G protein-coupled receptors and obesity

Abstract

G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity and diabetes. Obesity is a complex chronic disease that requires long term management predisposing to type 2 diabetes, heart disease, and some cancers. The therapeutic landscape for GPCR as targets of anti-obesity medications has undergone significant changes with the approval of semaglutide, the first peptide glucagon like peptide 1 receptor agonist (GLP-1RA) achieving double digit weight loss (≥10%) and cardiovascular benefits. The enhanced weight loss, with the expected beneficial effect on obesity-related complications and reduction of major adverse cardiovascular events (MACE), has propelled the commercial opportunity for the obesity market leading to new players entering the space. Significant progress has been made on approaches targeting GPCRs such as single peptides that simultaneously activate GIP and/or GCGR in addition to GLP1, oral tablet formulation of GLP-1, small molecules nonpeptidic oral GLP1R and fixed-dose combination as well as add-on therapy for patients already treated with a GLP-1 agonist.

Keywords: GIP; GLP-1; amylin; glucagon; obesity; semaglutide; tirzepatide.

Figure 1

G-protein coupled receptors (GPCRs) and peptides discussed. The anorexigenic hormones (blue) are released from various organs mostly in the gastrointestinal system and pancreas and modulate GPCRs leading to food intake suppression, reduced gastric emptying and increased energy expenditure. Inset. GPCR signaling: Balanced agonists activate both the G protein- and β-arrestin-dependent signaling pathway while biased agonists selectively activate the GPCR-dependent signaling pathway affecting cellular response through second messenger activation or the β-arrestin-dependent signaling pathway. Glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), gastric inhibitory polypeptide (GIP), peptide YY (PYY), cannabinoid receptor 1 (CB1R), Leap-2 (Liver-expressed antimicrobial peptide 2), melanocortin 4 receptor (MC4R), amylin receptor (AmR), 5-hydroxytryptamine receptor 2C (5-HT2CR). AgRP (Agouti-Related Protein), POMC (proopiomelanocortin); NTS, nucleus tractus solitarius; ARC, Arcuate nucleus; PVN, paraventricular nucleus.

Figure 2

Timeline and discoveries discussed in this minireview with therapeutic relevance in obesity.