Fam172a Mediates the Stimulation of Hypothalamic Oxytocin Neurons to Suppress Obesity-Induced Anxiety.

Summary

In mice, activation of paraventricular hypothalamic oxytocin neurons reduced obesity-induced anxiety-like behavior, while inhibition worsened it. The anxiety susceptibility gene Fam172a is enriched in these neurons, downregulated by high-fat diet/stress, and modulates intranuclear Argonaute 2 and mRNA degradation to control oxytocin secretion; gain- and loss-of-function experiments respectively ameliorated or exacerbated anxiety-like behavior.

Key Findings

• Activation of PVN oxytocin neurons ameliorated obesity-induced anxiety-like behavior; inhibition worsened it.
• Fam172a is highly expressed in PVN oxytocin neurons but is downregulated by high-fat diet and acute stress.
• Fam172a modulates intranuclear transport of Argonaute 2, influencing mRNA degradation and oxytocin secretion.
• Overexpression of Fam172a improved, while disruption exacerbated, obesity-anxiety-like behavior in mice.

Clinical Implications

While preclinical, the work nominates oxytocin signaling and Fam172a as candidate targets for obesity-associated anxiety, motivating biomarker development and human translational studies in neuroendocrine circuits.

Limitations

• Findings are limited to murine models; human relevance and peripheral biomarkers remain untested
• Behavioral phenotyping and circuit specificity may not capture the full complexity of human anxiety disorders

Future Directions

Validate Fam172a and oxytocin pathway markers in humans with obesity-associated anxiety; develop selective modulators or gene therapy approaches and test causality with neuromodulation.