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Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity.
- Source :
-
Nature communications [Nat Commun] 2024 Oct 04; Vol. 15 (1), pp. 8588. Date of Electronic Publication: 2024 Oct 04. - Publication Year :
- 2024
-
Abstract
- Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Male
Mice
Osteogenesis drug effects
Glucose metabolism
Glucocorticoids metabolism
Signal Transduction
Bone Resorption metabolism
Bone Resorption prevention & control
Diet, High-Fat adverse effects
Osteoblasts metabolism
Osteoblasts drug effects
Obesity metabolism
Obesity etiology
Obesity genetics
11-beta-Hydroxysteroid Dehydrogenase Type 1 metabolism
11-beta-Hydroxysteroid Dehydrogenase Type 1 genetics
11-beta-Hydroxysteroid Dehydrogenase Type 1 antagonists & inhibitors
Mice, Knockout
Mice, Inbred C57BL
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39362888
- Full Text :
- https://doi.org/10.1038/s41467-024-52965-4