Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss
Open accessAbstract
New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. 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 behavioral 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 relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies.
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- Authors
- Buller, S., & Blouet, C.
- Affiliations
- University of Cambridge (GB)
- Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2024-04-01
- Volume
- 326
- Issue
- 4
- Pages
- E472-E480
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC11193531
- OpenAlex
- W4392004912
- Cited by
- 40
- References
- 13
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 11
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Medical Research Council (MT/S011552/1)
- Diabetes UK (22/0006401)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- incretins, incretin receptor agonists, glucagon-like peptide-1, GLP-1 receptor agonists, blood-brain barrier, appetite suppression, weight loss, obesity, energy homeostasis, neural circuits
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Appetite, Brain, Diabetes Mellitus, Type 2, Humans, Weight Loss, Glucagon-Like Peptide 1, Incretins
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