<scp>SRM</scp> ‐Mediated Spermidine Synthesis Links Lipid Overload With <scp>AMPK</scp> Pathway to Regulate Hepatic Insulin Signaling and Gluconeogenesis

Polyamine metabolism is essential for cell proliferation and differentiation; however, its specific role in insulin signaling regulation remains poorly understood. Here, we uncover an unexpected role for spermidine synthase (SRM) in linking lipid overload to insulin resistance. In a teleost fish model, we demonstrate high fat diet (HFD) suppresses hepatic SRM expression via X-box binding protein 1 (XBP1)-dependent transcriptional repression. Loss of SRM, either by pharmacological inhibition or siRNA-mediated knockdown, impairs insulin signaling, as evidenced by decreased AKT phosphorylation and increased expression of gluconeogenic enzymes. Conversely, overexpression of SRM enhances insulin sensitivity and suppresses gluconeogenesis. Mechanistically, SRM-mediated regulation of the insulin signaling pathway is dependent on its downstream metabolite spermidine (SPD), which functions through AMP-activated protein kinase (AMPK) pathway, as the beneficial effects of SPD are abolished by the AMPK inhibitor Compound C. In addition, dietary HFD significantly decreases hepatic SPD levels by 35% and reduces the p-AKT/AKT ratio by 58% in croaker, while it elevates blood glucose levels by 39%. Conversely, SPD supplementation increases the p-AKT/AKT ratio by 131% and lowers blood glucose levels by 20%, compared with the HFD group. Taken together, our findings establish the SRM-SPD axis as a critical link between nutritional stress and insulin resistance, and highlight SPD as a potential nutraceutical for combating insulin resistance and glucose intolerance in teleost fish.