Stem cell reportsJul 9, 2026

GLP-1 influences bone marrow stem cell development through HIF-2-AKT signals and helps maintain spongy bone in steroid-related osteoporosis

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 10, 2026

Abstract

GLP-1 suppressed adipogenesis and promoted osteogenesis of bone marrow stem cells in a dose-dependent manner.

Transcriptomic analysis revealed that GLP-1 regulates key pathways, including PI3K-AKT and hypoxia signaling, in bone marrow stem cells.
GLP-1 may inhibit the activation of AKT during fat cell formation while altering AKT signaling dynamics during bone cell formation.
The bone-protective effect of semaglutide in osteoporotic mice was significantly reduced in mice lacking HIF-2α.
Loss of HIF-2α appears to largely eliminate the regulatory effects of GLP-1 on AKT activity.

Simplified

Bone marrow mesenchymal stem cell (BMSC) lineage commitment contributes to metabolic bone diseases, but whether glucagon-like peptide-1 (GLP-1) regulates osteo-adipogenic fate remains unclear. Here, RNA sequencing was performed to identify potential pathways regulated by GLP-1 in BMSCs, followed by gain- and loss-of-function experiments. Furthermore, BMSC-specific Hif-2α knockout mice with glucocorticoid-induced osteoporosis were treated with semaglutide to evaluate skeletal effects. GLP-1 suppressed adipogenesis and promoted osteogenesis of BMSCs in a dose-dependent manner. Transcriptomic analysis identified PI3K-AKT and hypoxia signaling as major GLP-1-regulated pathways. Mechanistically, GLP-1 inhibited AKT activation during adipogenesis and reshaped AKT signaling dynamics during osteogenesis. Loss of HIF-2α largely abolished GLP-1-mediated regulation of AKT activity. In vivo, semaglutide improved trabecular bone mass in osteoporotic mice, whereas this bone-protective effect was markedly diminished in Hif-2α-knockout mice. Our findings suggest that GLP-1 modulates BMSC lineage commitment by inhibiting adipogenesis and enhancing osteogenesis through HIF-2α-associated regulation of AKT signaling.

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Competing interests

Declaration of interests The authors declare no competing interests.

PubMed

GLP-1 influences bone marrow stem cell development through HIF-2-AKT signals and helps maintain spongy bone in steroid-related osteoporosis

Abstract

Full Text

Funding

Competing interests

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