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Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase.

ABSTRACT: Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor alpha (PPARalpha). We now show that leptin stimulates fatty acid oxidation and PPARalpha gene expression in the C2C12 muscle cell line through the activation of AMPK containing the alpha2 subunit (alpha2AMPK) and through changes in the subcellular localization of this enzyme. Activated alpha2AMPK containing the beta1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, alpha2AMPK containing the beta2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPARalpha gene transcription. A nuclear localization signal and Thr(172) phosphorylation of alpha2 were found to be essential for nuclear translocation of alpha2AMPK, whereas the myristoylation of beta1 anchors alpha2AMPK in the cytoplasm. The prevention of alpha2AMPK activation and the change in its subcellular localization inhibited the metabolic effects of leptin. Our data thus suggest that the activation of and changes in the subcellular localization of alpha2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPARalpha gene expression in muscle cells.

SUBMITTER: Suzuki A

PROVIDER: S-EPMC1900064 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase.

Suzuki Atsushi A Okamoto Shiki S Lee Suni S Saito Kumiko K Shiuchi Tetsuya T Minokoshi Yasuhiko Y

Molecular and cellular biology 20070409 12

Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor alpha (PPARalpha). We now show that leptin stimulates fatty acid oxidation and PPARalpha gene expression in the C2C12 muscle cell line through the activation of AMPK containing the alpha2 subunit (alpha2AMPK) and through changes in the subcellular localization of this enzyme. Activ ...[more]

PMID: 17420279

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Project description:ABCA12 (ATP binding cassette transporter, family 12) is a cellular membrane transporter that facilitates the delivery of glucosylceramides to epidermal lamellar bodies in keratinocytes, a process that is critical for permeability barrier formation. Following secretion of lamellar bodies into the stratum corneum, glucosylceramides are metabolized to ceramides, which comprise approximately 50% of the lipid in stratum corneum. Gene mutations of ABCA12 underlie harlequin ichthyosis, a devastating skin disorder characterized by abnormal lamellar bodies and a severe barrier abnormality. Recently we reported that peroxisome proliferator-activated receptor (PPAR) and liver X receptor activators increase ABCA12 expression in human keratinocytes. Here we demonstrate that ceramide (C(2)-Cer and C(6)-Cer), but not C(8)-glucosylceramides, sphingosine, or ceramide 1-phosphate, increases ABCA12 mRNA expression in a dose- and time-dependent manner. Inhibitors of glucosylceramide synthase, sphingomyelin synthase, and ceramidase and small interfering RNA knockdown of human alkaline ceramidase, which all increase endogenous ceramide levels, also increased ABCA12 mRNA levels. Moreover, simultaneous treatment with C(6)-Cer and each of these same inhibitors additively increased ABCA12 expression, indicating that ceramide is an important inducer of ABCA12 expression and that the conversion of ceramide to other sphingolipids or metabolites is not required. Finally, both exogenous and endogenous ceramides preferentially stimulate PPARdelta expression (but not other PPARs or liver X receptors), whereas PPARdelta knockdown by siRNA transfection specifically diminished the ceramide-induced increase in ABCA12 mRNA levels, indicating that PPARdelta is a mediator of the ceramide effect. Together, these results show that ceramide, an important lipid component of epidermis, up-regulates ABCA12 expression via the PPARdelta-mediated signaling pathway, providing a substrate-driven, feed-forward mechanism for regulating this key lipid transporter.

Dataset Information

Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase.

Publications

Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase.

Similar Datasets

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