Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans

Roland H Stimson, Jonas Andersson, Ruth Andrew, Doris N Redhead, Fredrik Karpe, Peter C Hayes, Tommy Olsson, Brian R Walker, Roland H Stimson, Jonas Andersson, Ruth Andrew, Doris N Redhead, Fredrik Karpe, Peter C Hayes, Tommy Olsson, Brian R Walker

Abstract

Objective: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from cortisone. 11beta-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11beta-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11beta-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo.

Research design and methods: Six healthy men underwent 9,11,12,12-[(2)H](4)-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein.

Results: Significant cortisol and 9,12,12-[(2)H](3)-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol . min(-1) . 100 g(-1) adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[(2)H](3)-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected.

Conclusions: Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11beta-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling.

Figures

FIG. 1.
FIG. 1.
Quantifying cortisol production using deuterated cortisol. d4-Cortisol is converted mainly in the kidney to d3-cortisone, with the loss of the deuterium on C11. The d3-cortisone is then reduced by 11β-HSD1, predominantly in the liver and adipose tissue, with the addition of an unlabeled hydrogen to form d3-cortisol. Differences between d3-cortisol and d4-cortisol metabolism therefore reflect 11β-HSD1 reductase activity.
FIG. 2.
FIG. 2.
Left panel: subcutaneous sampling; right panel: visceral sampling. Plasma measurements during deuterated cortisol infusion. Data are means ± SE for n = 6 (subcutaneous measurements) and n = 4 (visceral measurements) during deuterated cortisol infusion, with plasma samples from arterialized (▪), portal or subcutaneous (⋄), and hepatic (▴) cannulae. Plasma cortisol concentrations (A), plasma d4-cortisol enrichment (C), and d4-cortisol–to–d3-cortisol ratio (E) for subcutaneous study. Plasma cortisol concentrations (B), plasma d4-cortisol enrichment (D), d4-cortisol–to–d3-cortisol ratio (F) for visceral study. Statistical comparison of mean values in steady state (180–210 min) is shown in Table 2.

