title: Narciclasine attenuates diet-induced obesity by promoting oxidative metabolism in skeletal muscle.
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.
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Sofi G
authors.initials: SG
authors.lastname: Julien
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.|Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
authors.forename: Sun-Yee
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Reinhard
authors.identifier: 0000-0001-7545-2819
authors.initials: R
authors.lastname: Brunmeir
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Sinnakannu
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Ge
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
authors.forename: Hongyu
authors.identifier: 0000-0002-3564-6069
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.affiliation: Magnetic Resonance Spectroscopy and Metabolic Imaging Group, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
authors.forename: Jadegoud
authors.identifier: 0000-0002-6050-5241
authors.initials: J
authors.lastname: Yaligar
authors.affiliation: Magnetic Resonance Spectroscopy and Metabolic Imaging Group, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
authors.forename: Bhanu Prakash
authors.identifier: 0000-0002-7555-7431
authors.initials: BP
authors.lastname: Kn
authors.affiliation: Magnetic Resonance Spectroscopy and Metabolic Imaging Group, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.
authors.forename: Sendhil S
authors.initials: SS
authors.lastname: Velan
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore, Republic of Singapore.
authors.forename: Pia V
authors.initials: PV
authors.lastname: Röder
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Qiongyi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Choon Kiat
authors.initials: CK
authors.lastname: Sim
authors.affiliation: 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.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Wu
authors.affiliation: Translational Laboratory in Genetic Medicine, A*STAR, Singapore, Republic of Singapore.
authors.forename: Marta
authors.initials: M
authors.lastname: Garcia-Miralles
authors.affiliation: Translational Laboratory in Genetic Medicine, A*STAR, Singapore, Republic of Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Mahmoud A
authors.identifier: 0000-0002-9030-0976
authors.initials: MA
authors.lastname: Pouladi
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Republic of Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore, Republic of Singapore.
authors.forename: Weiping
authors.identifier: 0000-0002-5023-2104
authors.initials: W
authors.lastname: Han
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore, Republic of Singapore.
authors.forename: Feng
authors.identifier: 0000-0003-2016-7521
authors.initials: F
authors.lastname: Xu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010617:Phenanthridines / Q000494:pharmacology* / Q000627:therapeutic use*; D010805:Physical Conditioning, Animal; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047151:Amaryllidaceae Alkaloids; D015415:Biomarkers; D005227:Fatty Acids; D010617:Phenanthridines; D020011:Protective Agents; D017382:Reactive Oxygen Species; C010753:narciclasine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D055372:AMP-Activated Protein Kinases