Obesity and emerging intervention strategies: Mechanistic insights and novel drug targets

ABSTRACT: Obesity, a global public health crisis driven by complex interactions of genetic, environmental, and behavioral factors, necessitates innovative therapeutic strategies. This review explores the pathogenesis of obesity, emphasizing genetic determinants, metabolic dysregulation, gut microbiota alterations, and energy imbalance. The evolution of anti-obesity pharmacotherapy has progressed from the use of high-risk agents such as amphetamines and thyroid extracts to modern gut hormone-based therapies, notably glucagon-like peptide-1 receptor agonists (GLP-1RAs), which effectively suppress appetite and improve glycemic control. Current pharmacologic agents target central appetite regulation or peripheral mechanisms. However, there are still risks such as muscle loss and long-term safety issues. Emerging therapeutic strategies are focusing on novel targets such as growth differentiation factor 15 (GDF15) and its specific receptor glial cell-line derived neurotrophic factor family receptor α-like (GFRAL), inhibin βE (INHBE), as well as bile acid receptors including the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Concurrently, the field is advancing multi-targeted drugs and drug combinations to enhance weight loss efficacy and reduce side effects. Furthermore, the development of oral formulations such as oral Semaglutide is expected to provide convenience for patients and enhance their willingness to receive treatment. In the future, with the development of multi-omics technologies and the widespread application of artificial intelligence, it is expected to support personalized therapies, thereby improving treatment efficacy and accuracy.