PRMT3-mediated post-translational adaptation to fasting regulates metabolic flexibility

Area of Science:

• Metabolic research
• Obesity research
• Molecular biology

Background:

• Obesity significantly impairs metabolic flexibility, hindering the body's ability to adapt to changing energy needs.
• Dietary interventions, such as time-restricted feeding (TRF), show promise in restoring metabolic flexibility.
• The precise molecular mechanisms linking obesity, metabolic flexibility, and feeding patterns require further elucidation.

Purpose of the Study:

• To investigate the role of PRMT3 and arginine methylation in regulating metabolic flexibility during feeding and fasting states.
• To explore the therapeutic potential of targeting PRMT3 for obesity and metabolic dysfunction.
• To elucidate the downstream targets and signaling pathways influenced by PRMT3 in adipocytes.

Main Methods:

• Utilized a diet-induced obesity (DIO) mouse model.
• Investigated the effects of pharmacological PRMT3 inhibition and TRF (16:8 regimen).
• Analyzed gene and protein expression, including PRMT3, ADMA, and SLC25A1, in visceral white adipose tissue (vWAT).
• Conducted adipocyte-specific gene deletion studies (Slc25a1).

Main Results:

• Feeding upregulates PRMT3 and ADMA via insulin-pAKT signaling; fasting reduces their expression.
• PRMT3 inhibition attenuated DIO and enhanced adipocyte glycolysis in male mice.
• PRMT3 directly methylates arginine residues, driving SLC25A1 expression during feeding.
• A 16:8 TRF regimen normalized PRMT3 and ADMA levels and suppressed SLC25A1.
• PRMT3 inhibition mimicked TRF benefits, improving metabolic flexibility.
• Adipocyte-specific Slc25a1 deletion protected against DIO and improved insulin sensitivity.

Conclusions:

• PRMT3-mediated arginine methylation in vWAT acts as a nutrient-responsive axis that impairs metabolic flexibility in obesity.
• Targeting PRMT3 represents a potential therapeutic strategy for combating obesity and associated metabolic disorders.
• The PRMT3-ADMA-SLC25A1 pathway is a critical regulator of adipocyte function and systemic metabolic health.