Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle.
Diabetes
; 66(7): 1858-1870, 2017 07.
Article
em En
| MEDLINE
| ID: mdl-28404596
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 with PIKE ablation 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Resistência à Insulina
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Músculo Esquelético
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Fibras Musculares Esqueléticas
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Metabolismo dos Lipídeos
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Proteínas Quinases Ativadas por AMP
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GTP Fosfo-Hidrolases
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Mitocôndrias Musculares
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Proteínas do Tecido Nervoso
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Obesidade
Limite:
Animals
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2017
Tipo de documento:
Article