LRRK2 negatively regulates glucose tolerance via regulation of membrane translocation of GLUT4 in adipocytes.
Fumitaka Kawakami, Motoki Imai, Yuki Isaka, Mark R Cookson, Hiroko Maruyama, Makoto Kubo, Matthew J Farrer, Makoto Kanzaki, Rei Kawashima, Tatsunori Maekawa, Shun Tamaki, Yoshifumi Kurosaki, Fumiaki Kojima, Kenichi Ohba, Takafumi Ichikawa
Author Information
Fumitaka Kawakami: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan. ORCID
Motoki Imai: Regenerative Medicine and Cell Design Research Facility, School of Allied Health Science, Kitasato University, Sagamihara, Japan.
Yuki Isaka: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Mark R Cookson: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. ORCID
Hiroko Maruyama: Department of Cytopathology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Makoto Kubo: Regenerative Medicine and Cell Design Research Facility, School of Allied Health Science, Kitasato University, Sagamihara, Japan.
Matthew J Farrer: Department of Neurology and Fixel Institute, University of Florida, Gainesville, FL, USA.
Makoto Kanzaki: Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
Rei Kawashima: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Tatsunori Maekawa: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Shun Tamaki: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Yoshifumi Kurosaki: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Fumiaki Kojima: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Kenichi Ohba: Department of Health Administration, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan.
Takafumi Ichikawa: Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Epidemiological studies have shown that abnormalities of glucose metabolism are involved in leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). However, the physiological significance of this association is unclear. In the present study, we investigated the effect of LRRK2 on high-fat diet (HFD)-induced glucose intolerance using Lrrk2-knockout (KO) mice. We found for the first time that HFD-fed KO mice display improved glucose tolerance compared with their wild-type (WT) counterparts. In addition, high serum insulin and leptin, as well as low serum adiponectin resulting from HFD in WT mice were improved in KO mice. Using western blotting, we found that Lrrk2 is highly expressed in adipose tissues compared with other insulin-related tissues that are thought to be important in glucose tolerance, including skeletal muscle, liver, and pancreas. Lrrk2 expression and phosphorylation of its kinase substrates Rab8a and Rab10 were significantly elevated after HFD treatment in WT mice. In cell culture experiments, treatment with a LRRK2 kinase inhibitor stimulated insulin-dependent membrane translocation of glucose transporter 4 (Glut4) and glucose uptake in mouse 3T3-L1 adipocytes. We conclude that increased LRRK2 kinase activity in adipose tissue exacerbates glucose tolerance by suppressing Rab8- and Rab10-mediated GLUT4 membrane translocation.
