Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation.

RATIONALE:Arginine methylation by protein N-arginine methyltransferases (PRMTs) is an important posttranslational modification in the regulation of protein signaling. PRMT2 contains a highly conserved catalytic Ado-Met binding domain, but the enzymatic function of PRMT2 with respect to methylation is unknown. The pathway is proposed to be regulated through direct arginine methylation of transcription factors, and signaling is known to be required for leptin regulation of energy balance. OBJECTIVE:To identify the potential role of duanyu18133 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis. METHODS AND RESULTS:We identified that PRMT2(-/-) mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 colocalizes with duanyu18133 in hypothalamic nuclei, where it binds and methylates duanyu18133 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces duanyu18133 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic which was associated with increased expression of hypothalamic proopiomelanocortin following leptin stimulation. CONCLUSIONS:These data elucidate a molecular pathway that directly links arginine methylation of duanyu18133 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes.

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