Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat

• 成果类型: Article
• 署名作者: Zhu, Yitao; Yao, Lu; Gallo-Ferraz, Ana L.; Bombassaro, Bruna; Simoes, Marcela R.; Abe, Ichitaro; Chen, Jing; Sarker, Gitalee; Ciccarelli, Alessandro; Zhou, Linna; Lee, Carl; Sidarta-Oliveira, Davi; Martinez-Sanchez, Noelia; Dustin, Michael L.; Zhan, Cheng; Horvath, Tamas L.; Velloso, Licio A.; Kajimura, Shingo; Domingos, Ana I.
• 署名单位: University of Oxford; Universidade Estadual de Campinas; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Oita University; Beijing Sport University; Francis Crick Institute; University of Oxford; Ludwig Institute for Cancer Research; University of Oxford; Kennedy Institute for Rheumatology; University of Oxford; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Yale University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6448
• DOI: 10.1038/s41586-024-07863-6
• 发表日期: 2024-10-03
• 关键词: adipose-tissue; feeding-behavior; mice lacking; leptin; npy; proliferation; noradrenaline; pericytes; neurons; GROWTH

摘要

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. We find that, relative to central neuropeptide Y, peripheral neuropeptide Y produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.