Obesity is now widely recognized as a chronic, relapsing metabolic disease characterized by dysregulated energy homeostasis, hormonal imbalance, and systemic inflammation. Adipose tissue functions as an active endocrine organ, influencing insulin sensitivity, lipid metabolism, and systemic metabolic regulation [1, 2].
The global burden of obesity continues to escalate, with strong associations to cardiometabolic diseases, including Type 2 Diabetes Mellitus, cardiovascular disease, and Nonalcoholic Fatty Liver Disease [3-5]. Importantly, obesity acts as a central driver of disease pathogenesis rather than merely a contributing factor.
Although lifestyle interventions remain fundamental, their long-term effectiveness is limited by compensatory physiological mechanisms, including reduced energy expenditure and increased appetite. These limitations underscore the need for effective pharmacological strategies [6, 7].
In this review, we provide a comprehensive overview of modern pharmacotherapy for obesity, focusing on incretin-based therapies and emerging multi-target approaches.
Recent research emphasizes obesity as a heterogeneous, systems-level disease driven by complex interactions among metabolic, neuroendocrine, and environmental factors [1, 2]. Incretin-based therapies have transformed treatment outcomes, and dual agonists demonstrate the advantages of multi-hormonal regulation [3, 9, 10]. Recent advances also highlight the importance of targeting adipose tissue remodeling and systemic metabolic crosstalk, including interactions between adipose tissue, liver, pancreas, and the central nervous system [14]. These insights support the development of integrated therapeutic approaches that extend beyond single-organ targeting.
Recent advances in obesity pharmacotherapy have expanded beyond glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to include multiple hormonal pathways that regulate energy balance and metabolism. GLP-1 receptor agonists remain the cornerstone of current pharmacological treatment, promoting weight loss through central appetite suppression, delayed gastric emptying, and enhanced glucose-dependent insulin secretion [3, 9]. Clinically approved agents such as semaglutide have demonstrated robust and sustained weight reduction, establishing GLP-1 signaling as a key therapeutic axis in obesity management.
In parallel, therapies targeting glucose-dependent insulinotropic polypeptide (GIP) have gained significant attention. Although the role of GIP in obesity has historically been controversial, recent evidence suggests that both GIP receptor agonism and antagonism may exert beneficial metabolic effects depending on the context. Dual GLP-1/GIP receptor agonists, such as tirzepatide, enhance weight loss through synergistic incretin signaling, improving insulin sensitivity and energy balance [10]. Conversely, GIP receptor antagonists are also under investigation for their potential to counteract obesity-associated metabolic dysregulation.
Beyond incretin-based approaches, glucagon receptor agonists represent another promising class of anti-obesity agents. Glucagon signaling increases energy expenditure, lipolysis, and hepatic fatty acid oxidation, making it an attractive target for weight reduction. However, its hyperglycemic effects have limited its use as monotherapy, leading to the development of multi-agonist strategies, such as GLP-1/glucagon co-agonists, that balance metabolic benefits while minimizing adverse effects [10].
In addition, amylin receptor agonists have emerged as a complementary therapeutic approach. Amylin, a hormone co-secreted with insulin, regulates satiety and gastric emptying. Long-acting amylin analogs, such as cagrilintide, have demonstrated significant weight loss effects, particularly when combined with GLP-1 receptor agonists, suggesting a synergistic mechanism targeting both central and peripheral pathways [15].
Collectively, these emerging pharmacological strategies highlight a shift toward multi-hormonal and multi-target approaches, aiming to address both energy intake and expenditure. This transition reflects a move toward mechanism-based therapeutic strategies for improved efficacy and durability. Furthermore, the integration of incretin-based therapies with additional metabolic regulators is increasingly being explored to overcome therapeutic plateaus and enhance long-term weight maintenance.
Future obesity pharmacotherapy is expected to shift beyond single-target interventions toward integrated, multi-target therapeutic strategies. A key driver of this transition will be the incorporation of physiologically relevant organoid models into obesity research and drug development. Patient-derived adipose, intestinal, hepatic, and pancreatic organoids faithfully recapitulate tissue architecture, cellular heterogeneity, and metabolic function, thereby overcoming many limitations of conventional two-dimensional cultures and animal models [16].
Advances in biomarker discovery and systems biology will enable precision medicine approaches, allowing for individualized treatment strategies. These developments are expected to improve both clinical outcomes and real-world applicability.
These platforms provide powerful tools for investigating obesity-associated metabolic dysfunction, identifying novel therapeutic targets, evaluating drug efficacy and safety, and predicting patient-specific treatment responses. Furthermore, integration of organoid technologies with multi-omics approaches, including transcriptomics, metabolomics, and proteomics, is expected to accelerate biomarker discovery and elucidate mechanisms underlying therapeutic responsiveness and resistance.
Combined with advances in systems biology and artificial intelligence-driven data analysis, organoid-based precision medicine platforms have the potential to optimize individualized treatment selection, improve long-term therapeutic outcomes, and facilitate the clinical translation of next-generation anti-obesity therapies (Figure 3). Collectively, organoid technology is poised to become a cornerstone of future obesity research, bridging mechanistic discoveries with personalized therapeutic development.