Leucine-rich repeat kinase 2 negatively regulates glucose tolerance via regulation of membrane translocation of Glucose transporter type 4 in adipocytes

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 the LRRK2 on high-fat diet induced glucose intolerance using Lrrk2-knock-out (Lrrk2-KO) mice. We found for the first time that high-fat (HFD) fed Lrrk2-KO mice display improved glucose tolerance and homeostatic model assessment of insulin resistance compared to their wild type (WT) counterparts. We found that Lrrk2 is highly expressed in adipose tissues compared with to other 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. Conversely, treatment with a LRRK2 kinase inhibitor stimulated insulin-dependent membrane translocation of insulin-dependent glucose transporter (GLUT4) in 3T3-L1 adipocytes. We conclude that increased LRRK2 kinase activity in adipose tissue exacerbates glucose intolerance by suppressing Rab8- and Rab10-mediated GLUT4 membrane translocation.