PTEN regulates vagal-insulin signaling to optimize autonomic output determining peripheral inflammatory and metabolic homeostasis.

Summary

Vagal neuron-specific PTEN deletion increases vagal output, upregulates dopaminergic signaling, elevates adipose sympathetic innervation and norepinephrine, and protects against high-fat diet–induced obesity, insulin resistance, and systemic inflammation. Conversely, vagal neuron insulin receptor deletion worsens metabolism, which is rescued by concurrent PTEN deletion, establishing an insulin–PI3K–PTEN axis in vagal control of metabolic homeostasis.

Key Findings

• Vagal neuron-specific PTEN deletion increases vagal output and upregulates dopaminergic signaling genes.
• Enhanced adipose sympathetic nerve density and norepinephrine accompany protection from diet-induced obesity, insulin resistance, and systemic inflammation.
• Vagal insulin receptor deletion exacerbates metabolic defects, which are rescued by concurrent PTEN deletion, defining an insulin–PI3K–PTEN axis.

Clinical Implications

Suggests precision neuromodulation (targeting vagal insulin signaling or PTEN activity) to treat obesity and insulin resistance; informs biomarker development linking autonomic tone, adipose innervation, and metabolic inflammation.

Limitations

• Findings are preclinical; safety and feasibility of targeting vagal PTEN/PI3K signaling in humans are unknown.
• Sex differences and long-term effects on cardiovascular autonomic balance were not detailed in the abstract.

Future Directions

Assess translatability via neuromodulation paradigms (e.g., targeted vagal stimulation) and pharmacologic PTEN/PI3K tuning; map human correlates of vagal insulin signaling and adipose innervation.