GLP-1R and dual GIPR/GLP-1R agonists reshape human adipocyte metabolism, highlighting preclinical evidence gaps

The global rise in obesity prevalence underscores an urgent need for effective pharmacological interventions beyond lifestyle changes. While GLP-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonists like tirzepatide have shown significant benefits in weight loss and related comorbidities, their precise cell type-specific molecular mechanisms in target tissues, particularly adipose tissue, remain incompletely understood. Understanding these mechanisms is crucial for optimizing therapeutic strategies for type 2 diabetes mellitus (T2DM) and cardiovascular disease.

This review systematically summarized current preclinical evidence on the effects of GLP-1R agonists and dual GIPR/GLP-1R agonists on the function of adipocytes. The analysis encompassed studies using both human- and animal-derived adipocyte models, including existing in vivo and in vitro research. The primary aim was to identify and synthesize available data regarding the molecular mechanisms by which these agents modulate adipocyte metabolism and function, highlighting areas where understanding is still limited.

The review found that most existing preclinical studies investigating the effects of GLP-1RAs and dual GIPR/GLP-1RAs on adipocyte function have been conducted predominantly in animal models, both in vivo and in vitro. These animal models, while providing foundational insights, may not fully recapitulate the complex pathophysiology of human adipose tissue. > The synthesis highlights a critical gap: the limited availability of preclinical evidence derived from human-derived cell models to fully elucidate the cell type-specific molecular mechanisms of these agonists in humans. This suggests an incomplete understanding of how these agents exert their pleiotropic effects on human adipocyte metabolism.