The dietary fatty acid 10E12Z-CLA induces epiregulin expression through COX-2 dependent PGF2α synthesis in adipocytes

Conjugated linoleic acids (CLAs) are a group of dietary fatty acids that are widely marketed as weight loss supplements. The isomer responsible for this effect is the trans-10, cis-12 CLA (10E12Z-CLA) isomer. 10E12Z-CLA treatment during differentiation of 3T3-L1 adipocytes induces expression of prostaglandin-endoperoxide synthase-2 (Cyclooxygenase-2; COX-2). This work demonstrates that COX-2 is also induced in fully differentiated 3T3-L1 adipocytes after a single treatment of 10E12Z-CLA at both the mRNA (20–40 fold) and protein level (7 fold). Furthermore, prostaglandin (PG)F2α, but not PGE2, is significantly increased 10 fold. In female BALB/c mice fed 0.5% 10E12Z-CLA for 10 days, COX-2 was induced in uterine adipose (2 fold). In vitro, pharmacological COX-2 inhibition did not block the effect of 10E12Z-CLA on adipocyte-specific gene expression although PGF2α was dose-dependently decreased. These studies demonstrate that PGF2α was not by itself responsible for the reduction in adipocyte character due to 10E12Z-CLA treatment. However, PGF2α, either exogenously or endogenously in response to 10E12Z-CLA, increased the expression of the potent mitogen and epidermal growth factor (EGF) receptor (EGFR) ligand epiregulin in 3T3-L1 adipocytes. Blocking PGF2α signaling with the PGF2α receptor (FP) antagonist AL-8810 returned epiregulin mRNA levels back to baseline. Although this pathway is not directly responsible for adipocyte dependent gene expression, these results suggest that this signaling pathway may still have broad effect on the adipocyte and surrounding cells.

► 10E12Z-CLA induces COX-2 synthesis in vitro and in vivo and specific induction of PGF2α.
► Inhibition of COX-2 was insufficient to inhibit the effects of 10E12Z-CLA on adipose.
► PGF2α acts in an autocrine manner on 3T3-L1 adipocytes to induce the mitogen epiregulin.
► Autocrine PGF2α signaling may enhance survival/proliferation of adipocytes or adjacent tissues in response to 10E12Z-CLA.