Review traces obesity therapy shift from leptin resistance to glucagon-like peptide-1 receptor agonists

The global obesity epidemic is a multifaceted health crisis, driving comorbidities like type 2 diabetes mellitus and cardiovascular disease. The discovery of leptin in 1994 revolutionized understanding of body weight regulation, but its therapeutic potential was limited by widespread leptin resistance. This gap necessitated the exploration of alternative mechanisms, leading to the emergence of glucagon-like peptide-1 (GLP-1), an incretin hormone, as a pivotal target for effective obesity management.

This narrative review systematically evaluated the historical development of obesity therapies, focusing on the conceptual shift from leptin biology to the clinical application of glucagon-like peptide-1 receptor analogs. The authors synthesized findings from extensive genetic studies, mechanistic investigations, and clinical trials to outline their unique mechanisms, gene polymorphisms, and hormonal interactions regulating energy homeostasis. The review specifically contrasted the limited efficacy of leptin-based approaches due to leptin resistance with the broad metabolic and cardiovascular benefits offered by GLP-1RAs.

The review concluded that while leptin profoundly advanced the understanding of body weight regulation, its therapeutic utility in general obesity was significantly hampered by prevalent leptin resistance. In contrast, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a highly effective class of therapeutics, demonstrating superior clinical outcomes.

GLP-1RAs aid in significant weight loss and robust glycemic control, alongside providing substantial metabolic and cardiovascular benefits. The article detailed how GLP-1RAs exert their effects through unique mechanisms involving the gut-brain-adipose axis, influencing satiety, gastric emptying, and insulin secretion. It also highlighted the role of specific gene polymorphisms in modulating individual responses to these therapies, emphasizing the complex hormonal interactions that underpin energy homeostasis.