Conditioned media derived from HepG2 cells treated with phosphoeleganin synthetic-derived compound PE/2 improve cytokine balance and metabolic response in 3T3-L1 adipocytes.
Abstract
The liver-adipose axis regulates insulin sensitivity and lipid metabolism, and its dysregulation contributes to metabolic disorders. PE/2, a semisynthetic derivative of the marine natural product phosphoeleganin, reduces IL-6 expression and secretion, enhancing insulin sensitivity in liver cells (HepG2). However, its role in liver-adipose communication is unclear. To clarify the impact of PE/2 on liver-adipose tissue crosstalk, the conditioned media approach was used. Protein and mRNA levels were analyzed by Western blot and Real-Time RT-PCR, respectively. Lipid and glucose metabolism were evaluated by Oil Red O staining and glucose consumption assays, respectively. Our results indicate that in 3T3-L1 adipocytes, conditioned media derived from PE/2-treated HepG2 cells (CMPE/2) increased adiponectin expression by 1.85-fold and reduced interleukin-8 and interleukin-1β mRNA levels by 43% and 52%, respectively, compared with conditioned media alone (CM). The protective adipokine phenotype induced by CMPE/2 was accompanied by 1.75-fold lipid accumulation and increased expression of adipogenic markers, including PPARγ, C/EBPα, GLUT4, and FABP4. To examine whether this profile translates into enhanced insulin sensitivity, we evaluated the insulin pathway. Interestingly, CM from insulin-stimulated HepG2 cells (CMIns) did not significantly increase insulin receptor (INSR) or Akt phosphorylation compared with CM from 3T3-L1 adipocytes. However, CM derived from HepG2 co-treated with insulin and PE/2 (CMIns+PE/2) increased INSR and Akt phosphorylation by 2.13- and 1.63-fold, respectively, compared to CM, and by 1.83- and 1.42-fold, respectively, compared to CMIns. Consistently, 3T3-L1 glucose consumption significantly improved in the presence of CMIns+PE/2. Treatment with the PI3K/Akt inhibitor LY294002 reversed the effects of CMIns+PE/2. Finally, supplementing recombinant IL-6 into CMPE/2-treated cells reduced the effect of this compound on the expression of inflammatory and adipogenic genes and on glucose consumption in 3T3-L1 adipocytes, corroborating the hypothesis that IL-6 is involved in the action mediated by PE/2. These findings suggest that PE/2 improves the metabolic-inflammatory profile in adipocytes by modulating hepatocyte-adipocyte crosstalk, highlighting its implication for metabolic dysfunctions associated with impaired liver-adipose communication.
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