Background

Anxiety disorders affect one in three people worldwide, yet current treatments, centered on brain neurotransmitters, fail many patients and often cause undesirable side effects. While these therapies act centrally, growing evidence suggests that emotional states are also influenced by signals from peripheral organs. We identify asprosin, a fasting-induced hormone secreted by adipose tissue, as a direct endocrine driver of anxiety. Asprosin crosses the blood-brain barrier and binds protein tyrosine phosphatase receptor delta (PTPRD), a neuronal receptor enriched in hippocampal neurons and genetically linked to anxiety risk. This work defines the first hormone–receptor circuit linking energy state to emotional behavior, one that is peripheral, mechanistically distinct, and therapeutically actionable.

Methods

We manipulated the asprosin-Ptprd signaling axis in mice using five approaches: (1) viral overexpression of asprosin (Ad5-FBN1 or AAV8-asprosin); (2) peripheral neutralization with an anti-asprosin monoclonal antibody (mAb); (3) genetic loss-of-function models, including Fbn1NPS/+ mice (asprosin-deficient) and Ptprd+/- mice; (4) pharmacologic inhibition using 7-butoxy-illudalic acid (7-BIA), a selective Ptprd inhibitor; and (5) stereotactic Cre-mediated deletion of Ptprd in specific brain regions. Anxiety-like behavior was quantified across well-validated assays: open field, light–dark, and elevated plus maze, under both basal conditions and chronic stress paradigms. Asprosin binding was assessed using alkaline phosphatase-tagged ligands, and whole-cell patch-clamp electrophysiology evaluated neuronal excitability.

Results

Reducing asprosin signaling through - genetic asprosin deficiency, pharmacologic sequestration with a monoclonal antibody, partial Ptprd loss and pharmacologic Ptprd inhibition - reduced baseline anxiety-like behavior across multiple assays. Conversely, elevating asprosin with viral overexpression increased baseline anxiety. When anxiety was induced using chronic stress paradigms, circulating asprosin surged, found to be driven by catecholamine release. Mechanistically, recombinant asprosin depolarized ventral CA1 pyramidal neurons and doubled their firing rate via a Ptprd-dependent, synapse-independent process. Region-specific deletion studies confirmed that Ptprd in ventral CA1 was necessary for stress-induced anxiety, identifying this subregion as the key node mediating asprosin-driven emotional changes.

Conclusion

This study reframes anxiety as a hormonally gated state regulated by a defined adipose-to-brain endocrine axis. The asprosin–Ptprd pathway operates independently of classical neurotransmission, offering dual therapeutic targets: a peripheral hormone and its central receptor. Our findings highlight the body’s peripheral pathways as an untapped source of insight and innovation in neuropsychiatric disease. It establishes the mechanistic foundation for the first hormone-based anxiolytic, a strategy that is translatable, safe, and designed to reach the millions of patients for whom current drugs fall short.