Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat

Yitao Zhu, Lu Yao, Ana L. Gallo-Ferraz, Bruna Bombassaro, Marcela R. Simões, Ichitaro Abe, Jing Chen, Gitalee Sarker, Alessandro Ciccarelli, Linna Zhou, Carl Lee, Davi Sidarta-Oliveira, Noelia Martínez-Sánchez, Michael L. Dustin, Cheng Zhan, Tamas L. Horvath, Licio A. Velloso, Shingo Kajimura and Ana I. Domingos ()
Additional contact information
Yitao Zhu: University of Oxford
Lu Yao: University of Oxford
Ana L. Gallo-Ferraz: University of Campinas
Bruna Bombassaro: University of Campinas
Marcela R. Simões: University of Campinas
Ichitaro Abe: Harvard Medical School
Jing Chen: Beijing Sport University
Gitalee Sarker: University of Oxford
Alessandro Ciccarelli: The Francis Crick Institute
Linna Zhou: University of Oxford
Carl Lee: University of Oxford
Davi Sidarta-Oliveira: University of Oxford
Noelia Martínez-Sánchez: University of Oxford
Michael L. Dustin: University of Oxford
Cheng Zhan: University of Science and Technology of China
Tamas L. Horvath: Yale University School of Medicine
Licio A. Velloso: University of Campinas
Shingo Kajimura: Harvard Medical School
Ana I. Domingos: University of Oxford

Nature, 2024, vol. 634, issue 8032, 243-250

Abstract: Abstract 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 neurons2,3 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 WAT4–6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.

Date: 2024
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DOI: 10.1038/s41586-024-07863-6

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