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^4,5,6. 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.

神经肽 Y （NPY） 的人类突变与高体重指数有关，但与饮食模式的改变无关¹。在这里，我们揭示了交感神经元^2,3 中的 NPY 预防肥胖的机制。透明化的小鼠棕色和白色脂肪组织（分别为 BAT 和 WAT）的成像确定 NPY⁺ 交感神经轴突是一个较小的子集，主要映射到脉管周围系统;对单细胞 RNA 测序数据集的分析确定 MURAL 细胞是脂肪组织中主要的 NPY 反应细胞。我们表明 NPY 维持壁细胞的增殖，壁细胞是 BAT 和 WAT 中产热脂肪细胞的来源^4,5,6。我们发现饮食诱导的肥胖导致 NPY⁺ 轴突神经病变和伴随的壁细胞耗竭。这种缺陷在交感神经元中去除 NPY 的小鼠中复制。交感神经元中 NPY 的丢失使肩胛间 BAT 变白，降低了其产热能力并减少了肥胖发作前的能量消耗。它还导致以常规食物喂养的小鼠成年发病肥胖，并使它们在不增加食物消耗的情况下更容易患上饮食诱导的肥胖。我们的结果表明，相对于中枢 NPY，交感神经产生的外周 NPY 通过维持独立于食物摄入的能量消耗，对体重产生相反的影响。