AICAR inhibits ceramide biosynthesis in skeletal muscle

Diabetology & Metabolic Syndrome

Benjamin T Bikman¹  Chad R Hancock²  John T Prince³  Mikayla O Thatcher¹  Braden J Tucker¹  M Andrew Bressler¹  Aimee E Hodson¹  Eric S Brassfield¹  Michael J Evanson¹  Tamil S Anthonymuthu³  Melissa E Smith¹  Katherine A Erickson¹ 

[1] Physiology and Developmental Biology, Brigham Young University, 593 WIDB, Provo, UT 84602, USA;Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA;Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA

关键词: Metabolic syndrome;    Obesity;    AMPK;    Ceramide;    AICAR;   

Others  :  814845
DOI  :  10.1186/1758-5996-4-45

 received in 2012-06-29, accepted in 2012-11-05,  发布年份 2012

【 摘 要 】

Background

The worldwide prevalence of obesity has lead to increased efforts to find therapies to treat obesity-related pathologies. Ceramide is a well-established mediator of several health problems that arise from adipose tissue expansion. The purpose of this study was to determine whether AICAR, an AMPK-activating drug, selectively reduces skeletal muscle ceramide synthesis.

Methods

Murine myotubes and rats were challenged with palmitate and high-fat diet, respectively, to induce ceramide accrual, in the absence or presence of AICAR. Transcript levels of the rate-limiting enzyme in ceramide biosynthesis, serine palmitoyltransferase 2 (SPT2) were measured, in addition to lipid analysis. Student’s t-test and ANOVA were used to assess the association between outcomes and groups.

Results

Palmitate alone induced an increase in serine palmitoyltransferase 2 (SPT2) expression and an elevation of ceramide levels in myotubes. Co-incubation with palmitate and AICAR prevented both effects. However, ceramide and SPT2 increased with the addition of compound C, an AMPK inhibitor. In rats fed a high-fat diet (HFD), soleus SPT2 expression increased compared with normal chow-fed littermates. Moreover, rats on HFD that received daily AICAR injections had lower SPT2 levels and reduced muscle ceramide content compared with those on HFD only.

Conclusions

These results suggest that AICAR reduces ceramide synthesis by targeting SPT2 transcription, likely via AMPK activation as AMPK inhibition prevented the AICAR-induced improvements. Given the role of skeletal muscle ceramide in insulin resistance, it is tempting to speculate that interventions that activate AMPK may lead to long-term ceramide reduction and improved metabolic function.

【 授权许可】

   
2012 Erickson et al.; licensee BioMed Central Ltd.

【 图 表 】

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