@article{d7b80c13f8334f8b95131629eb902331,
title = "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.",
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",
author = "Yiming Zhang and Higgins, {Cassandra B.} and {Van Tine}, {Brian A.} and Bomalaski, {John S.} and DeBosch, {Brian J.}",
note = "Funding Information: Part of this study was funded by a sponsored research agreement awarded by Polaris Pharmaceuticals (to B.J.D.). B.J.D. is the lead inventor on US Patent Application #17/050,318. Relevant US Patent Publication #US2021/0077598, toward which the presented data are material. J.S.B. is an employee of Polaris Pharmaceuticals, Inc. Funding Information: This work was supported by grants from the NIDDK (1R01DK126622-01A1), NHLBI (1R01HL147968-01A1), AASLD (Pilot Research Award), NCCIH (1R21AT010520-01), NIH/National Center for Advancing Translational Sciences (NCATS, #UL1TR002345), NIH R56 (DK115764), AGA-Gilead Sciences Research Scholar Award in Liver Disease, the AGA-Allergan Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease, the Washington University Digestive Disease Research Core Center (P30DK52574), Washington University Diabetes Research Center (P30DK020579), the Nutrition & Obesity Research Center (P30DK056341), The Association for Aging Research Junior Faculty Award, the Robert Wood Johnson Foundation, Washington University Center for Autophagy Therapeutics Research, and the Longer Life Foundation. Y.Z. is a predoctoral student supported by the Washington University School of Medicine Pediatric Gastroenterology Research Training Grant (NIDDK, T32DK077653). B.J.D. conceived and coordinated the study. B.J.D. and Y.Z. wrote the paper. Y.Z. C.B.H. and B.J.D. designed, performed, and analyzed the experiments. B.V.T. coordinated, performed, and analyzed metabolomics experiments. J.S.B. coordinated ADI-PEG 20 experiments and analyzed the data. All authors reviewed the results and approved the final version of the manuscript. Part of this study was funded by a sponsored research agreement awarded by Polaris Pharmaceuticals (to B.J.D.). B.J.D. is the lead inventor on US Patent Application #17/050,318. Relevant US Patent Publication #US2021/0077598, toward which the presented data are material. J.S.B. is an employee of Polaris Pharmaceuticals, Inc. Funding Information: This work was supported by grants from the NIDDK ( 1R01DK126622-01A1 ), NHLBI ( 1R01HL147968-01A1 ), AASLD (Pilot Research Award), NCCIH ( 1R21AT010520-01 ), NIH/National Center for Advancing Translational Sciences (NCATS, # UL1TR002345 ), NIH R56 ( DK115764 ), AGA-Gilead Sciences Research Scholar Award in Liver Disease , the AGA-Allergan Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease , the Washington University Digestive Disease Research Core Center ( P30DK52574 ), Washington University Diabetes Research Center ( P30DK020579 ), the Nutrition & Obesity Research Center ( P30DK056341 ), The Association for Aging Research Junior Faculty Award , the Robert Wood Johnson Foundation , Washington University Center for Autophagy Therapeutics Research , and the Longer Life Foundation . Y.Z. is a predoctoral student supported by the Washington University School of Medicine Pediatric Gastroenterology Research Training Grant (NIDDK, T32DK077653 ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2022",
month = jan,
day = "18",
doi = "10.1016/j.xcrm.2021.100498",
language = "English",
volume = "3",
journal = "Cell Reports Medicine",
issn = "2666-3791",
number = "1",
}