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Article: β-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130

Titleβ-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130
Authors
Issue Date2022
Citation
Nature Metabolism, 2022, v. 4, n. 5, p. 608-626 How to Cite?
AbstractImpaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that β-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic β-cells independent of the actions of FGF21. β-cell-specific deletion of Klb but not Fgf21 deletion causes defective GSIS and glucose intolerance in mice and defective GSIS in islets of type-2 diabetic mice is mitigated by adenovirus-mediated restoration of KLB. Mechanistically, KLB interacts with and stabilizes the cytokine receptor subunit GP130 by blockage of ubiquitin-dependent lysosomal degradation, thereby facilitating interleukin-6-evoked STAT3–HIF1α signaling, which in turn transactivates a cluster of glycolytic genes for adenosine triphosphate production and GSIS. The defective glycolysis and GSIS in Klb-deficient islets are rescued by adenovirus-mediated replenishment of STAT3 or HIF1α. Thus, KLB functions as a key cell-surface regulator of GSIS by coupling the GP130 receptor signaling to glucose catabolism in β-cells and represents a promising therapeutic target for diabetes.
Persistent Identifierhttp://hdl.handle.net/10722/342652
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGeng, Leiluo-
dc.contributor.authorLiao, Boya-
dc.contributor.authorJin, Leigang-
dc.contributor.authorYu, Jiasui-
dc.contributor.authorZhao, Xiaoyu-
dc.contributor.authorZhao, Yuntao-
dc.contributor.authorZhong, Ling-
dc.contributor.authorWang, Baile-
dc.contributor.authorLi, Jiufeng-
dc.contributor.authorLiu, Jie-
dc.contributor.authorYang, Jin Kui-
dc.contributor.authorJia, Wei-
dc.contributor.authorLian, Qizhou-
dc.contributor.authorXu, Aimin-
dc.date.accessioned2024-04-17T07:05:18Z-
dc.date.available2024-04-17T07:05:18Z-
dc.date.issued2022-
dc.identifier.citationNature Metabolism, 2022, v. 4, n. 5, p. 608-626-
dc.identifier.urihttp://hdl.handle.net/10722/342652-
dc.description.abstractImpaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that β-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic β-cells independent of the actions of FGF21. β-cell-specific deletion of Klb but not Fgf21 deletion causes defective GSIS and glucose intolerance in mice and defective GSIS in islets of type-2 diabetic mice is mitigated by adenovirus-mediated restoration of KLB. Mechanistically, KLB interacts with and stabilizes the cytokine receptor subunit GP130 by blockage of ubiquitin-dependent lysosomal degradation, thereby facilitating interleukin-6-evoked STAT3–HIF1α signaling, which in turn transactivates a cluster of glycolytic genes for adenosine triphosphate production and GSIS. The defective glycolysis and GSIS in Klb-deficient islets are rescued by adenovirus-mediated replenishment of STAT3 or HIF1α. Thus, KLB functions as a key cell-surface regulator of GSIS by coupling the GP130 receptor signaling to glucose catabolism in β-cells and represents a promising therapeutic target for diabetes.-
dc.languageeng-
dc.relation.ispartofNature Metabolism-
dc.titleβ-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s42255-022-00572-2-
dc.identifier.pmid35551509-
dc.identifier.scopuseid_2-s2.0-85129883299-
dc.identifier.volume4-
dc.identifier.issue5-
dc.identifier.spage608-
dc.identifier.epage626-
dc.identifier.eissn2522-5812-
dc.identifier.isiWOS:000794104800001-

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