PDF herunterladen
Horm Metab Res 2016; 48(08): 523-528
DOI: 10.1055/s-0042-108728
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Evidence of Reduced CBG Cleavage in Abdominal Obesity: A Potential Factor in Development of the Metabolic Syndrome

M. A. Nenke
1   Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
2   Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia
,
J. G. Lewis
3   Steroid & Immunobiochemistry Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand
,
W. Rankin
1   Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
2   Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia
4   Chemical Pathology Directorate, SA Pathology, Adelaide, SA, Australia
,
D. J Torpy
1   Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
2   Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 26. Januar 2016

accepted 04. Mai 2016

Publikationsdatum:
14. Juni 2016 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Erratum zu diesem Artikel:

Evidence of Reduced CBG Cleavage in Abdominal Obesity: A Potential Factor in Development of the Metabolic SyndromeHorm Metab Res 2016; 48(09): 620-620
DOI: 10.1055/s-0036-1593824

Abstract

Corticosteroid-binding globulin (CBG) is involved in the regulation of cortisol delivery. Neutrophil elastase-mediated cleavage of high to low affinity CBG (haCBG to laCBG) induces cortisol release at inflammatory sites. Past studies have shown reduced CBG in obesity, an inflammatory state, particularly in central adiposity/metabolic syndrome. We performed an observational, cross-sectional study of the effects of obesity, age and sex on ha/laCBG in 100 healthy volunteers. Total and haCBG levels were 11% higher in women but did not vary with age or menopausal status. Total CBG levels were lower with increased body weight and waist circumference; laCBG levels were lower with increased body weight, waist circumference, body mass index and body fat; higher haCBG levels were seen with increased body fat. The relation between CBG and adiposity appeared to be driven predominantly by the metabolic syndrome group. The results suggest reduced CBG cleavage in central obesity, possibly contributing to the characteristic inflammatory phenotype of the central obesity and metabolic syndrome. The mechanism of gender differences in CBG levels is unclear.

