The role of the proprotein convertase Furin in diabetes and obesity.

Endoplasmic reticulum (ER) stress in the pancreatic ß-cells, the hypothalamus, or the liver is emerging as one of the main causative factors for diabetes and obesity. This is supported by the fact that treatment of obese/diabetic mice with chemical compounds that decrease ER stress reverses the phenotypes. Unfortunately, the molecular mechanisms underlying ER stress are not fully understood. Genome-wide screens have identified Furin, encoding an enzyme involved in the activation of many proproteins, as a susceptibility gene for diabetes. We have demonstrated that mice in which Furin is inactivated in ß-cells develop diabetes and have marked ER stress. Preliminary data suggest that this phenotype can be reversed by treatment with chemical chaperones. A pilot study also showed that mice lacking Furin in the liver became glucose intolerant. Furin is known to affect hepatic lipid metabolism which is a potential causal mechanism for ER stress. ER stress in ß-cells often coincides with ER stress in the hypothalamus. Therefore, we will also generate a mouse model lacking Furin in the hypothalamus. In this project we will first determine if ER stress is also present in mice lacking Furin in liver and hypothalamus and examine the molecular mechanism(s) leading to ER stress. Subsequently we will identify and validate Furin substrates that contribute to this phenotype. Finally, we will examine if chemical chaperones can rescue the obesity/diabetes phenotype in these mouse model.