👤 Savanna Breit

Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs interact not only with heterotrimeric G proteins but can also recruit beta-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate that MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found that the appetite-suppressing effect of setmelanotide, an MC4R agonist approved by the FDA for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs. Show less

Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets. Islets were isolated from wild-type (WT), Gipr-knockout (Gipr The triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either Gipr or Gcgr. However, the triagonist failed to enhance insulin secretion in islets lacking both Glp-1r and Gipr and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9-39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed Trpm5 Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq-TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist. Show less

This review aims to evaluate the efficacy and safety of olezarsen (Tryngolza) in treating familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by severe hypertriglyceridemia. A comprehensive literature search was conducted via PubMed from January 2022 to mid-March 2025, using keywords such as olezarsen, antisense oligonucleotide, triglyceride, hypertriglyceridemia, apolipoprotein C3 (APOC3), and cardiovascular. Relevant English-language studies assessing the pharmacokinetics, pharmacology, efficacy, or safety of olezarsen were included. Data from the US Food and Drug Administration (FDA)-approved package insert were also reviewed. Olezarsen is an antisense oligonucleotide targeting APOC3 mRNA, a key regulator of plasma triglyceride levels. It has been shown to significantly reduce triglyceride levels via APOC3 protein degradation. Clinical trials have demonstrated substantial reductions in triglyceride levels and APOC3, with minimal adverse events. Phase 2 and 3 trials showed consistent efficacy and safety profiles, with common adverse events including COVID-19 infection, abdominal pain, and diarrhea.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:Olezarsen offers a targeted and effective treatment for FCS, addressing limitations of traditional therapies such as fibrates, omega-3 fatty acids, and statins. Its novel mechanism of action and once-monthly dosing regimen may improve patient adherence, providing significant advancement in FCS management. Olezarsen represents a new treatment for FCS, offering a targeted approach to significantly reduce triglyceride levels. Its integration into clinical practice has the potential to transform the management of FCS; however, more studies are needed to firmly establish its role. Show less