Journal
CELL REPORTS MEDICINE
Volume 3, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2021.100498
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Funding
- NIDDK [1R01DK126622-01A1]
- NHLBI [1R01HL147968-01A1]
- AASLD (Pilot Research Award)
- NCCIH [1R21AT010520-01]
- NIH/National Center for Advancing Translational Sciences (NCATS) [UL1TR002345]
- AGA-GileadSciencesResearch Scholar Award in Liver Disease
- AGA-Allergan Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease [P30DK52574]
- Washington University Diabetes Research Center [P30DK020579]
- Nutrition & Obesity Research Center [P30DK056341]
- Association for Aging Research Junior Faculty Award
- Robert Wood Johnson Foundation
- Washington University Center for Autophagy Therapeutics Research
- Longer Life Foundation
- Washington University School of Medicine Pediatric Gastroenterology Research Training Grant (NIDDK) [T32DK077653]
- NIHR56 [DK115764]
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Arginine catabolism through activation of systemic autophagy can effectively modulate energy metabolism and reverse multiple complications in obese mice. This study provides potential therapeutic utility for arginine catabolism in the treatment of obesity.
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.
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