Topology-Driven Activation of the GLP-1 Receptor Promotes Adipose Tissue Browning

Obesity and type 2 diabetes represent an escalating global health burden, underscoring the need for fundamentally new strategies to modulate metabolic signaling. The glucagon-like peptide-1 receptor (GLP-1R) is a thoroughly validated metabolic target that, over the past decade, has underpinned the development of several highly effective therapeutic modalities. Here, we introduce a class of topology-dependent agonists that modulate GLP-1R signaling by imposing defined receptor geometries. Through controlled dimerization or oligomerization, these engineered ligands constrain extracellular domain-transmembrane domain conformations, thereby inducing GLP-1R activation. Importantly, in animal models, a bivalent DARPin-based GLP-1R agonist markedly increased brown adipose tissue content and thermogenesis, thereby promoting weight loss via an appetite-independent mechanism.