AICAR inhibits ceramide biosynthesis in skeletal muscle

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.

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.

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.

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.