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

Leiluo Geng, Boya Liao, Leigang Jin, Jiasui Yu, Xiaoyu Zhao, Yuntao Zhao, Ling Zhong, Baile Wang, Jiufeng Li, Jie Liu, Jin Kui Yang, Wei Jia, Qizhou Lian*, Aimin Xu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Impaired 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.

Original languageEnglish
Pages (from-to)608–626
Number of pages19
JournalNature Metabolism
Volume4
Issue number5
DOIs
Publication statusPublished - May 2022

Scopus Subject Areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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