Abstract 135: Cellular Senescence in the Paraventricular Nucleus - Novel Implications for Obesity-Induced Sympathoexcitation

Abstract

Oxidative stress in the paraventricular nucleus (PVN) of the hypothalamus has been implicated in the pathogenesis of 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). Previous studies from our laboratory show evidence for cellular senescence in the rostral ventrolateral medulla (RVLM) of the brainstem in obesity. Whether obesity induces senescence in the PVN, an upstream driver of the RVLM to promote neuroinflammation and increases in SNA is not clear. Hence, we hypothesized that obesity triggers the induction of cellular senescence in the PVN, 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=4) or normal chow diet (Controls;10% fat; n=4) for 16 weeks. At the end of the dietary treatment, brains were isolated from the animals for assessment of senescence markers in the PVN. Data were analyzed by unpaired students t-test and expressed as mean±SE. HFD treatment significantly increased the mRNA expression levels of senescence marker p16 ink4a (1.20±0.35 vs 3.76±0.67, fold change, normal diet vs HFD, p<0.05), which is a cyclin-dependent kinase inhibitor involved in inducing cell cycle arrest. This was accompanied with SASP characterized by increased expression levels of cytokines and chemokines, namely IL-1β (1.03±0.15 vs 1.80±0.21, p<0.05), IL-6 (1.01±0.08 vs 1.81±0.28, p<0.05), MCP1 (1.02±0.14 vs 2.45±0.09, p<0.05) and TNFα (1.09±0.11 vs 2.24±0.22, p<0.05) compared to controls. Beta-actin was used as the house keeping gene. Collectively, our results show for the first time, evidence for obesity associated cellular senescence in the PVN of the hypothalamus. In our next series of experiments, we plan to utilize p16 reporter mice to eliminate senescent cells and investigate the mechanistic role of senescence in the PVN in obesity-induced sympathoexcitation.