Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation.
BACKGROUND
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 JAK-STAT pathway is proposed to be regulated through direct arginine methylation of STAT transcription factors, and STAT3 signaling is known to be required for leptin regulation of energy balance.


OBJECTIVE
To identify the potential role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis.


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 STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces STAT3 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, 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 STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes.
Iwasaki
Hiroaki
H
Brigham and Women's Hospital, 75 Francis St, PB408, Boston, MA 02115, USA.
Kovacic
Jason C
JC
Olive
Michelle
M
Beers
Jeanette K
JK
Yoshimoto
Takanobu
T
Crook
Martin F
MF
Tonelli
Leonardo H
LH
Nabel
Elizabeth G
EG
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D006003:Glycogen / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation / Q000502:physiology; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D006003:Glycogen; D008780:Methyltransferases; C553397:PRMT2 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; C464934:protein arginine methyltransferase 2
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