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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Endocrine Disorders 1/2015

AMPD1 regulates mTORC1-p70 S6 kinase axis in the control of insulin sensitivity in skeletal muscle

Zeitschrift:
BMC Endocrine Disorders > Ausgabe 1/2015
Autoren:
Andreas AK Tandelilin, Tetsuaki Hirase, Athanasius W Hudoyo, Jidong Cheng, Keiko Toyama, Hiroko Morisaki, Takayuki Morisaki
Wichtige Hinweise
An erratum to this article can be found at http://​dx.​doi.​org/​10.​1186/​s12902-015-0078-2.
An erratum to this article is available at http://​dx.​doi.​org/​10.​1186/​s12902-015-0078-2.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Conceived and designed the experiments: TM HM. Performed the experiments: AT TH AH JC KT. Analyzed the data: TM JC HM. Contributed materials: AT TH AH KT. Wrote the paper: TM TH. All authors read and approved the final manuscript.

Abstract

Background

Insulin resistance triggered by excess fat is a key pathogenic factor that promotes type 2 diabetes. Understanding molecular mechanisms of insulin resistance may lead to the identification of a novel therapeutic target for type 2 diabetes. AMPD1, an isoform of AMP deaminase (AMPD), is suggested to play roles in the regulation of glucose metabolism through controlling AMP-activated protein kinase (AMPK) activation. We reported that the diet-induced insulin resistance was improved in AMPD1-deficient mice compared to wild type mice. To further delineate this observation, we studied changes of insulin signaling in skeletal muscle of wild type (WT) and AMPD1-deficient mice.

Methods

Phosphorylation levels of kinases and expression levels of mTOR components were quantified by immunoblotting using protein extracts from tissues. The interaction between mTOR and Raptor was determined by immunoblotting of mTOR immunoprecipitates with anti-Raptor antibody. Gene expression was studied by quantitative PCR using RNA extracted from tissues.

Results

Phosphorylation levels of AMPK, Akt and p70 S6 kinase in skeletal muscle were higher in AMPD1-deficient mice compared to WT mice after high fat diet challenge, while they did not show such difference in normal chow diet. Also, no significant changes in phosphorylation levels of AMPK, Akt or p70 S6 kinase were observed in liver and white adipose tissue between WT and AMPD1-deficient mice. The expression levels of mTOR, Raptor and Rictor tended to be increased by AMPD1 deficiency compared to WT after high fat diet challenge. AMPD1 deficiency increased Raptor-bound mTOR in skeletal muscle compared to WT after high fat diet challenge. Gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and β, downstream targets of p70 S6 kinase, in skeletal muscles was not changed significantly by AMPD1 deficiency compared to the wild type after high fat diet challenge.

Conclusion

These data suggest that AMPD1 deficiency activates AMPK/Akt/mTORC1/p70 S6 kinase axis in skeletal muscle after high fat diet challenge, but not in normal chow diet. These changes may contribute to improve insulin resistance.
Literatur
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