Article
Cell Biology
Xiaoxue Jiang, Kan Liu, Haizhou Jiang, Hanrui Yin, En-duo Wang, Hong Cheng, Feixiang Yuan, Fei Xiao, Fenfen Wang, Wei Lu, Bo Peng, Yousheng Shu, Xiaoying Li, Shanghai Chen, Feifan Guo
Summary: This study demonstrates that lysosomal amino acid accumulation is associated with insulin resistance, highlighting the role of lysosomal membrane protein SLC7A14 in promoting insulin resistance. SLC7A14 acts as a transporter leading to the accumulation of lysosomal γ-aminobutyric acid (GABA), which inhibits mTORC2 activity and induces insulin resistance. The findings suggest that targeting SLC7A14 may provide a therapeutic approach for treating insulin resistance and GABA-related diseases, as well as providing insights into the upstream mechanisms of mTORC2.
Article
Biochemistry & Molecular Biology
Dan Li, Yuande Wang, Meixiang Yang, Zhongjun Dong
Summary: The lack of mTOR kinase severely impairs NK cell development in mice. mTOR, Raptor, and Rictor play different roles in regulating NK cell development at different stages, with mTOR being essential for early NK cell differentiation.
CELL DEATH AND DIFFERENTIATION
(2021)
Article
Cell Biology
Kiyoto Nishi, Akira Yoshii, Lauren Abell, Bo Zhou, Ricardo Frausto, Julia Ritterhoff, Timothy S. McMillen, Ian Sweet, Yibin Wang, Chen Gao, Rong Tian
Summary: It was found that deficiency of Ppm1k leads to reduced metabolism of branched-chain amino acids (BCAAs) and protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in liver cells. It was observed that BCKAs suppress the activity of liver mitochondrial pyruvate carrier (MPC) and pyruvate-supported respiration. Selective suppression of pyruvate-supported gluconeogenesis was seen in Ppm1k-deficient mice and could be restored through pharmacological activation of BCKA catabolism by BT2. Furthermore, liver MPC was found to be most sensitive to circulating BCKA levels, making it a sensor of BCAA metabolism.
Article
Biochemistry & Molecular Biology
Delong Meng, Qianmei Yang, Chase H. Melick, Brenden C. Park, Ting-Sung Hsieh, Adna Curukovic, Mi-Hyeon Jeong, Junmei Zhang, Nicholas G. James, Jenna L. Jewell
Summary: The study identified ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a critical regulator of mTORC1, which inhibits cell growth through preventing the lysosomal transport and activation of mTORC1, and is also an independent prognostic factor for the overall survival of pancreatic cancer patients.
Article
Gastroenterology & Hepatology
Lingling Zhang, Yanqiu Li, Ying Wang, Yugang Qiu, Hanchuan Mou, Yuanyao Deng, Jiyuan Yao, Zhiqing Xia, Wenzhe Zhang, Di Zhu, Zeyu Qiu, Zhongjie Lu, Jirong Wang, Zhouxin Yang, GenXiang Mao, Dan Chen, Leimin Sun, Leiming Liu, Zhenyu Ju
Summary: During liver regeneration, mTORC2 plays a role in lipid metabolism by facilitating FA transportation into hepatocytes through the GluCer-PPAR-alpha pathway.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2022)
Review
Nutrition & Dietetics
He Yao, Kai Li, Jie Wei, Yajun Lin, Yinghua Liu
Summary: Branched-chain amino acids (BCAAs) play important regulatory roles in glucose and lipid metabolism, protein synthesis, and longevity. Studies have shown associations between circulating BCAA levels or dietary intake of BCAAs and longevity, sarcopenia, obesity, and diabetes. However, the effects of BCAAs on aging and insulin resistance vary in different populations, and contradictory conclusions have been drawn. The regulatory mechanism may be related to endogenous BCAA levels, BCAA metabolism, mTOR-related autophagy, and the recent discovery that insulin resistance may be independent of longevity.
FRONTIERS IN NUTRITION
(2023)
Review
Endocrinology & Metabolism
Phillip J. White, Robert W. McGarrah, Mark A. Herman, James R. Bain, Svati H. Shah, Christopher B. Newgard
Summary: The association of obesity and insulin resistance with increased levels of branched-chain and aromatic amino acids and decreased glycine levels is well-established. Human metabolomics and genetic studies have further confirmed these observations, with preclinical studies identifying mechanisms involved in amino acid homeostasis disruption and its connection to dysregulated glucose and lipid metabolism, particularly in the development of insulin resistance, type 2 diabetes, and cardiovascular diseases.
