Amino acids-Rab1A-mTORC1 signaling controls whole-body glucose homeostasis

• DOI: 10.1016/j.celrep.2021.108830
• Publication Date: 2021-03-18T21:14:55Z
• Authors: Xin Zhang; Xiaowen Wang; Ziqiang Yuan; Sarah J. Radford; Chen Liu; Steven K. Libutti; X.F. Steven Zheng
• Keywords: Cell Nucleus; Homeodomain Proteins; 0301 basic medicine; Protein Stability; Down-Regulation; Mechanistic Target of Rapamycin Complex 1; Models, Biological; Article; 3. Good health; Mice, Inbred C57BL; Islets of Langerhans; Protein Transport; 03 medical and health sciences; Glucose; Diabetes Mellitus, Type 2; Organ Specificity; Hyperglycemia; Glucose Intolerance; Insulin Secretion; Animals; Homeostasis; Insulin; Amino Acids; Signal Transduction

Rab1A is a small GTPase known for its role in vesicular trafficking. Recent evidence indicates that Rab1A is essential for amino acids (aas) sensing and signaling to regulate mTORC1 in normal and cancer cells. However, Rab1A's in vivo function in mammals is not known. Here, we report the generation of tamoxifen (TAM)-induced whole body Rab1A knockout (Rab1A-/-) in adult mice. Rab1A-/- mice are viable but become hyperglycemic and glucose intolerant due to impaired insulin transcription and β-cell proliferation and maintenance. Mechanistically, Rab1A mediates AA-mTORC1 signaling, particularly branched chain amino acids (BCAA), to regulate the stability and localization of the insulin transcription factor Pdx1. Collectively, these results reveal a physiological role of aa-Rab1A-mTORC1 signaling in the control of whole-body glucose homeostasis in mammals. Intriguingly, Rab1A expression is reduced in β-cells of type 2 diabetes (T2D) patients, which is correlated with loss of insulin expression, suggesting that Rab1A downregulation contributes to T2D progression.