Neuropeptide Y (NPY) is secreted by sympathetic nerves, but its direct impact on thermogenic adipocytes is unknown. Here we uncover the mechanism by which peripheral NPY protects from obesity. Our imaging of cleared murine brown and white adipose tissue (BAT and WAT) established that NPY+ sympathetic axons are only a minority that mostly maps to the peri-vasculature; our analysis of single-cell RNA-sequencing datasets identifies mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains mural cells, which are known to be a source of beige cells in both BAT and WAT and that NPY facilitates the differentiation to thermogenic adipocytes. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of the mural cell pool of beige fat progenitors. This defect is replicated in conditional knockout (cKO) mice with NPY specifically abrogated from sympathetic neurons. These cKO mice have whitened BAT with reduced thermogenic ability and lower energy expenditure even before the onset of obesity; they develop adult-onset obesity on a regular chow diet and are more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that relative to central NPY, peripheral NPY produced by the sympathetic nerves has the opposite effect on body weight homeostasis by sustaining the proliferation of the mural cell progenitors of thermogenic adipocytes.
Physiology in Focus 2024 (Northumbria University, UK) (2024) Proc Physiol Soc 59, SA13
Research Symposium: Sympathetic neuron-derived NPY protects from obesity by sustaining the mural progenitors of thermogenic adipocytes.
Yitao Zhu1, Lu Yao1, Ana Domingos1, Shingo Kajimura1, Ichitaro Abe1, Ana Gallo-Ferraz1, Bruna Bombassaro1, Marcela Simoes1, Licio Velloso1,
1Department of Physiology, Anatomy and Genetics, University of Oxford Oxford United Kingdom, 2Beth Israel Deaconess Medical Center, Division of Endocrinology, Diabetes & Metabolism, Harvard Medical School Boston United States, 3Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, Oita Japan, 4Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Brazil. Campinas Brazil,
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