References

    1. Macfarlane DP, Forbes S, Walker BR: Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol 197: 189–204, 2008
    1. Seckl JR, Walker BR: 11β-Hydroxysteroid dehydrogenase type 1: a tissue-specific amplifier of glucocorticoid action. Endocrinology 142: 1371–1376, 2001
    1. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM: 11Beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 25: 831–866, 2004
    1. Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect ‘Cushing's disease of the omentum’? Lancet 349: 1210–1213, 1997
    1. Sandeep TC, Andrew R, Homer NZ, Andrews RC, Smith K, Walker BR: Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 54: 872–879, 2005
    1. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DEW, Johnson O, Walker BR: Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86: 1418–1421, 2001
    1. Walker BR: Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157: 545–559, 2007
    1. Hughes KA, Webster SP, Walker BR: 11-Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors in type 2 diabetes mellitus and obesity. Expert Opin Investig Drugs 17: 481–496, 2008
    1. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS: A transgenic model of visceral obesity and the metabolic syndrome. Science 294: 2166–2170, 2001
    1. Katz JR, Mohamed-Ali V, Wood PJ, Yudkin JS, Coppack SW: An in vivo study of the cortisol-cortisone shuttle in subcutaneous abdominal adipose tissue. Clin Endocrinol 50: 63–68, 1999
    1. Wake DJ, Stimson RH, Tan GD, Homer NZ, Andrew R, Karpe F, Walker BR: Effects of peroxisome proliferator-activated receptor (PPAR) {alpha} and {gamma} agonists on 11{beta}-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. J Clin Endocrinol Metab 92: 1848–1856, 2007
    1. Aldhahi W, Mun E, Goldfine AB: Portal and peripheral cortisol levels in obese humans. Diabetologia 47: 833–836, 2004
    1. Tarantino G, Lobello R, Scopacasa F, Contaldo F, Pasanisi F, Cirillo M, De Caterina M, Conca P, Terracciano D, Gennarelli N, Ariello M, Mazzarella C, Grimaldi E, Macchia V: The contribution of omental adipose tissue to adipokine concentrations in patients with the metabolic syndrome. Clin Invest Med 30: E192–E199, 2007
    1. Walker BR, Campbell JC, Fraser R, Stewart PM, Edwards CRW: Mineralocorticoid excess and inhibition of 11β-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf) 27: 483–492, 1992
    1. Andrew R, Smith K, Jones GC, Walker BR: Distinguishing the activities of 11beta-hydroxysteroid dehydrogenases in vivo using isotopically labelled cortisol. J Clin Endocrinol Metab 87: 277–285, 2002
    1. Andrew R, Westerbacka J, Wahren J, Yki-Jarvinen H, Walker BR: The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes 54: 1364–1370, 2005
    1. Basu R, Singh RJ, Basu A, Chittilapilly EG, Johnson CM, Toffolo G, Cobelli C, Rizza RA: Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-beta hydroxysteroid dehydrogenase (11beta-hsd) type 1 pathway. Diabetes 53: 2051–2059, 2004
    1. Basu R, Edgerton DS, Singh RJ, Cherrington A, Rizza RA: Splanchnic cortisol production in dogs occurs primarily in the liver: evidence for substantial hepatic specific 11{beta} hydroxysteroid dehydrogenase type 1 activity. Diabetes 55: 3013–3019, 2006
    1. Coppack SW, Fisher RM, Gibbons GF, Humphreys SM, McDonough MJ, Potts JL, Frayn KN: Postprandial substrate deposition in human forearm and adipose tissues in vivo. Clin Sci (Lond) 79: 339–348, 1990
    1. Larsen OA, Lassen NA, Quaade F: Blood flow through human adipose tissue determined with radioactive xenon. Acta Physiol Scand 66: 337–345, 1966
    1. Samra JS, Frayn KN, Giddings JA, Clark ML, MacDonald IA: Modification and validation of a commercially available portable detector for measurement of adipose tissue blood flow. Clin Physiol 15: 241–248, 1995
    1. Burns E, Triger DR, Tucker GT, Bax ND: Indocyanine green elimination in patients with liver disease and in normal subjects. Clin Sci (Lond) 80: 155–160, 1991
    1. Wolfe RL, Chinkes DL: Arterial-venous balance technique to measure amino acid kinetics. In Isotope Tracers in Metabolic Research. Principles and Practice of Kinetic Analysis. 2nd ed. New York, John Wiley and Sons, 2005, p. 381–420
    1. Leevy CM, Mendenhall CL, Lesko W, Howard MM: Estimation of hepatic blood flow with indocyanine green. J Clin Invest 41: 1169–1177, 1962
    1. Zoli M, Magalotti D, Bianchi G, Gueli C, Orlandini C, Grimaldi M, Marchesini G: Total and functional hepatic blood flow decrease in parallel with ageing. Age Ageing 28: 29–33, 1999
    1. Richter S, Mucke I, Menger MD, Vollmar B: Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response. Am J Physiol Gastrointest Liver Physiol 279: G454–G462, 2000
    1. Lautt WW: Regulatory processes interacting to maintain hepatic blood flow constancy: vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction. Hepatol Res 37: 891–903, 2007
    1. Menzel J, Schober O, Reimer P, Domschke W: Scintigraphic evaluation of hepatic blood flow after intrahepatic portosystemic shunt (TIPS). Eur J Nucl Med 24: 635–641, 1997
    1. Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, Andrew R, Yki-Jarvinen H, Olsson T, Walker BR: Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol (Oxf) 66: 440–446, 2007
    1. Tyler FH: The effect of liver disease on adrenal cortical function. Am J Clin Nutr 5: 377–380, 1957
    1. Kawai S, Ichikawa Y, Homma M: Differences in metabolic properties among cortisol, prednisolone, and dexamethasone in liver and renal diseases: accelerated metabolism of dexamethasone in renal failure. J Clin Endocrinol Metab 60: 848–854, 1985
    1. Stewart PM, Burra P, Shackleton CHL, Sheppard MC, Elias E: 11β-Hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic liver disease. J Clin Endocrinol Metab 76: 748–751, 1993
    1. Basu R, Singh RJ, Basu A, Chittilapilly EG, Johnson MC, Toffolo G, Cobelli C, Rizza RA: Obesity and type 2 diabetes do not alter splanchnic cortisol production in humans. J Clin Endocrinol Metab 90: 3919–3926, 2005
    1. Rodriguez-Laiz JM, Banares R, Echenagusia A, Casado M, Camunez F, Perez-Roldan F, de Diego A, Cos E, Clemente G: Effects of transjugular intrahepatic portasystemic shunt (TIPS) on splanchnic and systemic hemodynamics, and hepatic function in patients with portal hypertension: preliminary results. Dig Dis Sci 40: 2121–2127, 1995
    1. Rector WG Jr, Hoefs JC, Hossack KF, Everson GT: Hepatofugal portal flow in cirrhosis: observations on hepatic hemodynamics and the nature of the arterioportal communications. Hepatology 8: 16–20, 1988
    1. Bosch J, Pizcueta P, Feu F, Fernandez M, Garcia-Pagan JC: Pathophysiology of portal hypertension. Gastroenterol Clin North Am 21: 1–14, 1992
    1. Westerbacka J, Yki-Jarvinen H, Vehkavaara S, Hakkinen A-M, Andrew R, Wake DJ, Seckl JR, Walker BR: Body fat distribution and cortisol metabolism in healthy men: enhanced 5β-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 88: 4924–4931, 2003
    1. Bujalska IJ, Walker EA, Tomlinson JW, Hewison M, Stewart PM: 11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol. Endocr Res 28: 449–461, 2002
    1. Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, Johnson O, Andrew R, Olsson T: Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87: 3330–3336, 2002
    1. Shafqat N, Elleby B, Svensson S, Shafqat J, Jornvall H, Abrahmsen L, Oppermann U: Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from glucocorticoid resistant (guinea pig) versus sensitive (human) species. J Biol Chem 278: 2030–2035, 2003
    1. Stewart PM, Boulton A, Kumar S, Clark PMS, Shackleton CHL: Cortisol metabolism in human obesity: impaired cortisone: cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 84: 1022–1027, 1999

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj