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

ABSTRACT 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.