Reduced glucocorticoid production rate, decreased 5alpha-reductase activity, and adipose tissue insulin sensitization after weight loss

Jeremy W Tomlinson, Joanne Finney, Beverly A Hughes, Susan V Hughes, Paul M Stewart, Jeremy W Tomlinson, Joanne Finney, Beverly A Hughes, Susan V Hughes, Paul M Stewart

Abstract

Objective: The epidemics of obesity, insulin resistance, and type 2 diabetes have heightened the need to understand mechanisms that contribute to their pathogenesis. Increased endogenous glucocorticoid production has been implicated based on parallels with Cushing's syndrome. We have assessed the impact of weight loss on glucocorticoid secretion and metabolism (notably 11beta-hydroxysteroid dehydrogenase type 1 and 5alpha-reductase [5alphaR] activity) and insulin sensitivity.

Research design and methods: Twenty obese volunteers were investigated before and after weight loss. Patients underwent hyperinsulinemic-euglycemic clamps with simultaneous adipose microdialysis and oral cortisone acetate administration. Changes in glucocorticoid secretion and metabolism were assessed using 24-h urine collections.

Results: Before weight loss, fat mass correlated with glucocorticoid secretion rate (total fat, r = 0.46, P < 0.05; trunk fat, r = 0.52, P < 0.05); however, glucocorticoid secretion rate was inversely related to insulin sensitivity (r = -0.51, P < 0.05). Hyperinsulinemia failed to suppress adipose tissue interstitial fluid glycerol release (180 +/- 50 micromol [basal] vs. 153 +/- 10 micromol [steady state], NS). After oral cortisone (25 mg), cortisol concentrations within adipose interstitial fluid increased (4.3 +/- 1.1 vs. 14.2 +/- 2.6 nmol/l, P < 0.01), but glycerol concentrations did not change. After weight loss, insulin sensitivity increased. Consistent with insulin sensitization, adipose tissue interstitial fluid glycerol concentrations fell under hyperinsulinemic conditions (186 +/- 16 vs. 117 +/- 9 micromol, P < 0.05). Glucocorticoid secretion decreased (11,751 +/- 1,520 vs. 7,464 +/- 937 microg/24 h, P < 0.05) as did 5alphaR activity (5alpha-tetrahydrocortisol-to-tetrahydrocortisol ratio 1.41 +/- 0.16 vs. 1.12 +/- 0.17, P < 0.005).

Conclusions: Obesity is associated with insulin resistance within adipose tissue and increased cortisol secretion rates; both are reversed with weight loss. Reduced 5alphaR activity after weight loss may decrease hypothalamo-pituitary-adrenal axis activation and reduce glucocorticoid metabolite production.

Figures

Figure 1
Figure 1
A schematic representation of the hyperinsulinemic euglycemic clamp protocol with cortisone administration and simultaneous adipose tissue microdialysis. Timing of samples taken for measurement of serum insulin (*) and cortisol and cortisone (†) are shown. Throughout the clamp, blood samples were also taken every 5 minutes for measurement of blood glucose.
Figure 2
Figure 2
Total GC secretion rate correlates positively with trunk (closed circles) and total fat mass (open triangles) in 20 health obese individuals before weight loss (A) and inversely correlate with insulin sensitivity as measured by hyperinsulinemic euglycemic clamp (B).
Figure 3
Figure 3
Adipose tissue microdialysate analysis in 14 obese individuals before (open squares) and after weight loss (closed circles), under basal and hyperinsulinemic conditions. Hyperinsulinemia increased interstitial fluid pyruvate (A) and lactate (B) concentrations equally before and after weight loss. Glucose concentrations were unaltered consistent with successful clamping of blood glucose levels and were also similar before and after weight loss. Glycerol concentrations failed to suppress prior to weight loss in keeping with adipose tissue insulin resistance, but fell significantly after weight loss († p

Figure 4

Serum (A) and adipose tissue…

Figure 4

Serum (A) and adipose tissue interstitial fluid (B) cortisol generation, and the ratio…

Figure 4
Serum (A) and adipose tissue interstitial fluid (B) cortisol generation, and the ratio of interstitial fluid cortisol to serum cortisol (C) following oral cortisone acetate (25mg) administration in 14 obese individuals before (open squares) and after weight loss (closed circles) († p
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    1. World Health Orgaization. [accessed January 2008]; web site http://www.who.int/en/
    1. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J Med. 1999;341:427–434. - PubMed
    1. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med. 1995;122:481–486. - PubMed
    1. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 1994;17:961–969. - PubMed
    1. Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JM. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension. 1999;33:1364–1368. - PubMed
Show all 37 references
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Figure 4
Figure 4
Serum (A) and adipose tissue interstitial fluid (B) cortisol generation, and the ratio of interstitial fluid cortisol to serum cortisol (C) following oral cortisone acetate (25mg) administration in 14 obese individuals before (open squares) and after weight loss (closed circles) († p

