Regulation of glucose and energy homeostasis by distinct G protein-signaling pathways in pancreatic alpha-cells and AGRP neurons

• Applicant: Dr. Doreen Thor
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225871110

Obesity and obesity-related diseases such as type 2 diabetes have reached epidemic proportions in the Western world. Two key goals in the treatment of type 2 diabetes are to reduce body weight and to regulate blood glucose. G protein-coupled receptors (GPCRs) form the largest family of cell surface receptors and regulate the activity of virtually every cell type by activating four major classes of heterotrimeric G proteins. Most heterotrimeric G proteins are expressed ubiquitously and nearly all GPCRs are found in many different tissues. As a result, it remains very challenging to assess the in vivo effects of stimulating a distinct G protein-signaling cascade in a specific cell type. Here, I will take advantage of new designer GPCRs (RASSLs) which are only activated by a pharmacologically inert drug (CNO). Specifically, I am planning to generate transgenic mice which express RASSLs in specific cell types (pancreatic α-cells and AGRP neurons). Treatment of the mutant mice with the RASSL ligand CNO should reveal the in vivo effects of activating distinct G-protein pathways in these metabolically very important cell types. The primary focus of the phenotyping studies will be on potential changes in glucose and energy homeostasis (including food intake). I anticipate that the outcome of these studies will lead to the identification of new targets for the treatment of type 2 diabetes and related metabolic disorders.

• DFG Programme: Research Grants