A natural thiophene from Eclipta prostrata (L.) combats obesity by enhancing adipocytes thermogenesis in high-fat diet-fed obese mice

The rising global prevalence of obesity has become a serious public health concern. Recent studies have revealed that natural products derived from medicinal plants can activate adipocytes thermogenesis, presenting promising therapeutic strategies for obesity management. Eclipta prostrata (L.) L., traditionally used for regulating blood glucose and lipid metabolism, has recently emerged as a potential anti-obesity herb. In this study, we identified 2,2′:5′,2″-terthiophene-5-carboxylic acid (T-CA), a naturally occurring thiophene derivative isolated from Eclipta prostrata, as a novel anti-obesity candidate. It enhanced thermogenesis in adipose tissue, effectively preventing and ameliorating high-fat diet (HFD)-induced obesity in mice while mitigating glucose and lipid dysregulation. Mechanistically, T-CA upregulated Perilipin 5 (Plin5), which in turn activated the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling pathway and reinforced lipid droplet (LD)–mitochondria coupling. These coordinated actions promoted mitochondrial biogenesis and fatty acid oxidation, thereby improving systemic metabolic homeostasis and enhancing resistance to diet-induced obesity. To summarize, T-CA represents an appealing approach for treating HFD-induced obesity by augmenting thermogenesis through mitochondrial activation and LD-mitochondria interactions.