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Nonetheless, the peripheral regulation governing the afferent\u2013efferent balance remains ambiguous. Here we show the enriched expression of both leptin receptor (\n                    <jats:italic>Lepr<\/jats:italic>\n                    ) and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -adrenergic receptor (\n                    <jats:italic>Adrb2<\/jats:italic>\n                    ) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues, using single-cell RNA sequencing on mouse sympathetic ganglia.\n                    <jats:italic>Lepr<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    sympathetic perineurial cells (SPCs) are molecularly similar to endothelial cells. Conditional knockout of\n                    <jats:italic>Adrb2<\/jats:italic>\n                    in\n                    <jats:italic>Lepr<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    cells, including SPCs, predisposes male mice to obesity by lowering energy expenditure and thermogenesis without affecting food intake. Notably, obesity-associated hyperleptinaemia causes apoptosis in SPCs, disrupting the perineurial barrier and concomitant adipose sympathetic neuropathy. This deleterious effect can be reversed by partial reduction of leptin or sympathomimetic \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -adrenergic receptor agonism. Clinically, we observed a male-specific synergistic effect of\n                    <jats:italic>LEPR<\/jats:italic>\n                    and\n                    <jats:italic>ADRB2<\/jats:italic>\n                    polymorphisms on increased body mass index risk in a large European population. We propose that SPCs coordinate the afferent and efferent arms of the neuroendocrine loop of leptin action to regulate energy expenditure and body weight.\n                  <\/jats:p>","DOI":"10.1038\/s42255-026-01555-3","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:01:40Z","timestamp":1783933300000},"page":"1563-1582","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The perineurium integrates leptin with its sympathetic outflow to protect against obesity"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2175-8705","authenticated-orcid":false,"given":"Gitalee","family":"Sarker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Haberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandhakumar","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-3474","authenticated-orcid":false,"given":"Thomas","family":"Monfeuga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrielle","family":"Maroteau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4552-0312","authenticated-orcid":false,"given":"Sofia","family":"Lundh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2530-6666","authenticated-orcid":false,"given":"David S.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Raimondi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9364-3349","authenticated-orcid":false,"given":"Karin","family":"Ziegler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3238-290X","authenticated-orcid":false,"given":"Tiago","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago N.","family":"Cordeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma","family":"Parekh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8214-6756","authenticated-orcid":false,"given":"Emilia","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5793-271X","authenticated-orcid":false,"given":"Paola","family":"Fern\u00e1ndez-Sanmart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Griebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4580-8196","authenticated-orcid":false,"given":"Noelia","family":"Martinez-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo A.","family":"Ar\u00fas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samson W.","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Shaked","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah C. 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