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Ywhaz/14-3-3ζ Deletion Improves Glucose Tolerance Through a GLP-1-Dependent Mechanism.
- Source :
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Endocrinology [Endocrinology] 2016 Jul; Vol. 157 (7), pp. 2649-59. Date of Electronic Publication: 2016 May 11. - Publication Year :
- 2016
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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.
- Subjects :
- 14-3-3 Proteins metabolism
Animals
Blood Glucose metabolism
Glucagon-Like Peptide-1 Receptor metabolism
Glucose Intolerance metabolism
Glucose Tolerance Test
Homeostasis physiology
Insulin blood
Mice
Mice, Knockout
Phosphorylation
Proto-Oncogene Proteins c-akt metabolism
14-3-3 Proteins genetics
Enteroendocrine Cells metabolism
Glucagon-Like Peptide 1 metabolism
Glucagon-Like Peptide-1 Receptor genetics
Glucose Intolerance genetics
Insulin-Secreting Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 157
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 27167773
- Full Text :
- https://doi.org/10.1210/en.2016-1016