The obesity epidemic is directly related to excessive intake of calorie dense, palatable foods and fluids. Food intake is influenced by a variety of signals, including homeostatic signals linked to metabolic status and fuel storage, short-term signals from a singular meal based on nutrient content, as well as signals related to the rewarding value of food. Yet the neural circuitry that integrates these signals is still not well understood. Central glucagon-like peptide 1 (GLP-1) has recently emerged as a critical contributor to the control of energy balance. GLP-1 neurons in the hindbrain receive information from the gastrointestinal (GI) tract through the vagus nerve, and project widely throughout the brain. Evidence supports a role for GLP-1 cells in mediating effects of GI satiety signals, and central GLP-1 receptor (GLP-1R) activation strongly suppresses food intake. My preliminary data suggest that the GLP-1 neuronal projection to the lateral septum (LS) influences food intake in rats and mice. Although the presence of GLP-1 fibers and receptors in the LS was previously documented, this is the first demonstration of a role for this pathway in feeding behavior. Central GLP-1 is also involved in the regulation of behavioral and endocrine stress responses, and GLP-1 neurons contribute to stress-induced hypophagia. Most recently, I have demonstrated that endogenous GLP-1R stimulation in the LS plays a role in stress-induced anorexia. This proposal seeks to expand on my preliminary findings.
Specific Aim 1 tests the hypothesis that LS- projecting GLP-1 neurons are activated by acute stress in rats and mice.
Specific Aim 2 investigates the targets of GLP-1R-expressing neurons. This analysis will help to begin to unravel candidate neural pathways through which LS GLP-1 signaling affects feeding as well as stress-induced suppression of feeding. The proposed experiments will enhance my training by allowing me to learn a number of new techniques including the restraint stress manipulation, use of viral vectors to induce gene expression, iontophoretic neural tracer injection, retrograde and anterograde neuronal tracing, advanced immunocytochemistry, and quantification and analysis of neuroanatomical data. Findings from the proposed studies will direct future work on both the role of septal GLP-1 signaling in food intake and stress-related behaviors as well as the function of LS GLP-1R bearing neurons that project to other feeding relevant brain areas, with the ultimate goal of identifying and better understanding the diverse neural circuitry that controls satiation and satiety as well as neuroendocrine effects of stress.
Obesity and its numerous comorbidities, including insulin resistance, glucose intolerance, diabetes mellitus, and hypertension, are now among the leading causes of preventable death in the United States; therefore, understanding the underlying neural circuitry that mediates the overconsumption of palatable foods and coordinates feeding behavior is critical to the development of potential treatments obesity and overeating. The research proposed here seeks to identify neural pathways involved in the control of food intake under both baseline and stressed conditions. The results of this research have the potential to move the field forward and to make advancements toward the long-term goal of understanding the neural circuitry that integrates the diverse signals that influence feeding.
| Terrill, Sarah J; Wall, Kaylee D; Medina, Nelson D et al. (2018) Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement. Am J Physiol Regul Integr Comp Physiol 315:R76-R83 |
| Terrill, Sarah J; Maske, Calyn B; Williams, Diana L (2018) Endogenous GLP-1 in lateral septum contributes to stress-induced hypophagia. Physiol Behav 192:17-22 |
| Maske, Calyn B; Loney, Gregory C; Lilly, Nicole et al. (2018) Intragastric nutrient infusion reduces motivation for food in male and female rats. Am J Physiol Endocrinol Metab 315:E81-E90 |
