Of mice and men: incretin actions in the central nervous system

Incretins have risen to the forefront of therapies for obesity and related metabolic complications, primarily because of their efficacy and relatively few side effects. Importantly, their efficacy in altering energy balance and decreasing body weight is apparently through actions in the central nervous system (CNS); the latter may have implications beyond obesity per se, i.e. in other disease states associated with obesity including CNS-related disorders. Here, we first describe the role of the CNS in energy homeostasis and then the current state of knowledge in terms of incretin physiology, pathophysiology and efficacy in preclinical and clinical studies. In the future, more clinical studies are needed to fully map mechanistic pathways underlying incretin actions and outcomes in the human CNS. Additionally, future research will likely lead to the discovery of additional novel incretins and/or more efficacious medications with less side effects through the improvement of current compounds with properties that would allow them to have more favorable pharmacokinetic and pharmacodynamic profiles and/or by combining known and novel incretins into safe and more efficacious combination therapies leading ultimately to more tangible benefits for our patients.