Atractylodis Rhizoma-derived nanovesicles suppress adipocyte IDO1/kynurenine-AhR-androgen receptor signaling in a mouse model of obesity-associated PCOS

Abstract Background Obesity-associated polycystic ovary syndrome (PCOS) is characterized by metabolic dysfunction, adipose inflammation and androgen excess, but the adipose mechanism linking metabolic stress to androgen-related pathology remains unclear. This study aimed to determine whether Atractylodis Rhizoma-derived exosome-like nanovesicles (AR-ELNs) ameliorate obesity-associated PCOS through modulation of an adipocyte-derived kynurenine pathway (KP)-aryl hydrocarbon receptor (AhR)/androgen receptor (AR) signaling. Methods A high-fat diet plus letrozole-induced mouse model, AR-ELN biodistribution and safety analyses, integrated transcriptomic and proteomic profiling, adipocyte-based mechanistic assays, reporter assays, co-immunoprecipitation, proximity ligation assays and adipocyte-specific Ido1 knockout mice were used. Results AR-ELNs displayed a multi-organ distribution pattern with relatively sustained retention in adipose tissue, were internalized by cultured adipocytes, and improved estrous cyclicity, reproductive hormone imbalance, glucose intolerance, insulin resistance, and adipose inflammatory remodeling. Multi-omics analysis identified a KP-AhR/AR-related metabolic-endocrine program in inguinal white adipose tissue that was partially reversed by AR-ELNs. PCOS adipose tissue showed increased indoleamine 2,3-dioxygenase 1 (IDO1), kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), kynurenine (Kyn)/tryptophan (Trp) ratio, aryl hydrocarbon receptor (AHR), androgen receptor (AR), and hydroxysteroid 17β-dehydrogenase 12 (HSD17B12), with reduced cytochrome P450 family 19 subfamily A member 1 (CYP19A1). Kyn promoted AhR-dependent AR nuclear accumulation, androgen-responsive transcription and AHR/AR interaction. Adipocyte-specific Ido1 deletion suppressed KP activation and improved reproductive, metabolic and inflammatory phenotypes. Conclusion AR-ELNs ameliorate obesity-associated PCOS in association with suppression of an adipocyte-centered IDO1/Kyn-AhR/AR signaling program, supporting adipose KP activation as a potential mechanistic link between obesity and androgen-related pathology in PCOS.