Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat
Open accessAbstract
Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns 1 . 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 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.
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The decrease in nerve density was particularly evident in adipose tissue, consistent with previous reports documenting decreased adipose-tissue innervation in obesity.
“Among other tissues, this decrease was particularly evident in adipose tissue, consistent with previous reports documenting decreased adipose-tissue innervation in obesity25–27.”
From A deep-learning framework reveals whole-body perturbations at cell level (2026) · cites this paper as [27]
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- Authors
- Zhu, Y., Yao, L., Gallo-Ferraz, A. L., Bombassaro, B., Simões, M. R., Abe, I., Chen, J., Sarker, G., Ciccarelli, A., Zhou, L., Lee, C., Sidarta-Oliveira, D., Martínez-Sánchez, N., Dustin, M. L., Zhan, C., Horvath, T. L., Velloso, L. A., Kajimura, S., & Domingos, A. I.
- Affiliations
- University of Oxford (GB)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Beth Israel Deaconess Medical Center (US)
- Beijing Sport University (CN)
- The Francis Crick Institute (GB)
- University of Science and Technology of China (CN)
- Corresponding author
- Domingos, Ana I.
- ORCID
- Venue
- Nature
- Published
- 2024-08-28
- Volume
- 634
- Issue
- 8032
- Pages
- 243-250
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11446830
- OpenAlex
- W4401947118
- Cited by
- 78
- References
- 54
- Citations by year
- 2026: 39 · 2025: 36 · 2024: 3
- FWCI
- 22.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Figshare (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- Wellcome Trust (208576/Z/17/Z)
- Francis Crick Institute (CC1069)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK135043, UM1DK105554, R01DK133948)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- neuropeptide Y, sympathetic neurons, obesity, brown adipose tissue, white adipose tissue, thermogenesis, mural cells, adipocyte proliferation, energy expenditure, diet-induced obesity, axonal neuropathy, body weight regulation
- MeSH terms
- Single-Cell Gene Expression Analysis, Animals, Axons, Body Weight, Adipose Tissue, Brown, Energy Metabolism, Feeding Behavior, Female, Male, Mice, Inbred C57BL, Neurons, Neuropeptide Y, Obesity, Sympathetic Nervous System, Adipocytes, Thermogenesis, Cell Proliferation, Mice, Adipose Tissue, White, Diet, High-Fat, Datasets as Topic
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