Hypothalamic Regulation of Adiposity: The Role of 11β-Hydroxysteroid Dehydrogenase Type 1

 

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Abstract

Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity despite receiving replacement doses of glucocorticoids. Urine analysis of cortisol and cortisone metabolites show that 11-OH/11-oxo ratios are significantly higher in patients with hypothalamic obesity, indicating enhanced 11β-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11β-HSD1 activity and a shift of the steroid inter-conversion towards cortisol may contribute to the effects of the latter in adipose tissue. The message from the hypothalamus to adipocyte 11β-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11β-HSD-1 activity and induce lipolysis. Tumor necrosis factor-α and interleukin-1β upregulate 11β-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through β-adrenergic upregulation and α-adrenergic downregulation of 11β-HSD-1 activity. Inhibition of 11β-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool.

References

• 1 Gura T. Tracing leptin’s partners in regulating body weight.  Science. 2000;  287 1738-1741
  CrossrefPubMedGoogle Scholar
• 2 Skorzewska A, Lal S, Waserman J, Guyda H. Abnormal food-seeking behavior after surgery for craniopharyngioma.  Neuropsychobiology. 1989;  21 17-20
  PubMedGoogle Scholar
• 3 Hoffman H J, de Silva M, Humphreys R P, Drake J M, Smith M L, Blaser S J. Aggressive surgical management of craniopharyngiomas in children.  J Neurosurg. 1992;  76 47-52
  Google Scholar
• 4 de Vile C J, Grant D B, Hayward R D. et al . Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging.  J Clin Endocrinol Metab. 1996;  81 2734-2737
  CrossrefPubMedGoogle Scholar
• 5 Tiosano D, Eisenstein I, Militianu D, Chrousos G P, Hochberg Z. 11β-Hydroxysteroid dehydrogenase activity in hypothalamic obesity.  J Clin Endocrinol Metab. 2003;  88 379-384
  CrossrefPubMedGoogle Scholar
• 6 Dunkelman S S, Fairhurst B, Plager J, Waterhouse C. Cortisol metabolism in obesity.  J Clin Endocrinol Metab. 1964;  24 832-841
  PubMedGoogle Scholar
• 7 Stewart P M. 11β-hydroxysteroid dehydrogenase: implications for clinical medicine.  Clin Endocrinol (oxf). 1996;  44 493-499
  CrossrefPubMedGoogle Scholar
• 8 Ricketts M L, Verhaeg J M, Bujalska I. et al . Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues.  J Clin Endocrinol Metab. 1998;  83 1325-1335
  CrossrefPubMedGoogle Scholar
• 9 Stewart P M, Boulton A, Kumar S, Clark P M, Shackleton C H. Cortisol metabolism in human obesity: impaired cortisone → cortisol conversion in subjects with central adiposity.  J Clin Endocrinol Metab. 1999;  84 1022-1027
  CrossrefPubMedGoogle Scholar
• 10 Rask E, Olsson T, Soderberg S, Andrew R, Livingstone D E, Johnson O, Walker B R. Tissue-specific dysregulation of cortisol metabolism in human obesity.  J Clin Endocrinol Metab. 2001;  86 1418-1421
  CrossrefPubMedGoogle Scholar
• 11 Sorva R, Takinen M R, Kuusi T, Perheentupa J, Nikkila E A. Elevate adipose tissue lipoprotein lipase activity in craniopharyngioma patients.  Metabolism. 1988;  37 418-421
  CrossrefPubMedGoogle Scholar
• 12 Bujalska I J, Kumar S, Stewart P M. Does central obesity reflect ”Cushing's disease of the omentum”?.  Lancet. 1997;  349 1210-1213
  CrossrefPubMedGoogle Scholar
• 13 Hiroaki M, Janice P, Hiroashi S. et al . A transgenic model of visceral obesity and metabolic syndrome.  Science. 2001;  294 2166-2170
  CrossrefPubMedGoogle Scholar
• 14 Friedberg M, Zoumakis E, Hiroi N, Bader T, Chrousos G P, Hochberg Z. Modulation of 11β-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers.  J Clin Endocrinol Metab. 2003;  88 385-393
  CrossrefPubMedGoogle Scholar
• 15 Masuzaki H, Paterson J, Shinyama H, Morton N M, Mullins J J, Seckl J R, Flier J S. A transgenic model of visceral obesity and metabolic syndrome.  Science. 2001;  294 2166-2170
  CrossrefPubMedGoogle Scholar
• 16 Ricketts M L, Shoesmith K J, Hewison M, Strain A, Eggo M C. Regulation of 11β-hydroxysteroid dehydrogenase type 1 in primary cultures of rat and human hepatocytes.  Journal of Endocrinology. 1998;  156 159-168
  CrossrefPubMedGoogle Scholar
• 17 Bader T, Zoumakis E, Friedberg M, Hiroi N, Chrousos G P, Hochberg Z. Human Adipose Tissue under in Vitro Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1: Differentiation and Metabolism Changes.  Horm Metab Res. 2002;  34 752-757
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Caramelli E, Strippoli P, di Giacomi T, Tietz C, Carinci P, Pasquali R. Lack of mutations of type 1 11beta-hydroxysteroid dehydrogenase gene in patients with abdominal obesity.  Endocr Res. 2001;  27 47-61
  CrossrefPubMedGoogle Scholar
• 19 Draper N, Echwald S M, Lavery G G, Walker E A, Fraser R, Davies E, Sorensen T I, Astrup A, Adamski J, Hewison M, Connell J M, Pedersen O, Stewart P M. Association studies between microsatellite markers within the gene encoding human 11beta-hydroxysteroid dehydrogenase type 1 and body mass index, waist to hip ratio, and glucocorticoid metabolism.  J Clin Endocrinol Metab. 2002;  87 4984-4990
  CrossrefPubMedGoogle Scholar
• 20 Gelernter-Yaniv L, Feng N, Sebring N G, Hochberg Z, Yanovski J A. Associations between a polymorphism in the 11-beta hydroxysteroid dehydrogenase type 1 gene and body composition.  Int J Obes Relat Metab Disord. 2003;  27 983-986
  CrossrefPubMedGoogle Scholar
• 21 Stewart P M. Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action.  Eur J Endocrinol. 2003;  149 163-168
  CrossrefPubMedGoogle Scholar
• 22 Rask E, Walker B R, Soderberg S, Livingstone D E, 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. 2002;  87 3330-3336
  CrossrefPubMedGoogle Scholar

Ze’ev Hochberg M. D., DSc

Meyer Children’s Hospital

POB 9602 · Haifa 31096 · Israel ·

Fax: + 972 (4) 854 21 57

Email: z_hochberg@rambam.health.gov.il