Genetic Dissection ot the Central GLP-1 System

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DESCRIPTION (provided by applicant): There remains intense interest in new therapies that safely and effectively lower blood glucose in diabetic subjects. The naturally occurring regulatory peptide glucagon-like peptide 1 (GLP-1) exhibits multiple desirable actions for a potential anti-diabetic agent, and protease-resistant long-acting GLP-1 analogs are currently available for the treatment of Type 2 diabetes. GLP-1 is also an endogenous neuropeptide that exerts actions in the central nervous system (CNS) that are less well understood. Given the increasing likelihood that one or more GLP-1 analogues will be used to treat diabetic patients, understanding the central role of GLP-1 is increasingly relevant for predicting the biological consequences of sustained GLP-1 administration. The CNS expression of GLP-1 is primarily in a subpopulation of cells within the caudal nucleus tractus solitaries (NTS). Caudal NTS subnuclei receive and process viscerosensory information from thoracic and abdominal viscera and the NTS is reciprocally connected with various brain areas, including hypothalamic areas such as the arcuate that regulate appetitive functions. Additionally, the NTS is located adjacent to a circumventricular organ, the area postrema (AP), and contains fenestrated capillaries, potentially allowing circulating peptides access to the nucleus. The NTS (including GLP-1 cells) is therefore in a prime position to process information arising from a variety of neural and humoral sources. Understanding which peptides, involved in energy balance, modulate neuronal activity of brainstem GLP-1 neurons will aid in the understanding of central GLP-1 regulation. We propose a model that predicts: 1) GLP-1 neurons in the NTS co-express the leptin receptor (Ob-R), and that leptin administration induces the activation of SOCS-3 and STAT-3 in these neurons, 2) leptin induces a membrane depolarization and/or increases excitatory synaptic activity within GLP-1 NTS neurons, and 3) deletion of leptin receptors specifically in GLP-1 neurons will result in hyperphagia and obesity. The studies offered in this application are designed to directly test the different components of this model.