title: Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle.
abstract: Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine that plays a central role in obesity-induced insulin resistance. It also controls cellular lipid metabolism, but the underlining mechanism is poorly understood. We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals withPIKEablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α-initiated metabolic changes in skeletal muscle.
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
authors.forename: Margaret Chui Ling
authors.initials: MCL
authors.lastname: Tse
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Oana
authors.initials: O
authors.lastname: Herlea-Pana
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brobst
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Drug Screening Center, Institute of Materia Medica, Beijing, People's Republic of China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: John
authors.initials: J
authors.lastname: Wood
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Zhixue
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
authors.forename: Aung Moe
authors.initials: AM
authors.lastname: Zaw
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
authors.forename: Billy K C
authors.initials: BKC
authors.lastname: Chow
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China chancb@hku.hk.
authors.forename: Chi Bun
authors.initials: CB
authors.lastname: Chan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001823:Body Composition; D059305:Diet, High-Fat; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015309:Glucose Clamp Technique; D047468:Immunoprecipitation; D000069285:Infliximab / Q000494:pharmacology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008124:Locomotion; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D018501:Antirheumatic Agents; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D000249:Adenosine Monophosphate; D000069285:Infliximab; D055372:AMP-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C529781:PIKE protein, mouse