Research ArticleMetabolism

Arginine Methylation of CRTC2 Is Critical in the Transcriptional Control of Hepatic Glucose Metabolism

Sci. Signal.  25 Feb 2014:
Vol. 7, Issue 314, pp. ra19
DOI: 10.1126/scisignal.2004479

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Getting a Sugar Rush from Arginine Methylation

Fasting causes the liver to produce and release glucose into the bloodstream, a process called gluconeogenesis. Fasting triggers the transcriptional activation of genes encoding gluconeogenic enzymes by CREB (cAMP response element–binding protein) and its coactivator CRTC2 (CREB-regulated transcription coactivator 2). Han et al. found that CRTC2 was targeted by the arginine methyltransferase PRMT6. In cells, arginine methylation of CRTC2 enhanced the association of CRTC2 with CREB and increased CREB activity. In mice, overexpression of PRMT6 increased the expression of genes encoding gluconeogenic enzymes and blood glucose concentrations, effects that required CRTC2. Obesity or insulin resistance leads to higher blood glucose concentrations, and acute deletion of PRMT6 restored blood glucose concentrations to normal in mice that were obese or insulin-resistant either through genetics or diet. Thus, hyperglycemia triggered by obesity or diet could be controlled by inhibiting the arginine methylation of CRTC2 by PRMT6.