto, K. H. Pietilainen, E. Ehrenborg, A. Rissanen, J. Kaprio, A. Hamsten, and H. Yki-Jarvinen Overexpression of 11{beta}-Hydroxysteroid Dehydrogenase-1 in Adipose Tissue Is Associated with Acquired Obesity and Features of Insulin Resistance: Studies in Young Adult Monozygotic Twins J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4414 - 4421. [Abstract] [Full Text] [PDF]

				N. M. Morton, L. Ramage, and J. R. Seckl Down-Regulation of Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 by High-Fat Feeding in Mice: A Potential Adaptive Mechanism Counteracting Metabolic Disease Endocrinology, June 1, 2004; 145(6): 2707 - 2712. [Abstract] [Full Text] [PDF]

				J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]

				Bibliography Scand J Public Health, November 1, 2003; 31(61_suppl): 85 - 91. [PDF]