Transthyretin gates GLP-1R-mediated affect by metabolic stat

GLP-1 receptor agonists are widely used to treat diabetes and obesity, yet their variable neuropsychiatric side effects including anxiety and depression in some individuals have remained mechanistically unknown. Here, we identify transthyretin (TTR) as a context-dependent mediator and biomarker for GLP-1R–driven affective behavior. We show that in normal-weight mice, hippocampal GLP-1R activation triggers a cAMP/PKA/Gli3 cascade that represses TTR expression, leading to impaired ERK/CREB-dependent synaptic plasticity and promotes anxiety- and depression-like behaviors. Conversely, in diet-induced obese models where hippocampal TTR is upregulated, and GLP-1R activation normalizes TTR levels, rescuing affective deficits. Translating these findings, we show that GLP-1R agonist reduces elevated serum TTR in obese humans. We therefore propose that baseline TTR levels serve as a critical biomarker: obese individuals with high TTR may achieve both metabolic and mental health benefits, whereas individuals with normal TTR levels are at risk for drug-induced affective disturbances. Our work establishes a molecular basis for the psychiatric side effects of GLP-1R-targeting therapies and provides a rationale for TTR-guided personalization of treatment.