title: Ywhaz/14-3-3ζ Deletion Improves Glucose Tolerance Through a GLP-1-Dependent Mechanism.
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.
authors.affiliation: Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Lim
authors.affiliation: Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.
authors.forename: Micah
authors.initials: M
authors.lastname: Piske
authors.affiliation: Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Lulo
authors.affiliation: Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics* / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; C000590975:Ywhaz protein, mouse