Perimenopause-induced insulin resistance via 5-HT dysregulation

The menopausal transition is associated with an increased risk of metabolic dysfunction, yet the mechanisms linking ovarian failure to impaired insulin sensitivity remain incompletely defined. While vasomotor symptoms have emerged as clinical markers of heightened metabolic risk, growing evidence suggests that dysregulated serotonergic signaling may contribute to glucose imbalance independent of estrogen decline. Using a 4-vinylcyclohexene diepoxide (VCD) mouse model that mimics early perimenopausal physiology-characterized by follicular depletion, elevated follicle-stimulating hormone, and preserved estradiol-we examined insulin sensitivity, serum and hepatic serotonin (5-HT) levels, hepatic lipid content, and insulin - signaling markers. Complementary in vitro experiments in AML-12 hepatocytes evaluated concentration-dependent effects of 5-HT on cell viability, lipid accumulation, and insulin signaling (IRS1/AKT phosphorylation). VCD-treated mice exhibited impaired insulin sensitivity despite normal body weight, fasting glucose, fasting insulin, and intact hepatic histology. Both circulating and hepatic 5-HT levels were significantly reduced in VCD mice. In vitro, 5-HT exerted dose-dependent effects on hepatocyte viability, with low concentrations enhancing proliferation and high concentrations inducing cytotoxicity. 5-HT increased p-IRS1/IRS1 and decreased p-AKT/AKT, indicating disrupted transmission of insulin signals from proximal to downstream nodes. Notably, 5-HT did not alter lipid droplet content in vivo or in vitro. Perimenopausal ovarian failure perturbs peripheral 5-HT homeostasis, which in turn disrupts hepatic insulin signaling independent of adiposity or steatosis. These findings identify gut-liver serotonergic communication as a previously unrecognized contributor to metabolic vulnerability during the menopausal transition and highlight peripheral 5-HT pathways as potential therapeutic targets for mitigating diabetes risk in women with perimenopausal symptoms.