The role of the proprotein convertases in diabetes and obesity

Obesity is a metabolic disorder which represents a major risk factor for type 2 diabetes (T2D). In recent years, genome-wide screens have identified a number of susceptibility genes for these metabolic disorders, although only few have been functionally validated. One of those susceptibility genes is Furin, coding for a proteolytic enzyme involved in the cleavage (and hence activation) of many precursor proteins such as hormones, neuropeptides, enzymes, receptors, and extracellular proteins. The aim of this study is to define the role of furin in obesity and T2D using conditional knockout mouse models. Our hypothesis is that impaired furin activity is an important contributor to endoplasmic reticulum stress and therefore may be rescued by chemical chaperones. This hypothesis is supported by our recent studies in insulin producing ß cells and preliminary data in hypothalamus, a brain region important for feeding regulation. The first objective is to define the impact of genetic ablation of Furin in the hypothalamus on glucose homeostasis and energy balance, and characterization of molecular pathways related to ER stress. The second objective is to determine if furin deficiency in hypothalamus is sufficient to cause ER stress-dependent leptin resistance and if ER homeostasis can be restored by chemical chaperones. The third objective is to investigate the role of furin in adipose tissue, an important endocrine tissue which is deregulated in obesity conditions.