biostudies-literatureZhu YNIDDK NIH HHSWellcome Trust243-250https://www.ebi.ac.uk/biostudies/studies/S-EPMC11446830biostudies-literatureUnknown634(8032)Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns¹. Here we uncover the mechanism by which NPY in sympathetic neurons^2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY⁺ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT^4-6. We found that diet-induced obesity leads to neuropathy of NPY⁺ axons and concomitant depletion of NatureSympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat.PMC11446830UM1 DK105554Yao LZhou LGallo-Ferraz ALSarker GCiccarelli AMartinez-Sanchez NVelloso LAZhu YChen JZhan CDustin MLAbe ILee CDomingos AIBombassaro BSidarta-Oliveira DKajimura SSimoes MRHorvath TLfalseSympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat.Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns¹. Here we uncover the mechanism by which NPY in sympathetic neurons^2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY⁺ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT^4-6. We found that diet-induced obesity leads to neuropathy of NPY⁺ axons and concomitant depletion of 2024-01-01T00:00:00Z2024 Oct2025-04-04T01:54:28.857Z2025-04-04T01:54:28.857ZS-EPMC114468303919864810.1038/s41586-024-07863-6