Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation. To do this, we generated mice expressing wild-type murine Arg2, enzymatically inactive Arg2 (Arg2) and Arg2 lacking its putative mitochondrial targeting sequence (Arg2). We expressed these hepatocyte-specific constructs in obese, diabetic () mice and performed genetic complementation analyses in hepatocyte-specific Arg2-deficent (Arg2) mice. We show that Arg2 attenuates hepatic steatosis, independent of mitochondrial localization or ureahydrolase activity, and that enzymatic arginase activity is dispensable for Arg2 to augment total body energy expenditure. In contrast, mitochondrial localization and ureahydrolase activity were required for Arg2-mediated reductions in fasting glucose and insulin resistance indices. Mechanistically, Arg2 and Arg2 failed to suppress glucose appearance during hyperinsulinemic-euglycemic clamping. Quantification of heavy-isotope-labeled glucose oxidation further revealed that mistargeting or ablating Arg2 enzymatic function abrogates Arg2-induced peripheral glucose oxidation. We conclude that the metabolic effects of Arg2 extend beyond its enzymatic activity, yet hepatocyte mitochondrial ureahydrolysis drives hepatic and peripheral oxidative metabolism. The data define a structure-based mechanism mediating hepatocyte Arg2 function and nominate hepatocyte mitochondrial ureahydrolysis as a key determinant of glucose oxidative capacity in mammals.

中文翻译：

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肝细胞精氨酸酶 2 的结构功能分析揭示线粒体尿素水解是葡萄糖氧化的决定因素

恢复肝脏和外周胰岛素敏感性对于预防或逆转代谢综合征和 2 型糖尿病至关重要。葡萄糖稳态部分包括肝葡萄糖产生和外周组织中胰岛素介导的葡萄糖摄取和氧化的复杂调节。我们之前发现肝细胞精氨酸酶 2 (Arg2) 是一种诱导型尿素水解酶，可在多种肥胖、胰岛素抵抗模型中改善葡萄糖稳态并增强葡萄糖氧化。因此，我们研究了肝细胞 Arg2 控制全身胰岛素作用和葡萄糖氧化的结构功能决定因素。为此，我们培育了表达野生型鼠 Arg2、酶失活 Arg2 (Arg2) 和缺乏假定线粒体靶向序列 (Arg2) 的 Arg2 的小鼠。我们在肥胖、糖尿病小鼠中表达了这些肝细胞特异性构建体，并在肝细胞特异性 Arg2 缺陷 (Arg2) 小鼠中进行了遗传互补分析。我们发现，Arg2 可以减轻肝脏脂肪变性，与线粒体定位或尿素水解酶活性无关，并且精氨酸酶活性对于 Arg2 增加全身能量消耗来说是可有可无的。相反，Arg2 介导的空腹血糖和胰岛素抵抗指数降低需要线粒体定位和尿素水解酶活性。从机制上讲，Arg2 和 Arg2 在高胰岛素-正常血糖钳夹过程中未能抑制葡萄糖的出现。重同位素标记的葡萄糖氧化的定量进一步揭示，错误定位或消除 Arg2 酶功能可消除 Arg2 诱导的外周葡萄糖氧化。我们得出的结论是，Arg2 的代谢作用超出了其酶活性，但肝细胞线粒体尿素水解驱动肝脏和外周氧化代谢。这些数据定义了介导肝细胞 Arg2 功能的基于结构的机制，并将肝细胞线粒体尿素水解作为哺乳动物葡萄糖氧化能力的关键决定因素。