Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism

Yiming Zhang, Cassandra B. Higgins, Brian A. Van Tine, John S. Bomalaski, Brian J. DeBosch

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Obesity is a multi-systemic disorder of energy balance. Despite intense investigation, the determinants of energy homeostasis remain incompletely understood, and efficacious treatments against obesity and its complications are lacking. Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase, arcA, promotes mammalian energy expenditure and insulin sensitivity and reverses dyslipidemia, hepatic steatosis, and inflammation in obese mice. Extending this, pharmacological arginine catabolism via pegylated arginine deiminase (ADI-PEG 20) recapitulates these metabolic effects in dietary and genetically obese models. These effects require hepatic and whole-body expression of the autophagy complex protein BECN1 and hepatocyte-specific FGF21 secretion. Single-cell ATAC sequencing further reveals BECN1-dependent hepatocyte chromatin accessibility changes in response to ADI-PEG 20. The data thus reveal an unexpected therapeutic utility for arginine catabolism in modulating energy metabolism by activating systemic autophagy, which is now exploitable through readily available pharmacotherapy.

Original languageEnglish
Article number100498
JournalCell Reports Medicine
Volume3
Issue number1
DOIs
StatePublished - Jan 18 2022

Keywords

  • ADI-PEG 20
  • Beclin-1
  • FGF21
  • GLUT
  • arcA
  • arginase
  • arginine
  • arginine deiminase
  • autophagy
  • caloric restriction
  • diabetes
  • energy metabolism
  • fasting
  • glucose transport
  • insulin resistance
  • liver
  • non-alcoholic fatty liver disease
  • obesity
  • thermogenesis

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