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Rottlerin diminished the lipid accumulation in 3T3‐L1 cell line and enhanced the uncoupling of oxidative phosphorylation in D16 cell line via LRP6 mediated pathway

Rottlerin is a polyphenol compound abundant in Mallotus philippensis. Rottlerin is well known as a PKCδ and mTOR inhibitor, followed by for its anti‐carcinogenic properties. It was recently demonstrated that rottlerin down‐regulates the level of LRP6, which is a novel nutraceutical target for hyperlipidemia and obesity. However, the precise mechanism remains largely unknown. Thus, we hypothesized that rottlerin would reduce adiposity in different adipocytes. We used 3T3‐L1 cell line as a white adipocyte model and D16 cell line as a brown adipocyte model for in vitro analysis. Cell cytotoxicity assay (MTT), lipid accumulation assay (oil red O staining), and immunoblotting were performed in the differentiated adipocytes. Rottlerin did not affect cell cytotoxicity in both differentiated 3T3‐L1 and D16 cell lines (up to 20 μM and 5 μM, respectively). In 3T3‐L1, rottlerin significantly reduced lipid accumulation in a dose‐dependent manner (5, 10, and 20 μM, P < 0.05); lipogenic enzymes including SCD1 and DGAT1 also correspondingly decreased (P < 0.05). More interestingly, SREBP1, a principal lipogenic transcription factor, also remarkably diminished in a dose‐dependent manner (P < 0.01). In differentiated D16, rottlerin enhanced the levels of UCP1 and PGC‐1α, indicating increased non‐shivering thermogenesis; likewise, the level of PRDM16, a co‐regulator of brown adipose development, was enhanced (P < 0.01). LRP6/β‐catenin was reduced in both 3T3‐L1 and D16 cell lines (all P < 0.001). Further analysis of the LRP6‐related pathway is required. In conclusion, rottlerin reduced lipid accumulation in 3T3‐L1 and improved uncoupling of oxidative phosphorylation in D16 via the LRP6 mediated pathway.