Beyond weight loss: How metabolism in human adipocytes is shaped by GLP-1R agonists and dual GIPR/GLP-1R agonists

Obesity is a chronic disease leading to multiple comorbidities, including type 2 diabetes mellitus (T2DM), cardiovascular disease, and several cancers. Its prevalence has dramatically risen worldwide, making it a major global concern. Although lifestyle interventions remain the cornerstone of management, their effectiveness is often, underscoring the need for novel pharmacological approaches. In this regard, glucagon-like receptor agonists (GLP-1RAs) and the novel dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, have shown significant benefits on obesity-related outcomes. Clinical evidence consistently supports their efficacy and safety in promoting weight loss. Furthermore, these agents appear to exert pleiotropic effects by modulating the function of multiple systems, including the cardiovascular, nervous, and gastrointestinal systems. However, the cell type–specific molecular mechanisms underlying their actions in target tissues, particularly adipose tissue, remain incompletely understood. Hence, this review aims to summarize current preclinical evidence on the effects of GLP-1R and dual GIPR/GLP-1R agonists on the function of human-and animal-derived adipocytes. Available data indicate that most studies have been conducted in animal models, both in vivo and in vitro models, which may not fully recapitulate human adipose tissue pathophysiology. Therefore, future studies should prioritize human-derived cell models to better elucidate and address the pathophysiological and pharmacological downstream effects of GLP-1, GIP, and their agonists in humans.