| Summary: | 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 14-3-3z in b-cell
function, but these studies were performed in tumor-derived MIN6 cells and systemic knockout mice. To
further characterize the regulatory roles of 14-3-3-z in b-cell function, we generated b-cell-specific 14-3-3z
knockout mice. Although no effects on b-cell mass were detected, potentiated glucose-stimulated insulin
secretion (GSIS), mitochondrial function, and ATP synthesis were observed. 14-3-3z deletion also altered
the b-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 14-3-3z is the critical isoform in bcells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of
Ywhaz/YWHAZ, the gene encoding 14-3-3z, 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 14-3-3z in the regulation of b-cell function and provides a
deeper understanding of how insulin secretion is controlled in b-cells.
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