Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany; Institute for Diabetes and Cancer (IDC) and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany; Institute for Diabetes and Cancer (IDC) and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Mol Metab. 2017 Jun 24;6(8):873-881. doi: 10.1016/j.molmet.2017.06.009. eCollection 2017 Aug.
Dietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD.
We conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling.
Serum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2α and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin.
Repletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.
饮食蛋白稀释（PD）与代谢优势相关，例如改善葡萄糖稳态和增加能量消耗。这种表型涉及肝脏在氨基酸不足时释放 FGF21；然而，饮食中特定氨基酸（AA）的稀释是否也需要，仍然不清楚。循环支链氨基酸（BCAA）对蛋白质摄入敏感，在肥胖人群和小鼠的血清中升高，被认为促进胰岛素抵抗。我们测试了在 AA 稀释（AAD）饮食中补充饮食 BCAA 是否足以逆转饮食 PD 的糖调节益处。
我们对健康人类和瘦鼠和高脂肪喂养或新西兰肥胖（NZO）小鼠进行了饮食 PD 后的血清 AA 谱分析。我们用三种氨基酸定义的饮食喂养野生型和 NZO 小鼠：对照、完全 AAD 或相同饮食加完整水平的 BCAA（AAD+BCAA）。我们量化了血清 AA，并根据代谢效率、身体成分、葡萄糖稳态、血清 FGF21 以及整合应激反应（ISR）和 mTORC1 信号的组织标志物来描述小鼠。
血清 BCAA 在食欲旺盛的 NZO 血清中升高，但在人类和小鼠模型中通过饮食 PD 始终降低。饮食 BCAA 的补充适度减弱了野生型小鼠的胰岛素敏感性和代谢效率，但不能恢复 NZO 小鼠的高血糖。尽管饮食 BCAA 补充未能减轻肝脏 ISR 的肝标志物，如 P-eIF2α 和 FGF21，但肝脏和外周 mTORC1 信号完全或部分恢复，与循环葡萄糖或胰岛素的变化无关。
饮食 PD 中补充 BCAA 足以对抗躯体 mTORC1 信号的变化，但不能逆转肝脏 ISR 或在饮食 PD 期间诱导 2 型糖尿病的胰岛素抵抗。
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