LRRK2 inhibition ameliorates dexamethasone-induced glucose intolerance via prevents impairment in GLUT4 membrane translocation in adipocytes

Motoki Imai, Fumitaka Kawakami, Makoto Kubo, Makoto Kanzaki, Hiroko Maruyama, Rei Kawashima, Tatsunori Maekawa, Yoshifumi Kurosaki, Fumiaki Kojima, Takafumi Ichikawa

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with Parkinson's disease. LRRK2 is a large protein with multiple functional domains, including a guanosine 5′-triphosphate (GTP)binding domain and a protein kinase domain. Recent studies indicated that the members of the Rab GTPase family, Rab8a and Rab10, which are involved in the membrane transport of the glucose transporter type 4 (GLUT4) during insulin-dependent glucose uptake, are phosphorylated by LRRK2. However, the physiological role of LRRK2 in the regulation of glucose metabolism is largely unknown. In the present study, we investigated the role of LRRK2 using dexamethasone (DEX)-induced glucose intolerance in mice. LRRK2 knockout (KO) mice exhibited suppressed glucose intolerance, even after treatment with DEX. The phosphorylation of LRRK2, Rab8a and Rab10 was increased in the adipose tissues of DEX-treated wild-type mice. In addition, inhibition of the LRRK2 kinase activity prevented the DEX-induced inhibition of GLUT4 membrane translocation and glucose uptake in cultured 3T3-L1 adipocytes. These results suggest that LRRK2 plays an important role in glucose metabolism in adipose tissues.

Original languageEnglish
Pages (from-to)1660-1668
Number of pages9
JournalBiological and Pharmaceutical Bulletin
Volume43
Issue number11
DOIs
Publication statusPublished - 2020 Nov 1

Keywords

  • Adipocyte
  • Dexamethasone
  • Glucose intolerance
  • Glucose transporter 4 (GLUT4)
  • Leucine-rich repeat kinase 2 (LRRK2)

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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