MOLECULAR METABOLISM
(2021)
Review
Cell Biology
Michaela E. Trautman, Nicole E. Richardson, Dudley W. Lamming
Summary: The proportion of people suffering from age-related diseases is increasing worldwide. Recent research has shown that low protein diets, particularly those low in branched-chain amino acids (BCAAs), can reduce mortality and promote metabolic health and extended lifespan in both humans and rodents. This article discusses the emerging evidence that BCAAs play a crucial role in healthy metabolism and longevity, and explores the physiological and molecular mechanisms behind the benefits of restricting dietary BCAAs. The findings suggest that the quality of protein, specifically the composition of dietary protein, may be a previously overlooked factor in metabolic dysfunction and reducing dietary BCAAs could be a promising new approach to delaying and preventing age-related diseases.
Review
Gastroenterology & Hepatology
Giuseppe Marrone, Amato Serra, Luca Miele, Marco Biolato, Antonio Liguori, Antonio Grieco, Antonio Gasbarrini
Summary: Liver cirrhosis is often accompanied by nutritional alterations, affecting about 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Imbalance of amino acids, especially branched-chain amino acids (BCAAs), has been shown to be associated with complications and prognosis in these patients. Various studies have explored the use of BCAAs supplementation as a therapeutic option, but uncertainties persist regarding its real efficacy, optimal administration route, and dosage.
WORLD JOURNAL OF GASTROENTEROLOGY
(2023)
Article
Cell Biology
Mengnan Zhu, Fukang Teng, Na Li, Li Zhang, Shuxian Zhang, Fan Xu, Jing Shao, Haipeng Sun, Huanhu Zhu
Summary: This study identified a lipid biosynthesis pathway that mediates amino acid sensing in the intestine and neuronal mTORC1, affecting development by regulating protein translation and ribosomal biogenesis. Findings suggest a similar mechanism may operate in mammals, providing new insights into the role of amino acid sensing mechanisms in animals.
DEVELOPMENTAL CELL
(2021)
Article
Multidisciplinary Sciences
Clement Bodineau, Mercedes Tome, Sarah Courtois, Ana S. H. Costa, Marco Sciacovelli, Benoit Rousseau, Elodie Richard, Pierre Vacher, Carlos Parejo-Perez, Emilie Bessede, Christine Varon, Pierre Soubeyran, Christian Frezza, Piedad del Socorro Murdoch, Victor H. Villar, Raul Duran
Summary: In this study, the authors demonstrate that reactivation of AMPK can inhibit glutamine-dependent activation of mTORC1 and glutamoptosis, revealing a dual metabolic connection between glutamine metabolism and mTORC1 through two pathways. This finding has significant implications for the design of future therapeutic strategies for diseases such as cancer.
NATURE COMMUNICATIONS
(2021)
Review
Food Science & Technology
Elzbieta Supruniuk, Ewa Zebrowska, Adrian Chabowski
Summary: Branched chain amino acids (BCAA) and their derivatives have multiple functions in the human body. Elevated fasting blood BCAA concentrations are considered as metabolic indicators of obesity, insulin resistance, dyslipidemia, nonalcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. However, the question of whether BCAA are mechanistic drivers of insulin resistance and its complications or simply markers of metabolic deregulation remains unanswered. The beneficial effects of BCAA on body weight, aerobic capacity, insulin secretion, and sensitivity require high catabolic potential towards amino acids and/or adequate BCAA intake. On the other hand, BCAA-related inhibition of lipogenesis and promotion of lipolysis may prevent impairment in insulin sensitivity. Therefore, this review discusses various strategies for modulating BCAA catabolism and explores the possible roles of BCAA in energy homeostasis.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
(2023)
Article
Endocrinology & Metabolism
Sindre Lee, Hanne L. Gulseth, Torgrim M. Langleite, Frode Norheim, Thomas Olsen, Helga Refsum, Jorgen Jensen, Kare Birkeland, Christian A. Drevon
Summary: The study found that obesity and insulin resistance are associated with elevated plasma levels of BCAAs, and insulin sensitivity is correlated with BCAA levels in the body. Global mRNA-sequencing pathway analysis revealed reduced BCAA metabolism in individuals with insulin resistance compared to normal individuals at baseline. Additionally, exercise for 12 weeks was shown to increase BCAA metabolism in both groups, as indicated by enhanced expression of the gene encoding BCKDH.
Article
Cell Biology
Mariana Borsa, Sandrine Obba, Felix C. Richter, Hanlin Zhang, Thomas Riffelmacher, Joana Carrelha, Ghada Alsaleh, Sten Eirik W. Jacobsen, Anna Katharina Simon
Summary: This study investigates the importance of autophagy in stem cells and finds that autophagy deficiency leads to stem cell loss and bone marrow failure, while inhibition of MTOR can rescue this loss and improve stem cell function.
Article
Medicine, General & Internal
Mona Synnove Bjune, Laurence Lawrence-Archer, Johnny Laupsa-Borge, Cathrine Horn Sommersten, Adrian McCann, Robert Clay Glastad, Iain George Johnston, Matthias Kern, Matthias Blueher, Gunnar Mellgren, Simon N. Dankel
Summary: The hepatic valine/3-HIB pathway plays an important role in the mechanism of fatty liver and may be a potential target for therapeutic intervention.