Targeting the GLP-2 receptor in the management of obesity

• Published in: Peptides (New York, N.Y. : 1980) Vol. 177; p. 171210
• Main Authors: Pálsson, Thorir G., Gilliam-Vigh, Hannah, Jensen, Benjamin A.H., Jeppesen, Palle B., Lund, Asger B., Knop, Filip K., Nielsen, Casper K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2024
• Subjects: Animals; GLP-2; Glucagon-Like Peptide 2 - metabolism; Glucagon-Like Peptide-2 Receptor - agonists; Glucagon-Like Peptide-2 Receptor - metabolism; Humans; Low-grade inflammation; Obesity; Obesity - drug therapy; Obesity - metabolism; NF-κΒ; Obesity; GLP-1; GIPR; SBS; CNS; MASH; IL-1β; MASLD; LPS; IL-6; GIP; POMC; Low-grade inflammation; TNF-α; IL-18; GLP-2; GLP-2R; GLP-1R; BMI
• ISSN: 0196-9781; 1873-5169; 1873-5169
• DOI: 10.1016/j.peptides.2024.171210

Recent advancements in understanding glucagon-like peptide 2 (GLP-2) biology and pharmacology have sparked interest in targeting the GLP-2 receptor (GLP-2R) in the treatment of obesity. GLP-2 is a proglucagon-derived 33-amino acid peptide co-secreted from enteroendocrine L cells along with glucagon-like peptide 1 (GLP-1) and has a range of actions via the GLP-2R, which is particularly expressed in the gastrointestinal tract, the liver, adipose tissue, and the central nervous system (CNS). In humans, GLP-2 evidently induces intestinotrophic effects (i.e., induction of intestinal mucosal proliferation and improved gut barrier function) and promotes mesenteric blood flow. However, GLP-2 does not seem to have appetite or food intake-reducing effects in humans, but its gut barrier-promoting effect may be of interest in the context of obesity. Obesity is associated with reduced gut barrier function, increasing the translocation of proinflammatory gut content to the circulation. This phenomenon constitutes a strong driver of obesity-associated systemic low-grade inflammation, which in turn plays a major role in the development of most obesity-associated complications. Thus, the intestinotrophic and gut barrier-improving effect of GLP-2, which in obese rodent models shows strong anti-inflammatory potential, may, in combination with food intake-reducing strategies, e.g., GLP-1 receptor (GLP-1) agonism, be able to rectify core pathophysiological mechanism of obesity. Here, we provide an overview of GLP-2 physiology in the context of obesity pathophysiology and review the pharmacological potential of GLP-2R activation in the management of obesity and related comorbidities. •GLP-2R activation is suspected of ameliorating low-grade inflammation in obese individuals via enhanced intestinal barrier function.•Activation of GLP-2R has not been proven to enhance weight loss when used as a standalone treatment.•In murine models, GLP-2R activation in POMC neurons is presumed to decrease satiety.•Combining GLP-2R agonism with weight-loss-inducing drugs like GLP-1R agonists could hold potential in treating obesity