Narciclasine attenuates diet-induced obesity and associated dysfunctions by promoting oxidative metabolism in skeletal muscle in mice and humans

Introduction: Given that only 20% of individuals with dietary restrictions are able to maintain long-term weight loss, increasing energy expenditure is becoming an attractive approach to combat obesity. Physical exercise is the ideal way to expend extra energy, but physical activity unfortunately continues to decline in the modern lifestyle and is even prevented in some cases. Thus, there is a need for novel pharmacological approaches that enhance energy expenditure by introducing the same beneficial metabolic effects as exercise in humans. Methods: Herein, we employ diet-induced obesity mouse model and human myotube cells; and various approaches such as Indirect calorimetry, RNAseq, Seahorse, quantitative RT-PCR, Digital Infrared Thermal Imaging to decipher the effects of narciclasine on bioenergetics. Results: Narciclasine (ncls)-treated mice fed a high-fat diet (HFD) showed significantly increased energy expenditure and voluntary physical activity, along with a marked reduction of fat accumulation in liver, skeletal muscle and adipose tissues as compared with vehicle treated control mice. In addition, ncls promoted Pgc1a gene expression, oxidative metabolism and a shift from glycolytic to oxidative fibers in the skeletal muscle of diet-induced obese mice. Intriguingly, ncls also enhanced heat production in vivo as well as in vitro in both murine and human primary myotubes, suggesting a role for this compound in muscle thermogenesis. Conclusion: Here, we report a novel pharmacological strategy that attenuates diet-induced obesity in mice by mimicking the beneficial metabolic effects of endurance training. Our current study demonstrates that narciclasine has promising potential for the prevention and the treatment of obesity in humans.

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Obesity Facts

8

1662-4033

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Supplement 1

1