Narciclasine attenuates diet-induced obesity by promoting oxidative metabolism in skeletal muscle

Obesity develops when caloric intake exceeds metabolic needs. Promoting energy expenditure represents an attractive approach in the prevention of this fast-spreading epidemic. Here, we report a novel pharmacological strategy in which a natural compound, narciclasine (ncls), attenuates diet-induced obesity (DIO) in mice by promoting energy expenditure. Moreover, ncls promotes fat clearance from peripheral metabolic tissues, improves blood metabolic parameters in DIO mice, and protects these mice from the loss of voluntary physical activity. Further investigation suggested that ncls achieves these beneficial effects by promoting a shift from glycolytic to oxidative muscle fibers in the DIO mice thereby enhancing mitochondrial respiration and fatty acid oxidation (FAO) in the skeletal muscle. Moreover, ncls strongly activates AMPK signaling specifically in the skeletal muscle. The beneficial effects of ncls treatment in fat clearance and AMPK activation were faithfully reproduced in vitro in cultured murine and human primary myotubes. Mechanistically, ncls increases cellular cAMP concentration and ADP/ATP ratio, which further lead to the activation of AMPK signaling. Blocking AMPK signaling through a specific inhibitor significantly reduces FAO in myotubes. Finally, ncls also enhances mitochondrial membrane potential and reduces the formation of reactive oxygen species in cultured myotubes.Narciclasine is a natural compound that attenuates diet-induced obesity in mice by promoting energy expenditure; it also induces a number of beneficial metabolic effects and activates AMPK signaling in skeletal muscle.Author summary: Obesity results from the imbalance of food intake and energy expenditure. Since the restriction of food intake is difficult and inefficient in maintaining long-term weight loss, enhancing energy expenditure is now an attractive approach in combating obesity. Here, we analysed the role in this process of a natural compound called narciclasine. We showed that narciclasine treatment reduces excess fat accumulation in peripheral metabolic tissues, improves blood metabolic parameters and insulin sensitivity in obese mice, and protects these mice from the loss of voluntary physical activity. Further investigation suggested that narciclasine enhances mitochondrial respiration and fatty acid consumption in the skeletal muscle. In addition, narciclasine strongly activates the AMP-activated protein kinase (AMPK) signaling, which is a central sensor of the cellular energy status and a key player in maintaining energy homeostasis, specifically in the skeletal muscle. Mechanistically, we found that narciclasine increases cAMP concentration and ADP/ATP ratio in muscle cells, which further lead to AMPK activation. Finally, we observed that narciclasine increases mitochondrial membrane potential and reduces the production of reactive oxygen species in muscle cells. Our findings suggest that narciclasine is a natural compound that attenuates diet-induced obesity in mice by promoting energy expenditure.