Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA.
Cell Rep Med. 2022 Jan 18;3(1):100498. doi: 10.1016/j.xcrm.2021.100498.
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, , 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.
肥胖是一种能量平衡的多系统紊乱。尽管进行了深入研究，但能量稳态的决定因素仍不完全清楚，缺乏有效的肥胖症及其并发症治疗方法。在这里，我们证明细菌毒力因子和精氨酸脱氨酶赋予的精氨酸亚氨基水解作用促进哺乳动物能量消耗和胰岛素敏感性，并逆转肥胖小鼠的血脂异常、肝脂肪变性和炎症。在此基础上，通过聚乙二醇化精氨酸脱氨酶（ADI-PEG 20）进行药理学精氨酸分解在饮食和遗传肥胖模型中再现了这些代谢效应。这些效应需要自噬复合物蛋白 BECN1 的肝和全身表达以及肝细胞特异性 FGF21 的分泌。单细胞 ATAC 测序进一步揭示了 ADI-PEG 20 响应下 BECN1 依赖性肝细胞染色质可及性变化。因此，数据显示通过激活全身自噬来调节能量代谢的精氨酸分解具有意外的治疗用途，现在可以通过现成的药物治疗来利用。
