| First Author | Mugabo Y | Year | 2022 |
| Journal | JCI Insight | Volume | 7 |
| Issue | 8 | PubMed ID | 35298439 |
| Mgi Jnum | J:324469 | Mgi Id | MGI:7278134 |
| Doi | 10.1172/jci.insight.156378 | Citation | Mugabo Y, et al. (2022) 14-3-3zeta Constrains insulin secretion by regulating mitochondrial function in pancreatic beta cells. JCI Insight 7(8):e156378 |
| abstractText | While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3zeta in beta cell function, but these studies were performed in tumor-derived MIN6 cells and systemic KO mice. To further characterize the regulatory roles of 14-3-3zeta in beta cell function, we generated beta cell-specific 14-3-3zeta-KO mice. Although no effects on beta cell mass were detected, potentiated glucose-stimulated insulin secretion (GSIS), mitochondrial function, and ATP synthesis were observed. Deletion of 14-3-3zeta also altered the beta cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the enhancements in GSIS and mitochondrial function, suggesting that 14-3-3zeta is the critical isoform in beta cells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3zeta, was inversely associated with insulin secretion, and pan-14-3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3zeta in the regulation of beta cell function and provides a deeper understanding of how insulin secretion is controlled in beta cells. |
