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.
