| First Author | Yang Y | Year | 2024 |
| Journal | Mol Cell Endocrinol | Volume | 582 |
| Pages | 112143 | PubMed ID | 38158148 |
| Mgi Jnum | J:352223 | Mgi Id | MGI:7575604 |
| Doi | 10.1016/j.mce.2023.112143 | Citation | Yang Y, et al. (2023) Branched-chain amino acid catabolic defect promotes alpha-cell proliferation via activating mTOR signaling. Mol Cell Endocrinol :112143 |
| abstractText | Elevated circulating level of branched-chain amino acids (BCAAs) is closely related to the development of type 2 diabetes. However, the role of BCAA catabolism in various tissues in maintaining glucose homeostasis remains largely unknown. Pancreatic alpha-cells have been regarded as amino acid sensors in recent years. Therefore, we generated alpha-cell specific branched-chain alpha-ketoacid dehydrogenase E1alpha subunit (BCKDHA) knockout (BCKDHA-alphaKO) mice to decipher the effects of BCAA catabolism in alpha-cells on whole-body energy metabolism. BCKDHA-alphaKO mice showed normal body weight, body fat, and energy expenditure. Plasma glucagon level and glucose metabolism also remained unchanged in BCKDHA-alphaKO mice. Whereas, the deletion of BCKDHA led to increased alpha-cell number due to elevated cell proliferation in neonatal mice. In vitro, only leucine among BCAAs promoted aTC1-6cell proliferation, which was blocked by the agonist of BCAA catabolism BT2 and the inhibitor of mTOR Rapamycin. Like Rapamycin, BT2 attenuated leucine-stimulated phosphorylation of S6 in alphaTC1-6cells. Elevated phosphorylation level of S6 protein in pancreatic alpha-cells was also observed in BCKDHA-alphaKO mice. These results suggest that local accumulated leucine due to defective BCAA catabolism promotes alpha-cell proliferation through mTOR signaling, which is insufficient to affect glucagon secretion and whole-body glucose homeostasis. |
