Leptin sensitizes hepatocytes to endotoxin toxicity via interleukin-1β signaling and drives adaptive immune activation in the liver.

Leptin, an adipose tissue-derived hormone, regulates multiple aspects of hepatic physiology beyond its well-established metabolic functions. Accumulating evidence indicates that leptin influences hepatocyte viability, yet its role in endotoxin-induced liver injury remains incompletely understood. In this study, we investigated the sensitizing effect of leptin on lipopolysaccharide (LPS)-induced hepatocyte toxicity. We found that leptin at a physiologically relevant concentration (20 ng/ml) markedly sensitized hepatocytes to LPS-stimulated apoptosis, whereas leptin or LPS alone exerted no significant effect. This sensitizing effect was not observed in hepatocytes derived from hepatocyte-specific interleukin-1 receptor type 1 (IL1R1)-deficient mice, indicating a critical role for IL-1R1 signaling in these effects. Essentially similar results were obtained for apoptotic cell death, as demonstrated by Annexin-V/7-AAD staining and altered expression of key biochemical markers of apoptosis. Moreover, leptin/LPS-induced apoptosis was significantly attenuated by neutralization of IL-1β, but not by an IL-1α antibody. The in vitro observations were further validated in vivo, where combined administration of leptin and LPS induced pronounced liver injury, as evidenced by elevated serum AST/ALT levels and enhanced apoptotic signaling, all of which were substantially prevented in hepatocyte-specific IL1R1 knockout mice. Additionally, co-treatment with leptin and LPS elicited robust inflammatory cytokine production under both in vitro and in vivo conditions; this effect was absent in IL1R1-deficient models. Notably, combined leptin and LPS stimulation promoted Th17 differentiation from naïve T cells, leading to B cell activation and enhanced antibody production in an IL1R1-dependent manner. Collectively, these results suggest that leptin sensitizes hepatocytes to endotoxin-induced apoptosis via IL-1β signaling-dependent mechanism, thereby amplifying hepatic inflammation and adaptive immune activation.