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PLoS Biol. 2017 Feb 16;15(2):e1002597. doi: 10.1371/journal.pbio.1002597. eCollection 2017 Feb.

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

Author information

1
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
2
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
3
Magnetic Resonance Spectroscopy and Metabolic Imaging Group, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
4
Institute of Molecular and Cell Biology, A*STAR, Singapore, Republic of Singapore.
5
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
6
Translational Laboratory in Genetic Medicine, A*STAR, Singapore, Republic of Singapore.
7
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.

Abstract

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.

PMID:
28207742
PMCID:
PMC5331945
DOI:
10.1371/journal.pbio.1002597
[Indexed for MEDLINE]
Free PMC Article
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