The efficacy of cannabinoid CB1 receptor antagonists in diet-induced obesity and its related metabolic complications is well established, but they are tied to central nervous system (CNS)-related adverse effects due to brain penetration. There is increasing interest in developing peripherally restricted compounds for use in the clinic, but the molecular mechanisms behind the metabolic benefits from CB1 receptor antagonists is still poorly understood.
Large-scale human genetic studies have revealed that loss-of-function INHBE variants are associated with a lower abdominal to gluteofemoral fat ratio, improved metabolic profile, and reduced fasting glucose levels.
After finding a mutation in METTL2A in a family with diabetes exhibiting a special phenotype, investigators at Zhejiang University School of Medicine studied its role in glucose and lipid metabolism in METTL2 (murine orthologue) knockout mice and wild-type mice fed a normal chow or a high-fat diet (HFD) for 20 weeks.
Targeting monoacylglycerol O-acyltransferase 2 (MGAT2), an enzyme highly expressed in the small intestine, has been validated as an antiobesity strategy in the preclinical setting.
Biolexis Therapeutics Inc. is working on developing orally available, small-molecule AMPK activators that have been found to stimulate AMPK activity as well as dose-dependently enhance glucose uptake in human tissue.
Biomed Industries Inc. has presented data on its IGF-1/GLP-1/GIP/GCGR quadruple agonist NA-931 for the treatment of obesity and metabolic disorders. The company has discovered a family of IGF-1 metabolites, known as NA-931, and its analogues NA-932 and NA-933, which are referred to as NA-931 compounds.
Injectable glucagon-like peptide 1 receptor (GLP-1R) agonists have shown efficacy in weight management and glycemic control. Semaglutide is available as an oral formulation, but it requires specific timing and conditions. Carmot Therapeutics Inc. has presented data for its oral GLP-1R agonist CT-996 from preclinical studies in obesity; the drug is currently in early clinical development.
Aldeyra Therapeutics Inc. has expanded its novel reactive aldehyde species (RASP) modulator pipeline with the discovery and advancement of new RASP modulators for the treatment of inflammatory and metabolic diseases.
Flagship Pioneering Inc. and Profound Therapeutics Inc., a Flagship-founded company, have announced a collaboration to conduct foundational research to identify potential next-generation first-in-class therapies for the treatment of obesity.
Ventyx Biosciences Inc. has released promising preclinical data for its CNS-penetrant NLRP3 inhibitor VTX-3232 in murine diet-induced obesity (DIO) models.
