Serotonin drives selective hepatic insulin resistance via HTR2A and HTR2B

Abstract Selective hepatic insulin resistance is characterized by preserved lipogenesis despite the failure to suppress gluconeogenesis, yet the detailed molecular mechanisms underlying this paradox remain incompletely understood. Here, we identify serotonin as an insulin independent regulator that differentially regulates hepatic lipid and glucose metabolism in insulin resistant states. Serotonin promoted hepatic lipogenesis through HTR2Amediated activation of the Ca 2+ -PI3K-AKT-mTORC1 signaling cascade, leading to SREBP1 activation independently of insulin receptor. In parallel, serotonin signaling through HTR2Bstimulates hepatic gluconeogenesis via a Ca 2+ -NO-cGMP-PKG pathway, resulting in CREB phosphorylation independently of PKA. Genetic disruption of HTR2A selectively attenuated hepatic lipogenesis, whereas deletion of HTR2B suppressed gluconeogenic gene expression and hepatic glucose production without affecting lipogenesis. Together, these findings establish serotonergic regulation as a dual, insulin independent driver of hepatic lipogenesis and gluconeogenesis under insulin resistant conditions, providing a mechanistic explanation for selective hepatic insulin resistance and identifying serotonin receptors as potential therapeutic targets for metabolic disease.