Conditioned media derived from HepG2 cells treated with phosphoeleganin synthetic-derived compound PE/2 improve cytokine balance and metabolic response in 3T3-L1 adipocytes
- 1Department of Translational Medicine, University of Naples Federico II
- 2Department of Pharmacy, University of Naples Federico II
Abstract
Background: 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.
Methods: 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.
Results: Our results indicate that in 3T3-L1 adipocytes, conditioned media derived from PE/2-treated HepG2 cells (CM PE/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 CM PE/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 (CM Ins ) 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 (CM Ins+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 CM Ins . Consistently, 3T3-L1 glucose consumption significantly improved in the presence of CM Ins+PE/2 . Treatment with the PI3K/Akt inhibitor LY294002 reversed the effects of CM Ins+PE/2 . Finally, supplementing recombinant IL-6 into CM PE/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.
Conclusion: 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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BibTeX
@article{mormone2026conditioned,
title = {{Conditioned media derived from HepG2 cells treated with phosphoeleganin synthetic-derived compound PE/2 improve cytokine balance and metabolic response in 3T3-L1 adipocytes}},
author = {Federica Mormone and Giusy Ferraro and Cristina Morelli and Francesca Fiory and Serena Cabaro and Giuseppe Perruolo and Marcello Casertano and Marialuisa Menna and Pietro Formisano and Concetta Imperatore and Francesco Oriente},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1909848},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1909848/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Conditioned media derived from HepG2 cells treated with phosphoeleganin synthetic-derived compound PE/2 improve cytokine balance and metabolic response in 3T3-L1 adipocytes
AU - Federica Mormone
AU - Giusy Ferraro
AU - Cristina Morelli
AU - Francesca Fiory
AU - Serena Cabaro
AU - Giuseppe Perruolo
AU - Marcello Casertano
AU - Marialuisa Menna
AU - Pietro Formisano
AU - Concetta Imperatore
AU - Francesco Oriente
PY - 2026
DA - 2026/10/23
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1909848
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1909848/full
AB - Background: 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. Methods: 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. Results: Our results indicate that in 3T3-L1 adipocytes, conditioned media derived from PE/2-treated HepG2 cells (CM PE/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 CM PE/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 (CM Ins ) 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 (CM Ins+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 CM Ins . Consistently, 3T3-L1 glucose consumption significantly improved in the presence of CM Ins+PE/2 . Treatment with the PI3K/Akt inhibitor LY294002 reversed the effects of CM Ins+PE/2 . Finally, supplementing recombinant IL-6 into CM PE/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. Conclusion: 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.
SN - 1663-9812
ER -