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Results showed that HFD feeding resulted in a marked decrease in skeletal innervation (69%\u201341% reduction in Beta-III-Tubulin-stained nerves, 38% reduction in CGRP-stained nerves in long bone periosteum). These changes in skeletal innervation were associated with significant alterations in bone mass and in cortical and trabecular bone microarchitecture of long bones. Single-cell RNA sequencing (scRNA-Seq) of sensory neurons and bone tissue was next utilized to reconstruct potential nerve-to-bone signaling interactions, including implication of sensory nerve-derived neurotrophins (\n                    <jats:italic>Bdnf)<\/jats:italic>\n                    , neuropeptides (\n                    <jats:italic>Gal, Calca<\/jats:italic>\n                    and\n                    <jats:italic>Calcb<\/jats:italic>\n                    ), and other morphogens (\n                    <jats:italic>Vegfa, Pdgfa<\/jats:italic>\n                    , and\n                    <jats:italic>Angpt2)<\/jats:italic>\n                    . Moreover, scRNA-Seq identified marked shifts in periosteal cell transcriptional changes within HFD-fed conditions, including a reduction in cell proliferation, an increase in adipogenic differentiation markers, and reductions in WNT, TGF\u03b2, and MAPK signaling activity. When isolated, periosteal cells from HFD-fed mice showed deficits in proliferative and osteogenic differentiation potential. Moreover, these cellular changes in proliferation and differentiation capacity were restored by treatment of HFD-exposed periosteal cells to sensory neuron-conditioned medium. In summary, HFD modeling of type 2 diabetes results in skeletal polyneuropathy. Moreover, the combination of multi-tissue scRNA-Seq and isolated in vitro studies strengthen the case for altered nerve-to-bone signaling in diabetic bone disease.\n                  <\/jats:p>","DOI":"10.1038\/s41413-025-00436-x","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T06:40:10Z","timestamp":1751611210000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Reduced somatosensory innervation alters the skeletal transcriptome at a single cell level in a mouse model of type 2 diabetes"],"prefix":"10.1038","volume":"13","author":[{"given":"Masnsen","family":"Cherief","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Gomez-Salazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjung","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungyong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Ramesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5437-0208","authenticated-orcid":false,"given":"Qizhi","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soohyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Archer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"Hoke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2002-622X","authenticated-orcid":false,"given":"Aaron W.","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"436_CR1","doi-asserted-by":"publisher","first-page":"144","DOI":"10.2174\/157339910791162970","volume":"6","author":"ML Isidro","year":"2010","unstructured":"Isidro, M. 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