EET, a Lipid Mediator, Upstream of PGC-1α, is Required for HO-1 Activation and Mitochondrial Function During Adipocyte Differentiation

Maayan Waldman ^1,2,3 Luca Vanella ^1,4 Lars Bellner ¹ Joseph Schragenheim ¹ Shailendra Singh ¹ Daohong Lin ¹ Anand Lakhkar ¹ Marco Raffaele ^1,4 Edith Hochhauser ² Michael Arad ³ Nader G. Abraham ¹

¹Department of Pharmacology, New York Medical College, NY, Valhalla
²Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University, Petah-Tikva
³Leviev Heart Center, Tel Aviv University, Sheba Medical Center, Ramat Gan
⁴Drug Science/Biochemistry, University of Catania, Department of . Catania, Italy and, Catania

Background: Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered pre-adipocyte function, enhanced the expression of peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) and increased mitochondrial function in the 3T3-L1-pre-adipocyte.

Methods and Results: Pre-adipocyte (3T3-L1) were differentiated for 5 days and treated with EET agonist. 3T3-L1 cells deficient in PGC-1α were generated using lentiviral shRNA-PPARGC1A. Cells treated with EET displayed a several fold increase in PGC-1α and a decrease in mitochondrial-derived ROS (MitoSox), p

Conclusion: This is the first study to show that a lipid mediator upstream of the PGC-1α signaling cascade, enhances HO-1 expression and decreases adipocyte differentiation. EET- PGC-1α interplay appears to modulate the adipocyte phenotype by regulating PGC-1α which is heme dependent and essential for mitochondrial function and HO-1 expression. This is manifest by a decrease in lipid accumulation and mitochondrial-ROS production and an increase in the canonical Wnt signaling cascade and insulin receptor phosphorylation.

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