Withanolides-enriched leaf extract of Withania somnifera exert anti-obesity effects by inducing brown adipocyte-like phenotype via tuning MAP-kinase signaling axis.

Present study investigated anti-obesity potential of Withania somnifera (L.) Dunal leaf extract (WSLE). Phytochemical characterization of WSLE was performed by UPLC/MS-QToF and HPLC-based analysis. WSLE was assessed for its effect on lipid metabolism and mitochondrial biogenesis in vitro using differentiated 3T3-L1 adipocytes. WSLE was found to contain 59 phytometabolites with a total of 10.601 μg withanolides per mg of extract. WSLE (30 μg/ml) treatment decreased basal levels of intracellular lipids and triglycerides to 13.85 % and 41.58 %, respectively. WSLE downregulated the expression of PPARγ, C/EBPα, C/EBPβ, and their target genes responsible for lipogenesis dose-dependently. An upregulation in expression of lipolytic (ATGL and HSL), thermogenic (PGC1α, UCP1, and PRDM16), and glucose transporter (GLUT4) genes was also observed. Furthermore, WSLE treatment increased glucose uptake by 1.5-fold. These beneficial effects of WSLE were abolished in presence of AMPK, p38MAPK, and ERK inhibitors. These observations were then validated in vivo using Caenorhabditis elegans as a model organism. Intriguingly, WSLE diminished fat accumulation in wild-type N2 worms as evident from reduced Oil-red-O staining and reduction in GFP expression of fat-5, 6, and 7 in transgenic strains. Overall, these results highlight anti-obesity potential of WSLE exerting its effects via alterations in AMPK/p38MAPK/ERK axis.