Glucagon-like peptide-1 (GLP-1), a product of the preproglucagon (PPG) gene, is synthesized in the intestine and the nucleus of the solitary tract (NTS) and regulates numerous physiological processes, including glucose homeostasis and food intake. Exendin-4 (Ex4), a highly potent, long-acting GLP-1 receptor (GLP-1r) agonist, is used clinically for the treatment of type 2 diabetes mellitus (T2DM). Interestingly, in patients Ex4 not only improves glycemic control, but it also produces weight loss. This finding raises the possibility that the GLP-1 system may be a viable therapeutic target for obesity. To this end, the purpose of this dissertation was to further characterize the role of the central nervous system (CNS) GLP-1 system in the regulation of energy balance.
Central administration of Ex4, like GLP-1, robustly reduces food intake. However, several lines of evidence suggest that Ex4 acts via distinct mechanisms. Therefore, we tested the hypothesis that the central anorectic effects of GLP-1 and Ex4 are different. Specifically, these effects, and their sensitivity to GLP-1r antagonists, were compared. In addition, the GLP-1r-dependence of central Ex4 was assessed in GLP-1r knockout (GLP-1r-/-) mice. Consistent with our hypothesis, central Ex4 reduced food intake at doses significantly lower than those required by GLP-1, and this effect was not blocked by GLP-1r antagonists. In contrast, GLP-1r antagonists completely blocked the anorectic effect of peripheral Ex4. Finally, central Ex4 failed to reduce food intake in GLP-1r-/- mice, indicating that this effect is in fact GLP-1r-dependent.
Although these data underscore the fact that central GLP-1r agonism is sufficient to reduce food intake, the role of the endogenous CNS GLP-1 system in the regulation of energy balance remains unclear. Therefore, we tested the hypothesis that endogenous CNS GLP-1 system activity is required for normal energy balance. Specifically, RNA interference was used to knock down NTS PPG, and chronic intracerebroventricular (ICV) infusion of the GLP-1r antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. Consistent with our hypothesis, both NTS PPG knockdown and chronic ICV Ex9 resulted in hyperphagia. However, whereas NTS PPG knockdown exacerbated high-fat diet-induced fat accumulation, chronic ICV Ex9 increased fat accumulation irrespective of diet. Finally, NTS PPG expression was found to correlate positively with fat mass, suggesting that CNS GLP-1 system activity may be altered in obesity.
Taken together, the data presented in this dissertation reveal a novel role for the CNS GLP-1 system in the long-term regulation of energy balance. Moreover, they indicate that the GLP-1r agonist Ex4 interacts uniquely with this system to produce a powerful anorectic signal. As such, future studies are warranted to determine optimal strategies to target the CNS GLP-1 system for the treatment of obesity.