Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/102820
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Type: Journal article
Title: Ywhaz/14-3-3ζ deletion improves glucose tolerance through a GLP-1-dependent mechanism
Other Titles: Ywhaz/14-3-3zeta deletion improves glucose tolerance through a GLP-1-dependent mechanism
Author: Lim, G.E.
Piske, M.
Lulo, J.E.
Ramshaw, H.S.
Lopez, A.F.
Johnson, J.D.
Citation: Endocrinology, 2016; 157(7):2649-2659
Publisher: Endocrine Society
Issue Date: 2016
ISSN: 0013-7227
1945-7170
Statement of
Responsibility: 
Gareth E. Lim, Micah Piske, James E. Lulo, Hayley S. Ramshaw, Angel F. Lopez, and James D. Johnson
Abstract: Multiple signaling pathways mediate the actions of metabolic hormones to control glucose homeostasis, but the proteins that coordinate such networks are poorly understood. We previously identified the molecular scaffold protein, 14-3-3ζ, as a critical regulator of in vitro β-cell survival and adipogenesis, but its metabolic roles in glucose homeostasis have not been studied in depth. Herein, we report that Ywhaz gene knockout mice (14-3-3ζKO) exhibited elevated fasting insulin levels while maintaining normal β-cell responsiveness to glucose when compared with wild-type littermate controls. In contrast with our observations after an ip glucose bolus, glucose tolerance was significantly improved in 14-3-3ζKO mice after an oral glucose gavage. This improvement in glucose tolerance was associated with significantly elevated fasting glucagon-like peptide-1 (GLP-1) levels. 14-3-3ζ knockdown in GLUTag L cells elevated GLP-1 synthesis and increased GLP-1 release. Systemic inhibition of the GLP-1 receptor attenuated the improvement in oral glucose tolerance that was seen in 14-3-3ζKO mice. When taken together these findings demonstrate novel roles of 14-3-3ζ in the regulation of glucose homeostasis and suggest that modulating 14-3-3ζ levels in intestinal L cells may have beneficial metabolic effects through GLP-1-dependent mechanisms. Multiple cell types secrete hormones that act in concert to ensure the rapid clearance of circulating glucose following the ingestion of nutrients. For example, insulin is released from pancreatic β-cells to promote glucose uptake in skeletal muscle and adipose tissue, and to reduce hepatic gluconeogenesis. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are secreted from intestinal endocrine L-cells and K-cells, respectively, whereby they potentiate glucose-induced insulin secretion from β-cells and delay gastric emptying (1). Within cell types relevant for glucose homeostasis, it is unclear how complex signaling networks are accurately coordinated. Molecular scaffold proteins coordinate signaling events by regulating protein subcellular localization, promoting protein stability, and nucleating macromolecular complexes (2, 3). Their interactions with target proteins are dependent on their recognition of specific motifs that are unique to each scaffold (3, 4). Despite their essential functions in coordinating signaling networks, only a few scaffold proteins have been investigated for their roles in glucose homeostasis. For example, β-arrestins, Akap150, and NLRP3 have been shown to be important in pancreatic β-cell function, glucose homeostasis, and adipogenesis (5–10). However, these examples represent a small fraction of identified scaffold proteins, and the role of other proteins families in glucose homeostasis remain understudied. The seven-member family of molecular scaffolds called 14-3-3 proteins is highly conserved and broadly expressed in metabolically relevant tissues. 14-3-3 proteins are known to bind to several insulin signaling proteins that are required for glucose metabolism and β-cell function, including Irs1, Irs2, Raf1, Foxo1, and As160/TBD1C4 (11–19). Members of the 14-3-3 family have also been shown to participate in the regulation of hormone and neurotransmitter exocytosis (20–22), which is particularly relevant to glucose homeostasis control (23, 24). We have demonstrated that the 14-3-3ζ isoform (encoded by the Ywhaz gene) has unique and critical roles in the regulation of β-cell survival and adipocyte differentiation (25, 26). Together with other studies, our recent findings prompted us to test the hypothesis that modulating 14-3-3ζ levels affects whole-body glucose homeostasis and metabolism. In the present study, we report that 14-3-3ζ deletion improves oral glucose tolerance in association with increased basal GLP-1 secretion from intestinal L cells. Modulating 14-3-3ζ expression in the intestine could potentially serve as a therapeutic approach to increase circulating GLP-1 levels and to improve glucose homeostasis. - See more at: http://press.endocrine.org/doi/10.1210/en.2016-1016#sthash.Lck6f8YR.dpuf
Keywords: Animals
Mice, Knockout
Mice
Glucose Intolerance
Insulin
Blood Glucose
14-3-3 Proteins
Glucose Tolerance Test
Phosphorylation
Homeostasis
Enteroendocrine Cells
Insulin-Secreting Cells
Proto-Oncogene Proteins c-akt
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
Rights: Copyright © 2016 by the Endocrine Society
DOI: 10.1210/en.2016-1016
Grant ID: NHMRC
Published version: http://dx.doi.org/10.1210/en.2016-1016
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