WY14643 combined with all-trans retinoic acid acts via p38 MAPK to induce "browning" of white adipocytes in mice

The ability of mammals to resist body fat accumulation is linked to their ability to expand the number of "brown adipocytes" within white fat depots. All-trans retinoic acid (t-RA) and peroxisome proliferator-activated receptor-alpha (PPAR alpha) have been implicated in "browning-like" or "browning" programs, respectively. However, a PPAR alpha-agonist (WY14643) failed to regulate the expression of the uncoupling protein 1(UCP1) gene unless combined with retinoic acid. This study investigated the effects of the PPAR alpha-agonist WY14643 combined with t-RA, on the "browning" of white adipocytes in mice mediated by UCP1, and the molecular mechanisms involved in this process. We compared the effects of WY14643 alone and WY14643 combined with t-RA or the p38 MAPK-inhibitor, SB203580, on white adipocytes after 24 h using the expression of UCP1, detected with RT-PCR and western blot. We also determined the mechanism by which p38 MAPK and phospho-p38 MAPK influence the process of "browning" using western blot. All concentrations of WY14643 failed to induce UCP1 mRNA expression, protein expression, or phosphorylation of p38 MAPK (P < 0.05). WY14643 combined with t-RA was observed to induce UCP1 mRNA expression, protein expression, and phosphorylation of p38 MAPK (P < 0.05). SB203580 combined with WY14643 and t-RA suppressed UCP1 mRNA expression, protein expression, and p38 MAPK phosphorylation (P < 0.05). WY14643 combined with t-RA can induce the transformation of white adipocytes to brown adipocytes through activation of the p38 MAPK signaling pathway.