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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has a prevalence of about 25% in the adult population, with steatosis present in >5% of hepatocytes, hepatocyte ballooning and fibrosis as the main hallmarks. Scientists have tested effects of the galectin-3 inhibitor modified citrus pectin (MCP) in ApoE knockout mice fed a western diet.

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.