11β-HSD1 inhibitor alleviates lipid metabolism disorder by activating the AMPK signaling pathway

Lipid metabolism disorders, which are closely linked to obesity, are significantly modulated by the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a key regulator of glucocorticoid (GC) activation. This study explored the therapeutic potential of H8, a curcumin analog and selective inhibitor of 11β-HSD1, in mitigating these disorders. Employing an in vitro model of GC-induced differentiation in 3T3-L1 adipocytes and an in vivo C57BL/6 mice model characterized by 11β-HSD1 overexpression, we demonstrated that treatment with H8 effectively reduced GC levels in both serum and cultured cells. Lipid accumulation, evaluated through Oil Red O and hematoxylin and eosin (HE) staining, was significantly diminished by H8 in both cellular and animal models. Mechanistic investigations revealed that H8 modulated lipid metabolism through dual mechanisms: inhibition of 11β-HSD1 and activation of the AMP-activated protein kinase (AMPK) signaling pathway. Immunohistochemical and immunofluorescence analyses corroborated these lipid-modulating effects, while RNA and protein profiling identified significant alterations in markers of lipid synthesis. Further examination of the interplay between 11β-HSD1 and AMPK led us to hypothesize that H8 ameliorates lipid metabolism disorders primarily through its inhibitory effects.