Driving arginine catabolism to activate systemic autophagy

Area of Science:

• Cellular Biology
• Metabolic Diseases
• Biochemistry

Background:

• Autophagy is a vital cellular process for homeostasis, but its impairment is linked to aging and diseases.
• Current methods to induce autophagy, like fasting, are difficult to sustain, and drug targets are limited.
• Obesity and its complications present a significant health challenge with unmet therapeutic needs.

Purpose of the Study:

• To investigate arginine catabolism as a novel strategy to activate autophagy.
• To evaluate the therapeutic potential of arginine catabolism for treating obesity and associated metabolic disorders.
• To identify pharmacological agents that can leverage arginine catabolism for therapeutic benefit.

Main Methods:

• Utilized hepatocyte-specific transgenic activation of arginine catabolism in mice.
• Administered pegylated arginine deiminase, an anti-tumor drug, systemically in obese mouse models.
• Assessed effects on energy expenditure, insulin sensitivity, lipid profiles, and liver fat accumulation.
• Investigated the roles of hepatocyte FGF21 and whole-body BECN1 expression in mediating the observed effects.

Main Results:

• Hepatocyte-specific and systemic arginine catabolism activation significantly improved metabolic parameters in obese mice.
• Treatment led to increased energy expenditure, enhanced insulin sensitivity, and reduced dyslipidemia and hepatic steatosis.
• These beneficial effects were dependent on hepatocyte FGF21 and whole-body BECN1 expression.
• Pegylated arginine deiminase demonstrated efficacy in promoting autophagy and ameliorating obesity-related complications.

Conclusions:

• Arginine catabolism is a viable pathway to induce autophagy and treat metabolic diseases like obesity.
• Pharmacological targeting of arginine catabolism, using agents like pegylated arginine deiminase, offers a promising therapeutic strategy.
• This approach holds potential for managing obesity and its associated health issues by modulating cellular self-digestion processes.