Format

Send to

Choose Destination
Diabetes. 2017 Jul;66(7):1858-1870. doi: 10.2337/db16-0270. Epub 2017 Apr 12.

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle.

Author information

1
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
2
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
3
Drug Screening Center, Institute of Materia Medica, Beijing, People's Republic of China.
4
School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
5
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
6
School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, People's Republic of China chancb@hku.hk.

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.

PMID:
28404596
PMCID:
PMC5482076
DOI:
10.2337/db16-0270
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center