References

    1. World Health Orgaization. [accessed January 2008]; web site
    1. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J Med. 1999;341:427–434.
    1. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med. 1995;122:481–486.
    1. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 1994;17:961–969.
    1. Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JM. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension. 1999;33:1364–1368.
    1. Duclos M, Gatta B, Corcuff JB, Rashedi M, Pehourcq F, Roger P. Fat distribution in obese women is associated with subtle alterations of the hypothalamic-pituitary-adrenal axis activity and sensitivity to glucocorticoids. Clin Endocrinol (Oxf) 2001;55:447–454.
    1. Pasquali R, Cantobelli S, Casimirri F, Capelli M, Bortoluzzi L, Flamia R, Labate AM, Barbara L. The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab. 1993;77:341–346.
    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. 2004;25:831–866.
    1. Jung RT. Obesity as a disease. Br Med Bull. 1997;53:307–321.
    1. Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, Lamonte MJ, Stroup AM, Hunt SC. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357:753–761.
    1. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741–752.
    1. Tomlinson JW, Moore JS, Clark PM, Holder G, Shakespeare L, Stewart PM. Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue. J Clin Endocrinol Metab. 2004;89:2711–2716.
    1. Alberts P, Engblom L, Edling N, Forsgren M, Klingstrom G, Larsson C, Ronquist-Nii Y, Ohman B, Abrahmsen L. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002;45:1528–1532.
    1. Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, Klingstrom G, Larsson C, Forsgren M, Ashkzari M, Nilsson CE, et al. Selective inhibition of 11{beta}-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003;144:4755–4762.
    1. Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Le Grand CB, Li Z, Metzger JM, Mundt SS, Noonan H, et al. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 2005;202:517–527.
    1. Berthiaume M, Laplante M, Festuccia W, Gelinas Y, Poulin S, Lalonde J, Joanisse DR, Thieringer R, Deshaies Y. Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. Endocrinology. 2007;148:2391–2397.
    1. Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf) 1996;45:605–611.
    1. Tomlinson JW, Sherlock M, Hughes B, Hughes SV, Kilvington F, Bartlett W, Courtney R, Rejto P, Carley W, Stewart PM. Inhibition of 11{beta}-HSD1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis. J Clin Endocrinol Metab. 2007;92(3):857–64.
    1. Defronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–E223.
    1. Stewart PM, Boulton A, Kumar S, Clark PM, Shackleton CH. Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab. 1999;84:1022–1027.
    1. Walker EA, Ahmed A, Lavery GG, Tomlinson JW, Kim SY, Cooper MS, Ride JP, Hughes BA, Shackleton CH, McKiernan P, Elias E, et al. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function. J Biol Chem. 2007;282:27030–27036.
    1. Tomlinson JW, Stewart PM. Mechanisms of Disease: Selective 11-HSD1 inhibition as a novel treatment for the metabolic syndrome. Nature Clinical Practice Endocrinology & Metabolism. 2005;1:92–99.
    1. Bhat BG, Hosea N, Fanjul A, Herrera J, Chapman J, Thalacker F, Stewart PM, Rejto P. Demonstration of Proof of Mechanism and Pharmacokinetics and Pharmacodynamic Relationship with PF-915275, an Inhibitor of 11{beta}HSD1, in Cynomolgus Monkeys. J Pharmacol Exp Ther. 2007;324(1):299–305.
    1. Gathercole LL, Bujalska IJ, Stewart PM, Tomlinson JW. Glucocorticoid modulation of insulin signaling in human subcutaneous adipose tissue. J Clin Endocrinol Metab. 2007;92:4332–4339.
    1. Larsson H, Ahren B. Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. J Clin Endocrinol Metab. 1996;81:4428–4432.
    1. Slavin BG, Ong JM, Kern PA. Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes. J Lipid Res. 1994;35:1535–1541.
    1. Rojas FA, Hirata AE, Saad MJ. Regulation of insulin receptor substrate-2 tyrosine phosphorylation in animal models of insulin resistance. Endocrine. 2003;21:115–122.
    1. Saad MJ, Folli F, Kahn JA, Kahn CR. Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest. 1993;92:2065–2072.
    1. Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25–61.
    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) 2007;66:440–446.
    1. Andrew R, Phillips DI, Walker BR. Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab. 1998;83:1806–1809.
    1. Andrews RC, Herlihy O, Livingstone DE, Andrew R, Walker BR. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. J Clin Endocrinol Metab. 2002;87:5587–5593.
    1. Finken MJ, Andrews RC, Andrew R, Walker BR. Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductases, but not 11beta-hydroxysteroid dehydrogenases. J Clin Endocrinol Metab. 1999;84:3316–3321.
    1. Stimson RH, Johnstone AM, Homer NZ, Wake DJ, Morton NM, Andrew R, Lobley GE, Walker BR. Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men. J Clin Endocrinol Metab. 2007;92:4480–4484.
    1. Livingstone DE, McInnes KJ, Walker BR, Andrew R. Increased A-ring reduction of glucocorticoids in obese Zucker rats: effects of insulin sensitization. Obes Res. 2005;13:1523–1526.
    1. Tsilchorozidou T, Honour JW, Conway GS. Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab. 2003;88:5907–5913.
    1. Stewart PM, Shackleton CHL, Beastall GH, Edwards CRW. 5a-reductase activity in polycystic ovary syndrome. Lancet. 1990;335:431–433.

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