L-Dihydroxyphenylalanine (L-Dopa) Induces Brown-like Phenotype in 3T3-L1 White Adipocytes via Activation of Dopaminergic and β3-adrenergic Receptors

Due to its propensity to boost energy expenditure, browning of white fat is emerging as an intriguing and prospective target for therapeutic intervention in obesity. Here, we report that L-dihydroxyphenylalanine (L-Dopa), used as a gold standard therapy in Parkinson’s disease, induces browning in 3T3-L1 adipocytes by increasing the expression levels of beige-specific marker genes such as Cd137, Cited1, Cidea, Tbx1, Prdm16, and Ucp1. In addition, exposure to L-Dopa induces a remarkable increase in the expressions of proteins involved in thermogenesis in white adipocytes. L-Dopa treatment also regulates 3T3-L1 adipocytes by markedly increasing protein expressions of p-AMPK, p-HSL, CPT1, ACOX1, and PPARα while decreasing FAS, ACC, C/EBPα, and PPARγ, suggesting enhanced lipolysis and fatty acid oxidation as well as reduced lipogenesis and adipogenesis, respectively. Molecular docking studies elucidated that L-Dopa binds to dopamine receptor D1 (DRD1) and β3-AR, thereby predicting the potential receptor candidates that activate protein kinase A (PKA), the master regulator of lipid metabolism. Mechanistic studies indicate that the browning potential of L-Dopa in 3T3-L1 white adipocytes is mediated by DRD1 and β3-AR activation, which consequently stimulates the PKA/p38 MAPK/ERK signaling pathway. In conclusion, L-Dopa appears to be a promising therapeutic candidate in the fight against obesity due to its inherent role in the browning of 3T3-L1 adipocytes via both the dopaminergic and adrenergic pathways. To our knowledge, this is the first report that demonstrates the browning potential of L-Dopa in white adipocytes. Our results may assist to expand the understanding on the contradictory findings in literature, related to the association between L-Dopa and weight loss observed in Parkinson’s disease patients.