1. Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis
- Author
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Yuji Ikeno, Allyson K. Palmer, Patrick Krüger, Kurt O. Johnson, Grigori Enikolopov, Mikolaj Ogrodnik, João F. Passos, Nino Giorgadze, Christine Inman, Marissa J. Schafer, Tamar Pirtskhalava, James L. Kirkland, Thomas von Zglinicki, Terry C. Burns, Larissa G.P. Langhi, Diana Jurk, Tamar Tchkonia, Edward Fielder, Rifqha A. Ruswhandi, Stella Victorelli, Ming Xu, Yi Zhu, Oleg Podgorni, and Moritz Weigl
- Subjects
Male ,Physiology ,Neurogenesis ,Dasatinib ,Cellular senescence ,Mice, Transgenic ,Anxiety ,Diet, High-Fat ,Tacrolimus ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Medicine ,Obesity ,Molecular Biology ,Cells, Cultured ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,030304 developmental biology ,0303 health sciences ,Behavior, Animal ,business.industry ,Brain ,Lipid Droplets ,Cell Biology ,Fibroblasts ,medicine.disease ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Cell metabolism ,Astrocytes ,Female ,Quercetin ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16(Ink4a)-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
- Published
- 2019
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