Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss

Am J Physiol Endocrinol Metab. 2024 Feb 21. doi: 10.1152/ajpendo.00250.2023. Online ahead of print.ABSTRACTIncretin-based pharmacotherapies provide novel efficient and safe therapeutic options to curb appetite and produce weight loss in obese patients. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioural mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood-brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood-brain-barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets ...
Source: American Journal of Physiology. Endocrinology and Metabolism - Category: Physiology Authors: Source Type: research