Obesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of life. Therefore, the urgency of the development of novel therapies is of a particular importance. A previous study of ours revealed that the natural pterocarpan, maackiain (MACK), significantly inhibits adipogenic differentiation in human adipocytes through a peroxisome proliferator-activated receptor gamma (PPAR&#
x3b3;)-dependent mechanism. Considering the observed anti-adipogenic potential of MACK, we aimed to further elucidate the molecular mechanisms that drive its biological activity in a <i>Caenorhabditis elegans</i> obesity model. Therefore, in the current study, the anti-obesogenic effect of MACK (25, 50, and 100 &#
x3bc;M) was compared to orlistat (ORST, 12 &#
x3bc;M) as a reference drug. Additionally, the hybrid combination between the ORST (12 &#
x3bc;M) and MACK (100 &#
x3bc;M) was assessed for suspected synergistic interaction. Mechanistically, the observed anti-obesogenic effect of MACK was mediated through the upregulation of the key metabolic regulators, namely, the nuclear hormone receptor 49 (<i>
nhr-49</i>) that is a functional homologue of the mammalian PPARs and the AMP-activated protein kinase (
aak-2/AMPK) in <i>C. elegans</i>. Collectively, our investigation indicates that MACK has the potential to limit lipid accumulation and control obesity that deserves future developments.