The proposed research focuses on the role of astrocytes in the Nucleus Tractus Solitarius (NTS) of the caudal brainstem in mediating the food intake and body weight suppressive effects of glucagon-like peptide-1 (GLP-1). Accumulating evidence indicates that the food intake suppressive effects of GLP-1 receptor (GLP-1R) agonists (exendin-4 and liraglutide, FDA-approved for the treatment of diabetes and obesity) are mediated, in part, through direct GLP-1R signaling in the CNS. However, the specific GLP-1R-expressing nuclei and cellular mechanisms within the CNS that mediate the metabolic effects of GLP-1R ligands remain largely unknown. While the collective literature clearly supports a role for neuronal processing in mediating GLP-1's effects on food intake, the contribution of GLP-1R signaling on astrocytes to energy balance control has not been examined. Given that astrocytes are critical for the modulation of glutamate in the extracellular space via the GLAST and GLT-1 transporters, it is intriguing to consider the idea that GLP-1R ligands act directly on astrocytes in energy balance relevant nuclei that receive glutamatergic inputs. The NTS is the first central nucleus to receive and process within-meal vagally-mediated glutamatergic satiation signals arising from the gastrointestinal tract. Therefore, building on our exciting preliminary studies, research proposed in this application will directly test the hypothesis that GLP-1R signaling in astrocytes within the NTS is physiologically and pharmacologically relevant for the regulation of food intake. Using state-of-the-art, cutting-edge technology and methodological approaches we will examine the following Specific Aims: [1] Determine in vivo the physiological relevance of GLP-1R signaling on NTS astrocytes in energy balance control. [2] Examine GLP-1R signaling on NTS astrocytes as a modulator of vagal-to-NTS glutamatergic neurotransmission using live cell Ca++ imaging and in vivo electrophysiology. [3] Examine the intracellular signaling and cytokine responses following GLP-1R activation of NTS astrocytes. The research proposed will provide a novel framework for a new wave of research aimed at elucidating the role that GLP-1-astrocyte signaling plays in regulating energy balance.
Project summary: Relevance to public health. New basic science discoveries show that pharmaceutical manipulation of the hormone glucagon-like peptide-1 (GLP-1) are viable treatment options for obesity, as food intake is suppressed by GLP-1 in obese humans and animal models. Surprisingly, the cellular mechanisms within the brain mediating these GLP-1 effects on body weight regulation remain largely unknown. This proposal will advance knowledge on the contribution that astrocytes within the brainstem have in mediating the energy balance effects of GLP-1-based pharmaceuticals as a means to improve therapeutic treatments for obesity and other associated diseases.
