Functional calibration of PPARγ by baicalein reverses bone-lipid imbalance in type 2 diabetic osteoporosis

Type 2 diabetic osteoporosis (T2DOP) is characterized by excessive bone marrow adiposity and impaired osteogenesis, a pathology driven primarily by PPARγ-mediated dysregulation of the osteogenic-adipogenic differentiation balance in BMSCs under hyperglycemic conditions. Baicalein (BCL) is a natural flavonoid and a key active constituent of Gegen Qinlian Decoction (GQD), has shown regulatory potential in various metabolic disorders. However, its specific role and underlying mechanisms in T2DOP remain to be fully elucidated.

We treated db/db mice with BCL for 8 weeks. Micro-CT and histomorphometric analyses evaluated bone microarchitecture, while histochemical staining assessed marrow adiposity. Immunohistochemistry and Western blot analysis examined the expression of osteogenic and adipogenic markers. In vitro, we subjected high glucose-treated BMSCs to osteogenic/adipogenic induction in the presence of BCL. Differentiation was evaluated by ARS and Oil Red O staining. Furthermore, we employed molecular docking, CETSA, and molecular dynamics simulations to confirm direct binding between BCL and PPARγ.

BCL significantly increased bone mineral density and trabecular number in db/db mice, while reducing marrow fat accumulation. In vitro, it promoted mineralization and suppressed lipid droplet formation. BCL downregulated PPARγ and adipogenic genes and enhanced osteogenic markers (Runx2, COL1A, OCN). Mechanistically, it bound strongly to the PPARγ ligand-binding domain, acting as a microenvironment-dependent modulator that recalibrates its transcriptional activity toward osteogenesis.

BCL attenuates T2DOP by directly targeting PPARγ and restoring its bone-lipid balance.