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
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Research Support, Non-U.S. Gov't
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
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3T3-L1 Cells
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Adipocytes, White / drug effects
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Adipocytes, White / enzymology*
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Adipocytes, White / metabolism
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Animals
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Carbohydrate Dehydrogenases / antagonists & inhibitors*
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Carbohydrate Dehydrogenases / genetics
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Carbohydrate Dehydrogenases / metabolism
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Enzyme Repression* / drug effects
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Growth Hormone / metabolism*
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Imidazoles / pharmacology
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Insulin / metabolism
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Insulin Resistance
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Mice
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Phosphorylation / drug effects
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Phthalazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Protein Processing, Post-Translational / drug effects
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Pyrazines / pharmacology
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Pyridines / pharmacology
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RNA, Messenger / metabolism
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Signal Transduction / drug effects
Substances
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3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
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Imidazoles
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Insulin
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Phthalazines
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Protein Kinase Inhibitors
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Pyrazines
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Pyridines
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RNA, Messenger
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insulin-like growth factor-1, mouse
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vatalanib
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Insulin-Like Growth Factor I
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Growth Hormone
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Carbohydrate Dehydrogenases
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galactose-6-phosphate dehydrogenase
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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Receptor, IGF Type 1