Introduction: Marine natural products are a great source for potential antidiabetic drugs. It was previously shown that phosphoeleganin (PE), a polyketide isolated from the Mediterranean sea squirt Sidnyum elegans, and its derived compound PE/3, inhibit protein tyrosine phosphatase 1B (PTP1B) improving insulin signaling in skeletal muscle cells. In contrast, another PE-derived molecule lacking phosphate group, PE/2, does not affect skeletal muscle insulin pathway. Methods: Insulin pathway was studied by treating HepG2 cells with phosphoeleganin PE, PE/2 and PE/3 in presence or absence of insulin. Furthermore, the influence of the compounds on the expression and secretion of several inflammatory molecules was evaluated at basal levels and, in presence of high glucose or palmitic acid. Proteins and mRNA levels were analyzed by Western blot and Real-Time RT-PCR, respectively. Secretion levels of inflammatory molecules were measured by Luminex multiassay. Results: Insulin stimulates the phosphorylation of its receptor and AKT by 1.5 and 3.5-fold, respectively. In presence of PE, PE/2 and PE/3, pINSR was increased by 1.9-, 1.8- and 1.6-fold, respectively while pAKT was increased by 7.1-, 6.0- and 5.1-fold, respectively. Surprisingly, only PE/2 has shown an additive effect on insulin-mediated reduction of phosphoenolpyruvate carboxykinase expression and on increased glycogen. Finally, PE and PE/2, unlike PE/3, decrease interleukin 6 (IL6) expression and secretion before and after palmitic acid incubation, while only PE reduces IL6 in presence of high glucose. Conclusion: The data obtained suggests that PE and PE/2 significantly improve insulin signalling and decrease IL6 levels in hepatic cells. As IL6 impairs insulin action, it could be hypothesized that PE and PE/2, by inhibiting IL6, may improve the hepatic insulin pathway.