Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss.
Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss.
复制标题
DOI：
10.1016/j.xcrm.2022.100810
复制
发表时间：
2022-11-15
影响因子：
14.3
通讯作者：
Owen, Bryn M.
中科院分区：
文献类型：
--
作者：
Hope, David C. D.;Hinds, Charlotte E.;Lopes, Tatiana;Vincent, Matthew L.;V. Shrewsbury, Jed;Yu, Arthur T. C.;Davies, Iona;Scott, Rebecca;Jones, Ben;Murphy, Kevin G.;Minnion, James S.;Sardini, Alessandro;Carling, David;Lutz, Thomas A.;Bloom, Stephen R.;Tan, Tricia M. M.;Owen, Bryn M.
胰高血糖素类似物显示出作为下一代多靶点抗肥胖治疗剂的组分的前景。慢性胰高血糖素治疗的生物学，特别是其诱导能量消耗和体重减轻的能力，仍然知之甚少。使用长效胰高血糖素类似物G108，我们证明胰高血糖素介导的体重减轻与其已知的氨基酸分解代谢作用相关的低氨基酸血症有内在联系。机制研究揭示了G108处理的小鼠对低血浆氨基酸的能量消耗反应，通过膳食氨基酸补充剂预防，并通过合理设计的低氨基酸饮食模拟。因此，低血浆氨基酸是G108介导的能量消耗和体重减轻的先决条件。然而，用额外的膳食蛋白预防低氨基酸血症并不影响G108改善肥胖小鼠的脂肪变性或肝脂肪变性的能力。这些研究提供了胰高血糖素介导的体重减轻的机制，并证实肝胰高血糖素受体是代谢性疾病治疗的有吸引力的分子靶点。G108，一种长效胰高血糖素类似物，刺激肝脏氨基酸catenomic能量消耗和体重减轻是对G108刺激的低氨基酸血症的反应膳食蛋白补充剂拯救血浆氨基酸G108改善肝脏脂肪变性和不依赖于膳食蛋白使用合理设计的GCGR激动剂，G108，Hope et al.证明胰高血糖素介导的能量消耗是由全身对低血浆氨基酸可用性的反应驱动的。然而，在肥胖小鼠中，改善脂肪肝疾病或血糖控制既不需要能量消耗也不需要体重减轻。
Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics. G108, a long-acting glucagon analog, stimulates hepatic amino acid catabolism Energy expenditure and weight loss is a response to G108-stimulated hypoaminoacidemia Dietary protein supplementation rescues plasma amino acids G108 improves glycemia and hepatic steatosis independent of dietary protein Using a rationally designed GCGR agonist, G108, Hope et al. demonstrate that glucagon-mediated energy expenditure is driven by a whole-body response to low plasma amino acid availability. However, neither energy expenditure nor weight loss are required for improvements in fatty liver disease or blood glucose control in obese mice.
登录
查看更多内容
影响因子：
5.2
作者：
Hope DCD;Vincent ML;Tan TMM
通讯作者：
Tan TMM
影响因子：
6.9
作者：
Kosinski, Jennifer R.;Hubert, James;Carrington, Paul E.;Chicchi, Gary G.;Mu, James;Miller, Corey;Cao, Jin;Bianchi, Elisabetta;Pessi, Antonello;SinhaRoy, Ranabir;Marsh, Donald J.;Pocai, Alessandro
通讯作者：
Pocai, Alessandro
影响因子：
5.2
作者：
Dai M;Lin T;Yue J;Dai L
通讯作者：
Dai L
影响因子：
3.7
作者：
More, Vijay R.;Lao, Julie;Carrington, Paul
通讯作者：
Carrington, Paul
影响因子：
4.6
作者：
Hinds CE;Owen BM;Hope DCD;Pickford P;Jones B;Tan TM;Minnion JS;Bloom SR
通讯作者：
Bloom SR