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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Amaryllidaceae Alkaloids / pharmacology*
  • Amaryllidaceae Alkaloids / therapeutic use*
  • Animals
  • Biomarkers / metabolism
  • Cell Respiration / drug effects
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Diet / adverse effects*
  • Diet, High-Fat
  • Energy Metabolism / drug effects
  • Enzyme Activation / drug effects
  • Fatty Acids / metabolism
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Slow-Twitch / drug effects
  • Muscle Fibers, Slow-Twitch / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Obesity / drug therapy*
  • Obesity / metabolism*
  • Oxidation-Reduction / drug effects
  • Phenanthridines / pharmacology*
  • Phenanthridines / therapeutic use*
  • Physical Conditioning, Animal
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Amaryllidaceae Alkaloids
  • Biomarkers
  • Fatty Acids
  • Phenanthridines
  • Protective Agents
  • Reactive Oxygen Species
  • narciclasine
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Cyclic AMP
  • AMP-Activated Protein Kinases

Grants and funding

This work was supported by intramural funding from the Agency for Science, Technology and Research (A*STAR) of Singapore, the Singapore-China Joint Research Programme (SG-CN JRP-1215c032) and the ETPL GAP Funding (ETPL/15-R15GAP-0003) to FX, and in part by the Biomedical Research Council Young Investigator Grant (13/1/16/YA/007) of A*STAR to SGJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.