The perineurium integrates leptin with its sympathetic outflow to protect against obesity

The regulatory mechanism of leptins afferent action in the brain, constituting a negative feedback loop, is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the relative strengths of the afferent and efferent arms remains ambiguous. Using single-cell RNA sequencing on murine sympathetic ganglia, we identified the unique expression of both the leptin receptor (LepR) and the beta 2 adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues. We show that LepR+ Sympathetic Perineurial Cells (SPCs) are molecularly similar to endothelial cells and that conditional knockout of Adrb2 in LepR+ SPCs predisposes mice to obesity without affecting food intake. Notably, we found that hyperleptinemia associated with obesity causes apoptosis in SPCs, leading to a significant erosion of the perineurial barrier and concomitant adipose sympathetic neuropathy. We further show that this deleterious effect can be reversed by sympathomimetic beta 2 adrenergic receptor agonism. These results have relevance to human obesity, as we observed a synergistic effect of highly common polymorphisms of LEPR and ADRB2 on the risk of increased BMI in a large European population. We propose that SPCs are the nexus of leptin action by integrating the afferent and efferent arms of the neuroendocrine loop to influence its setpoint.