G protein-coupled receptor 119 exerts anti-inflammatory effects on the liver of zebrafish (Danio rerio) via mediating Gs/cAMP-dependent pathway

Hepatic inflammation is a prevalent health issue in farmed fish, which severely compromises liver function and immune homeostasis. G protein-coupled receptor 119 (GPR119) has been implicated in metabolic and immune regulation in mammals; however, its role in teleost fish remains largely unexplored. In this study, zebrafish (Danio rerio) GPR119 was cloned and systematically characterized with respect to its sequence features, tissue distribution, and subcellular localization. Functional analyses demonstrated that activation of GPR119 by the selective agonist MBX-2982 significantly suppressed the expression of pro-inflammatory cytokines in zebrafish hepatocytes. Both gain- and loss-of-function experiments further confirmed the anti-inflammatory role of GPR119 under palmitic acid (PA) - and lipopolysaccharide-induced inflammatory conditions in vitro, and in vivo. Mechanistically, GPR119 activation engaged G_s- and G_q-dependent signaling, leading to enhanced cyclic adenosine monophosphate (cAMP)-cAMP-response element binding protein (CREB) activity, inhibition of nuclear Factor kappa-B (NF-κB) p65 phosphorylation, and attenuation of inflammatory gene expression. In addition, β-Arrestin-extracellular regulated protein kinases (ERK)-associated signaling was involved in the fine-tuning of CREB-mediated inflammatory regulation. Collectively, these findings identify GPR119 as a critical negative regulator of hepatic inflammation in zebrafish and provide mechanistic insights into its immunomodulatory function, highlighting its potential as a therapeutic target for improving liver health in aquaculture species.