C1QL3 (complement C1q-like 3) is a secreted synaptic organizer with dual roles in neural circuit formation and glucose homeostasis. In the brain, C1QL3 functions as a synaptic organizer that regulates excitatory synapse formation in the hippocampus and determines postsynaptic kainate receptor localization at mossy fiber synapses 1. C1QL3 exerts these effects by binding to the adhesion-GPCR BAI3 through a hexameric complex mechanism involving calcium-mediated interactions 2. Loss of C1QL3 impairs neuronal integrity, including dendritic arborization and spine density, while simultaneously affecting microglial activation and producing hyperactivity with working memory deficits 3. Metabolically, C1QL3 acts as a negative regulator of glucose homeostasis. Via BAI3 signaling in pancreatic β-cells, C1QL3 inhibits cAMP-stimulated insulin secretion 4, a mechanism particularly relevant in obesity-associated diabetes 5. Systemic C1QL3 knockout improves glucose tolerance, insulin sensitivity, and lipid metabolism, with reduced hepatic glucose output and hepatic steatosis 6. These findings reveal C1QL3 as a pleiotropic regulator integrating synaptic plasticity with metabolic control, positioning it as a potential therapeutic target in type 2 diabetes and metabolic disorders.