A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue
Abstract
Mutations in the leptin gene (ob) result in a metabolic disorder that includes severe obesity 1, and defects in thermogenesis 2 and lipolysis 3, both of which are adipose tissue functions regulated by the sympathetic nervous system. However, the basis of these sympathetic-associated abnormalities remains unclear. Furthermore, chronic leptin administration reverses these abnormalities in adipose tissue, but the underlying mechanism remains to be discovered. Here we report that ob/ob mice, as well as leptin-resistant diet-induced obese mice, show significant reductions of sympathetic innervation of subcutaneous white and brown adipose tissue. Chronic leptin treatment of ob/ob mice restores adipose tissue sympathetic innervation, which in turn is necessary to correct the associated functional defects. The effects of leptin on innervation are mediated via agouti-related peptide and pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Deletion of the gene encoding the leptin receptor in either population leads to reduced innervation in fat. These agouti-related peptide and pro-opiomelanocortin neurons act via brain-derived neurotropic factor-expressing neurons in the paraventricular nucleus of the hypothalamus (BDNF PVH). Deletion of BDNF PVH blunts the effects of leptin on innervation. These data show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.
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High expression of BDNF within the ventromedial hypothalamic nucleus (VMH) enhanced the SNS output of lipolytic signalling.
“Recent studies revealed that high expression of BDNF within the ventromedial hypothalamic nucleus (VMH) enhanced the SNS output of lipolytic signalling [22].”
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 [26]
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- Authors
- Wang, P., Loh, K. H., Wu, M., Morgan, D. A., Schneeberger, M., Yu, X., Chi, J., Kosse, C., Kim, D., Rahmouni, K., Cohen, P., & Friedman, J.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Iowa (US)
- Rockefeller University (US)
- Corresponding author
- Loh, Ken H.
- Friedman, Jeffrey
- ORCID
- Venue
- Nature
- Published
- 2020-07-22
- Volume
- 583
- Issue
- 7818
- Pages
- 839-844
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3044817976
- Cited by
- 332
- References
- 34
- Citations by year
- 2026: 53 · 2025: 44 · 2024: 72 · 2023: 52 · 2022: 54 · 2021: 47 · 2020: 10
- FWCI
- 20.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, brain-derived neurotrophic factor, sympathetic innervation, adipose tissue, agouti-related protein, proopiomelanocortin neurons, hypothalamic arcuate nucleus, paraventricular nucleus, leptin receptor, obesity, energy homeostasis, thermogenesis, lipolysis, leptin resistance
- MeSH terms
- Adipose Tissue, Animals, Arcuate Nucleus of Hypothalamus, Lipolysis, Male, Mice, Inbred C57BL, Neurons, Pro-Opiomelanocortin, Sympathetic Nervous System, Signal Transduction, Brain-Derived Neurotrophic Factor, Leptin, Thermogenesis, Subcutaneous Fat, Mice, Agouti-Related Protein
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