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Upregulation of hepatic flavin-containing monooxygenase 3 by increased corticosterone via glucocorticoid receptor contributes to gestational diabetes mellitus.

Binxin Chen,Mingyang Chen,Xiaoyi Pan,Mengru Bai,Dongli Sun,Huidi Jiang,Nengming Lin,Zhiyuan Ma

Published 2025 in Drug Metabolism And Disposition

ABSTRACT

Gestational diabetes mellitus (GDM) significantly increases the risk of various complications during pregnancy and elevates the lifelong susceptibility to metabolic disorders. Previous studies have indicated elevated cortisol levels in women with GDM, and hepatic flavin-containing monooxygenase 3 (FMO3) contributes to diabetes mellitus. However, the specific mechanism by which cortisol affects FMO3 and its roles in GDM remain unclear. This study uncovered a novel signaling axis wherein cortisol/corticosterone elevation during GDM activates the glucocorticoid receptor, thereby inducing hepatic FMO3 upregulation. This molecular cascade culminated in increased hepatic trimethylamine N-oxide production, which exacerbated hyperglycemia through activation of the protein kinase B-forkhead box O1-O1-glucose-6-phosphatase axis. Notably, pharmacological inhibition of FMO3 using 3,3'-Diindolylmethane (a diet-derived bioactive compound) significantly improved glucose tolerance in pregnant mice by suppressing both trimethylamine N-oxide biosynthesis and protein kinase B-forkhead box O1-O1-glucose-6-phosphatase signaling. Our findings elucidated the glucocorticoid-driven regulatory mechanism of hepatic FMO3 in GDM pathogenesis and suggested the potential of the FMO3 inhibitor as a candidate agent for modulating glucose homeostasis in GDM. SIGNIFICANCE STATEMENT: Pregnancy-induced glucocorticoid activates hepatic flavin-containing monooxygenase 3, driving trimethylamine N-oxide production to exacerbate hyperglycemia through the forkhead box O1-O1-glucose-6-phosphatase axis. Our study identifies flavin-containing monooxygenase 3 as a therapeutic target for gestational diabetes mellitus and suggests 3,3'-diindolylmethane as a promising candidate to improve glucose homeostasis in gestational diabetes mellitus management.

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