Cellular Senescence in the Rostral Ventrolateral Medulla (RVLM) – Novel Implications for Obesity‐Induced Sympathoexcitation

Abstract

Oxidative stress in the RVLM, a key brainstem region that regulates sympathetic nerve activity (SNA) and blood pressure has been associated with obesity‐induced hypertension. Chronic oxidative stress is a known stimulus for induction of cellular senescence, a state of irreversible growth arrest in proliferating cells. Senescent cells are also a potential source of neuroinflammation as they secrete cytokines, chemokines and proteases through acquisition of senescence‐associated secretory phenotype (SASP). Whether obesity induces senescence in the brainstem to promote neuroinflammation and increases in SNA is not clear. Hence, we hypothesized that obesity triggers the induction of cellular senescence in the RVLM, which in turn contributes to neuroinflammation and increases in SNA leading to the development of hypertension. To address this hypothesis, 2 months‐old male C57BL/6J mice were fed a high‐fat diet (HFD; 60% fat; n=5) or normal chow diet (Controls;10% fat; n=5) for 16 weeks. At the end of the dietary treatment, brainstem was isolated from the animals for assessment of senescence in the RVLM. Data were analyzed by unpaired students t‐test and expressed as mean ± SE. HFD treatment significantly increased the expression of senescence marker p16ink4a (1.15 ± 0.22 vs 2.17 ± 0.37, fold change, normal diet vs HFD, p<0.05), which is involved in cell cycle arrest. This was accompanied with SASP characterized by increased expression levels of cytokines and chemokines, namely IL‐1β (1.02 ± 0.09 vs 1.35 ± 0.05, p<0.05), MCP1 (1.03 ± 0.13 vs 1.48 ± 0.05, p<0.05) and TNFα (1.04 ± 0.15 vs 1.42 ± 0.09, p<0.05) compared to controls. In addition, the number of cells positive for senescence associated β‐galactosidase activity (SA‐β‐gal) was significantly higher in the RVLM of HFD animals compared to controls. In the next series of experiments, we utilized p16‐senescence reporter mice to investigate obesity‐induced senescence in the RVLM. These mice express red fluorescent protein (RFP) under the control of p16 promoter and hence senescent cells are genetically labeled with RFP expression. HFD treatment in p16‐reporter mice resulted in significant increases in the number of RFP positive cells in the RVLM, further confirming obesity‐induced senescence in the RVLM. Collectively, our results show for the first time, evidence for obesity associated cellular senescence in the RVLM. Future studies will characterize the cellular type and investigate the mechanistic role of senescence in the RVLM in obesity‐induced sympathoexcitation.Support or Funding InformationRAC fund, CVHS, Oklahoma State UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.