Key words

cortisol - high-affinity CBG - low-affinity CBG - inflammation
 

  • References

  • 1 Lewis JG, Bagley CJ, Elder PA, Bachmann AW, Torpy DJ. Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin Chim Acta 2005; 359: 189-194
    CrossrefPubMedGoogle Scholar
  • 2 Hammond GL, Smith CL, Underhill DA. Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J Steroid Biochem Mol Biol 1991; 40: 755-762
    CrossrefPubMedGoogle Scholar
  • 3 Musa BU, Doe RP, Seal US. Serum protein alterations produced in women by synthetic estrogens. J Clin Endocrinol Metab 1967; 27: 1463-1469
    CrossrefPubMedGoogle Scholar
  • 4 Bartalena L, Hammond GL, Farsetti A, Flink IL, Robbins J. Interleukin-6 inhibits corticosteroid-binding globulin synthesis by human hepatoblastoma-derived (Hep G2) cells. Endocrinology 1993; 133: 291-296
    CrossrefPubMedGoogle Scholar
  • 5 Tsigos C, Kyrou I, Chrousos GP, Papanicolaou DA. Prolonged suppression of corticosteroid-binding globulin by recombinant human interleukin-6 in man. J Clin Endocrinol Metab 1998; 83: 3379
    CrossrefPubMedGoogle Scholar
  • 6 Fernandez-Real JM, Grasa M, Casamitjana R, Pugeat M, Barret C, Ricart W. Plasma total and glycosylated corticosteroid-binding globulin levels are associated with insulin secretion. J Clin Endocrinol Metab 1999; 84: 3192-3196
    CrossrefPubMedGoogle Scholar
  • 7 Crave JC, Lejeune H, Brebant C, Baret C, Pugeat M. Differential effects of insulin and insulin-like growth factor I on the production of plasma steroid-binding globulins by human hepatoblastoma-derived (Hep G2) cells. J Clin Endocrinol Metab 1995; 80: 1283-1289
    CrossrefPubMedGoogle Scholar
  • 8 Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW. Hormone binding globulins undergo serpin conformational change in inflammation. Nature 1988; 336: 257-258
    CrossrefPubMedGoogle Scholar
  • 9 Chan WL, Carrell RW, Zhou A, Read RJ. How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration. J Clin Endocrinol Metab 2013; 98: 3315-3322
    CrossrefPubMedGoogle Scholar
  • 10 Lewis JG, Elder PA. Intact or “active” corticosteroid-binding globulin (CBG) and total CBG in plasma: determination by parallel ELISAs using monoclonal antibodies. Clin Chim Acta 2013; 416: 26-30
    CrossrefPubMedGoogle Scholar
  • 11 Lewis JG, Saunders K, Dyer A, Elder PA. The half-lives of intact and elastase cleaved human corticosteroid-binding globulin (CBG) are identical in the rabbit. J Steroid Biochem Mol Biol 2015; 149C: 53-57
    PubMedGoogle Scholar
  • 12 Nenke MA, Rankin W, Chapman MJ, Stevens NE, Diener KR, Hayball JD, Lewis JG, Torpy DJ. Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications. Clin Endocrinol (Oxf) 2015; 82: 801-807
    CrossrefPubMedGoogle Scholar
  • 13 Nenke MA, Holmes M, Rankin W, Lewis JG, Torpy DJ. Corticosteroid-binding globulin cleavage is paradoxically reduced in alpha-1 antitrypsin deficiency: Implications for cortisol homeostasis. Clin Chim Acta 2016; 452: 27-31
    CrossrefPubMedGoogle Scholar
  • 14 Nenke MA, Lewis JG, Rankin W, McWilliams L, Metcalf RG, Proudman SM, Torpy DJ. Reduced corticosteroid-binding globulin cleavage in active rheumatoid arthritis. Clin Endocrinol (Oxf) 2016; April 8 [Epub ahead of print]
    PubMedGoogle Scholar
  • 15 Geer EB, Islam J, Buettner C. Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinol Metab Clin North Am 2014; 43: 75-102
    CrossrefPubMedGoogle Scholar
  • 16 Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab 2009; 94: 2692-2701
    CrossrefPubMedGoogle Scholar
  • 17 Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith Jr SC. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-1645
    CrossrefPubMedGoogle Scholar
  • 18 Schafer HH, de Villiers JD, Sivukhina E, Lewis J, Wande D, Perembe B, Jirikowski G. Altered homeostasis of systemic glucocorticoids as related to obesity, glucose tolerance, and smoking. Horm Metab Res 2013; 45: 245-251
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Lewis JG, Borowski KK, Shand BI, George PM, Scott RS. Plasma sex hormone-binding globulin, corticosteroid-binding globulin, cortisol, and free cortisol levels in outpatients attending a lipid disorders clinic: a cross-sectional study of 1137 subjects. Horm Metab Res 2010; 42: 274-279
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 20 Lewis JG, Shand BI, Frampton CM, Elder PA, Scott RS. Plasma levels of sex hormone-binding globulin, corticosteroid-binding globulin and cortisol in overweight subjects who develop impaired fasting glucose: a 3-year prospective study. Horm Metab Res 2009; 41: 255-259
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Fernandez-Real JM, Pugeat M, Grasa M, Broch M, Vendrell J, Brun J, Ricart W. Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. J Clin Endocrinol Metab 2002; 87: 4686-4690
    CrossrefPubMedGoogle Scholar
  • 22 Lapidus L, Lindstedt G, Lundberg PA, Bengtsson C, Gredmark T. Concentrations of sex-hormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women. Clin Chem 1986; 32: 146-152
    CrossrefPubMedGoogle Scholar
  • 23 Meyer EJ, Nenke MA, Rankin W, Lewis JG, Torpy DJ. Corticosteroid-binding globulin: a review of basic and clinical advances. J Hum Nutr Diet 2016; May 23 [Epub ahead of print] DOI: 10. 1055/s-0042-108071.
    PubMedGoogle Scholar
  • 24 del Mar Grasa M, Cabot C, Adan C, de Matteis R, Esteve M, Cinti S, Fernandez JA, Lopez RX, Alemany A. Corticosteroid-binding globulin synthesis and distribution in rat white adipose tissue. Mol Cell Biochem 2001; 228: 25-31
