Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice.
11 beta-HSD1
H6PDH
glucocorticoids
metabolic syndrome
visceral fat
Journal
Clinical science (London, England : 1979)
ISSN: 1470-8736
Titre abrégé: Clin Sci (Lond)
Pays: England
ID NLM: 7905731
Informations de publication
Date de publication:
15 11 2019
15 11 2019
Historique:
received:
03
07
2019
revised:
07
10
2019
accepted:
18
10
2019
pubmed:
7
11
2019
medline:
23
5
2020
entrez:
8
11
2019
Statut:
ppublish
Résumé
Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral obesity and metabolic syndrome (MS). 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is critical for controlling intracellular GC production, and this process is tightly regulated by hexose-6-phosphate dehydrogenase (H6PDH). To better understand the integrated molecular physiological effects of adipose H6PDH, we created a tissue-specific knockout of the H6PDH gene mouse model in adipocytes (adipocyte-specific conditional knockout of H6PDH (H6PDHAcKO) mice). H6PDHAcKO mice exhibited almost complete absence of H6PDH expression and decreased intra-adipose corticosterone production with a reduction in 11β-HSD1 activity in adipose tissue. These mice also had decreased abdominal fat mass, which was paralleled by decreased adipose lipogenic acetyl-CoA carboxylase (ACC) and ATP-citrate lyase (ACL) gene expression and reduction in their transcription factor C/EBPα mRNA levels. Moreover, H6PDHAcKO mice also had reduced fasting blood glucose levels, increased glucose tolerance, and increased insulin sensitivity. In addition, plasma free fatty acid (FFA) levels were decreased with a concomitant decrease in the expression of lipase adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in adipose tissue. These results indicate that inactivation of adipocyte H6PDH expression is sufficient to cause intra-adipose GC inactivation that leads to a favorable pattern of metabolic phenotypes. These data suggest that H6PDHAcKO mice may provide a good model for studying the potential contributions of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo. Our study suggests that suppression or inactivation of H6PDH expression in adipocytes could be an effective intervention for treating obesity and diabetes.
Identifiants
pubmed: 31696216
pii: 220863
doi: 10.1042/CS20190679
pmc: PMC7493827
mid: NIHMS1626583
doi:
Substances chimiques
Blood Glucose
0
Fatty Acids, Nonesterified
0
Glucocorticoids
0
Carbohydrate Dehydrogenases
EC 1.1.-
galactose-6-phosphate dehydrogenase
EC 1.1.1.-
11-beta-Hydroxysteroid Dehydrogenase Type 1
EC 1.1.1.146
Corticosterone
W980KJ009P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2189-2202Subventions
Organisme : NIDDK NIH HHS
ID : SC1 DK104821
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007598
Pays : United States
Organisme : NIDA NIH HHS
ID : R24 DA017298
Pays : United States
Organisme : NIMHD NIH HHS
ID : S21 MD000103
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001881
Pays : United States
Informations de copyright
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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