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

Julien, Sofi G., Kim, Sun-Yee, Brunmeir, Reinhard, Sinnakannu, Joanna R., Ge, Xiaojia, Li, Hongyu, Ma, Wei, Yaligar, Jadegoud, Prakash, Bhanu, Velan, Sendhil s., Röder, Pia V., Zhang, Qiongyi, Sim, Choon Kiat, Wu, Jingyi, Garcia-Miralles, Martia, Pouladi, Mahmoud A., Xie, Wei, McFarlane, Craig, Han, Weiping, Xu, Feng, and UNSPECIFIED (2017) Narciclasine attenuates diet-induced obesity by promoting oxidative metabolism in skeletal muscle. PLoS Biology, 15 (2). e1002597.

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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.

Item ID: 52362
Item Type: Article (Research - C1)
ISSN: 1545-7885
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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funders: Agency for Science Technology and Research (A*STAR), Singapore, Singapore-China Joint Research Programme (SG), ETPL Gap Funding, Biomedical Research Council, Singapore (BMRC)
Projects and Grants: SG-CN JRP-1215c032, ETPL/15-R15GAP-0003, BMRC Young Investigator Grant 13/1/16/YA/007
Date Deposited: 28 Mar 2018 04:12
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310111 Signal transduction @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3208 Medical physiology > 320801 Cell physiology @ 20%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320507 Metabolic medicine @ 40%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920106 Endocrine Organs and Diseases (excl. Diabetes) @ 40%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 40%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 20%
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