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

Abstract

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.

• Authors: Xin Zhang, Xiaowen Wang, Ziqiang Yuan, Sarah J Radford, Chen Liu, Steven K Libutti, X F Steven Zheng
• Journal: Cell reports (Cell Rep) Vol. 34 Issue 11 Pg. 108830 (03 16 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 33730578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids
• Homeodomain Proteins
• Insulin
• Trans-Activators
• pancreatic and duodenal homeobox 1 protein
• Mechanistic Target of Rapamycin Complex 1
• rab1 GTP-Binding Proteins
• Glucose

Topics

• Amino Acids (metabolism)
• Animals
• Cell Nucleus (metabolism)
• Diabetes Mellitus, Type 2 (metabolism)
• Down-Regulation
• Glucose (metabolism)
• Glucose Intolerance (complications, metabolism)
• Homeodomain Proteins (metabolism)
• Homeostasis
• Hyperglycemia (metabolism)
• Insulin (genetics, metabolism)
• Insulin Secretion
• Islets of Langerhans (metabolism)
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice, Inbred C57BL
• Models, Biological
• Organ Specificity
• Protein Stability
• Protein Transport
• Signal Transduction
• Trans-Activators (metabolism)
• Transcription, Genetic
• rab1 GTP-Binding Proteins (metabolism)
• Mice