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

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.

• Authors: Yiming Zhang, Cassandra B Higgins, Brian A Van Tine, John S Bomalaski, Brian J DeBosch
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 3 Issue 1 Pg. 100498 (01 18 2022) ISSN: 2666-3791 [Electronic] United States
• PMID: 35106510 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s).

Chemical References

• Beclin-1
• fibroblast growth factor 21
• Polyethylene Glycols
• Fibroblast Growth Factors
• Arginine
• Hydrolases
• ADI PEG20
• arginine deiminase
• Glucose

Topics

• Animals
• Arginine (metabolism)
• Autophagy
• Beclin-1 (metabolism)
• Dependovirus (metabolism)
• Diabetes Mellitus, Experimental (genetics, pathology)
• Diet, Western
• Dyslipidemias (pathology)
• Energy Metabolism
• Fatty Liver (pathology)
• Fibroblast Growth Factors (metabolism)
• Glucose (metabolism)
• Hepatocytes (metabolism)
• Homeostasis
• Hydrolases (chemistry, metabolism)
• Insulin Resistance
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Polyethylene Glycols (chemistry)
• Thermogenesis