Mechanism of repression of 11β-hydroxysteroid dehydrogenase type 1 by growth hormone in 3T3-L1 adipocytes

Endocr J. 2014;61(7):675-82. doi: 10.1507/endocrj.ej13-0528. Epub 2014 May 23.

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P<0.05). 11β-HSD1 mRNA levels in cells treated with GH in the presence of 1 μM linsitinib were not different from those in absence of linsitinib (35.9% vs. 33.9%). The increase in IGF-I mRNA levels with GH and 1 μM linsitinib was not different from that in the absence of linsitinib (359% vs. 347%). H6PDH mRNA levels were significantly decreased in cells treated with IGF-I for 8 and 24 h (55.6% and 33.7%, P<0.05). In the presence of 1 μM linsitinib, there was no repression of H6PDH mRNA (111.4%). H6PDH mRNA levels were significantly decreased in cells treated with GH in the absence of linsitinib for 24 h (55.9%, P<0.05), but not for 8 h (89.5%). The presence of 1 μM linsitinib also prevented repression of H6PDH mRNA by GH over 24 h (107.8%). These results suggest that GH directly represses 11β-HSD1 mRNA rather than acting via the IGF-I receptor, and that GH represses H6PDH through locally produced IGF-I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • 3T3-L1 Cells
  • Adipocytes, White / drug effects
  • Adipocytes, White / enzymology*
  • Adipocytes, White / metabolism
  • Animals
  • Carbohydrate Dehydrogenases / antagonists & inhibitors*
  • Carbohydrate Dehydrogenases / genetics
  • Carbohydrate Dehydrogenases / metabolism
  • Enzyme Repression* / drug effects
  • Growth Hormone / metabolism*
  • Imidazoles / pharmacology
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Phosphorylation / drug effects
  • Phthalazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • Pyrazines / pharmacology
  • Pyridines / pharmacology
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects

Substances

  • 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
  • Imidazoles
  • Insulin
  • Phthalazines
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyridines
  • RNA, Messenger
  • insulin-like growth factor-1, mouse
  • vatalanib
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Carbohydrate Dehydrogenases
  • galactose-6-phosphate dehydrogenase
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Receptor, IGF Type 1