Urolithin A Induces Brown-like Phenotype in 3T3-L1 White Adipocytesviaβ3-adrenergic Receptor-p38 MAPK Signaling Pathway

Recently, pharmacological activation of thermogenesis in brown fat and induction of white fat browning (beiging) have been considered as promising strategies in the development of anti-obesity drugs. During the screening of natural compounds that may stimulate thermogenesis, urolithin A (UroA), which is metabolized from pomegranate ellagitannins by gut microflora, was identified as a potent anti-obesity candidate. In the present study, we elucidated the role of UroA to induce the brown-like phenotype in 3T3-L1 white adipocytes. UroA treatments of up to 50 mu M were non-toxic to cells. UroA at 15 mu M significantly increased the protein expression levels of brown-fatspecific markers such as UCP1, PRDM16, PGC-1 alpha, C/EBP beta, and PPAR alpha. In addition, it remarkably increased the expression of beige-specific genes, includingCd137, Cidea, Cited1, Tbx1, andTmen26, in 3T3-L1 white adipocytes and significantly elevated expressions of the brown-fatspecific genes (Ppargc1, Prdm16, andUcp1) in white adipocytes. Furthermore, UroA treatment of 3T3-L1 white adipocytes cells reduced the expression of key adipogenic transcription factors, whereas enhanced lipolysis and the fat oxidation process. Mechanistic study revealed that UroA treatment induces browning in white adipocytes via activation of beta 3-AR- and p38 MAPK-dependent signaling pathways. Taken together, UroA has the potential to treat obesity by its capacity to recruit beige fat cells in white adipocyte tissue, thereby contributing to an increase in thermogenesis.