    CrossrefPubMedGoogle Scholar
  • 25 Ousova O, Guyonnet-Duperat V, Iannuccelli N, Bidanel JP, Milan D, Genet C, Llamas B, Yerle M, Gellin J, Chardon P, Emptoz-Bonneton A, Pugeat M, Mormede P, Moisan MP. Corticosteroid binding globulin: a new target for cortisol-driven obesity. Mol Endocrinol 2004; 18: 1687-1696
    CrossrefPubMedGoogle Scholar
  • 26 Barat P, Duclos M, Gatta B, Roger P, Mormede P, Moisan MP. Corticosteroid binding globulin gene polymorphism influences cortisol driven fat distribution in obese women. Obes Res 2005; 13: 1485-1490
    CrossrefPubMedGoogle Scholar
  • 27 Joyner JM, Hutley LJ, Bachmann AW, Torpy DJ, Prins JB. Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency. Am J Physiol Endocrinol Metab 2003; 284: E1049-E1054
    CrossrefPubMedGoogle Scholar
  • 28 Torpy DJ, Bachmann AW, Grice JE, Fitzgerald SP, Phillips PJ, Whitworth JA, Jackson RV. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab 2001; 86: 3692-3700
    CrossrefPubMedGoogle Scholar
  • 29 Hill LA, Vassiliadi DA, Simard M, Pavlaki A, Perogamvros I, Hadjidakis D, Hammond GL. Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman. J Clin Endocrinol Metab 2012; 97: 4260-4267
    CrossrefPubMedGoogle Scholar
  • 30 Lewis JG, Shand BI, Elder PA, Scott RS. Plasma sex hormone-binding globulin rather than corticosteroid-binding globulin is a marker of insulin resistance in obese adult males. Diabetes Obes Metab 2004; 6: 259-263
    CrossrefPubMedGoogle Scholar
  • 31 Wilson EA, Jawad MJ, Donaldson ES. Corticosteroid-binding globulin as a biologic assay for endogenous estrogen in patients with and without endometrial carcinoma. Am J Obstet Gynecol 1981; 139: 661-664
    CrossrefPubMedGoogle Scholar
  • 32 Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997; 82: 1313-1316
    CrossrefPubMedGoogle Scholar
  • 33 Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282: 2131-2135
    CrossrefPubMedGoogle Scholar
  • 34 Mansuy-Aubert V, Zhou QL, Xie X, Gong Z, Huang JY, Khan AR, Aubert G, Candelaria K, Thomas S, Shin DJ, Booth S, Baig SM, Bilal A, Hwang D, Zhang H, Lovell-Badge R, Smith SR, Awan FR, Jiang ZY. Imbalance between neutrophil elastase and its inhibitor alpha1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab 2013; 17: 534-548
    CrossrefPubMedGoogle Scholar
  • 35 Lewis JG, Elder PA. The reactive centre loop of corticosteroid-binding globulin (CBG) is a protease target for cortisol release. Mol Cell Endocrinol 2014; 384: 96-101
    CrossrefPubMedGoogle Scholar
  • 36 Wensveen FM, Valentic S, Sestan M, Turk Wensveen T, Polic B. The “Big Bang” in obese fat: Events initiating obesity-induced adipose tissue inflammation. Eur J Immunol 2015; 45: 2446-2456
    CrossrefPubMedGoogle Scholar
  • 37 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548-2556
    CrossrefPubMedGoogle Scholar
  • 38 Simard M, Hill LA, Lewis JG, Hammond GL. Naturally occurring mutations of human corticosteroid-binding globulin. J Clin Endocrinol Metab 2015; 100: E129-E139
    CrossrefPubMedGoogle Scholar
  • 39 Mihrshahi R, Lewis JG, Ali SO. Hormonal effects on the secretion and glycoform profile of corticosteroid-binding globulin. J Steroid Biochem Mol Biol 2006; 101: 275-285
    CrossrefPubMedGoogle Scholar
  • 40 Sakai F, Cheix F, Clavel M, Colon J, Mayer M, Pommatau E, Saez S. Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol 1978; 76: 219-226
    CrossrefPubMedGoogle Scholar
  • 41 Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, Pugeat M. Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab 2006; 91: 2165-2170
    CrossrefPubMedGoogle Scholar
  • 42 Verhoog N, Allie-Reid F, Vanden Berghe W, Smith C, Haegeman G, Hapgood J, Louw A. Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPbeta. PLoS One 2014; 9: e110702
    CrossrefPubMedGoogle Scholar
  • 43 Lewis JG, Fredericks R, Fee CJ, Elder PA. Corticosteroid-binding globulin (CBG) reactive centre loop antibodies and surface plasmon resonance interrogate the proposed heat dependent “flip-flop” mechanism of human CBG. J Steroid Biochem Mol Biol 2016; 158: 38-45
    CrossrefPubMedGoogle Scholar
  • 44 Moore DE, Kawagoe S, Davajan V, Mishell DR, Nakamura RM. An in vivo system in man for quantitation of estrogenicity. I. Physiologic changes in binding capacity of serum corticosteroid-binding globulin. Am J Obstet Gynecol 1978; 130: 475-481
    CrossrefPubMedGoogle Scholar
  • 45 Ho JT, Lewis JG, O’Loughlin P, Bagley CJ, Romero R, Dekker GA, Torpy DJ. Reduced maternal corticosteroid-binding globulin and cortisol levels in pre-eclampsia and gamete recipient pregnancies. Clin Endocrinol (Oxf) 2007; 66: 869-877
    CrossrefPubMedGoogle Scholar
  • 46 Mitchell E, Torpy DJ, Bagley CJ. Pregnancy-associated corticosteroid-binding globulin: high resolution separation of glycan isoforms. Horm Metab Res 2004; 36: 357-359
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 47 Smith CL, Hammond GL. Hormonal regulation of corticosteroid-binding globulin biosynthesis in the male rat. Endocrinology 1992; 130: 2245-2251
    PubMedGoogle Scholar
  • 48 Grasa MM, Cabot C, Adan C, Sanchis D, Balada F, Estruch J, Fernandez-Lopez JA, Remesar X, Alemany M. Effect of oleoyl-estrone administration on corticosterone binding to tissues of lean and obese Zucker rats. J Steroid Biochem Mol Biol 1998; 66: 165-169
    CrossrefPubMedGoogle Scholar