HSV-1 (herpes simplex virus 1), an important human pathogen, establishes lifelong latency in neurons in trigeminal ganglia and the central nervous system. In contrast to productive infection, the only viral transcript abundantly expressed in latently infected neurons is the latency associated transcript (LAT).
The hypothalamus, one of the major regulatory centers in the brain, controls various homeostatic processes, and hypothalamic neural stem cells (htNSCs) have been observed to interfere with hypothalamic mechanisms regulating aging. NSCs play a pivotal role in the repair and regeneration of brain cells during neurodegenerative diseases and rejuvenate the brain tissue microenvironment. The hypothalamus was recently observed to be involved in neuroinflammation mediated by cellular senescence. Cellular senescence, or systemic aging, is characterized by a progressive irreversible state of cell cycle arrest that causes physiological dysregulation in the body and it is evident in many neuroinflammatory conditions, including obesity. Upregulation of neuroinflammation and oxidative stress due to senescence has the potential to alter the functioning of NSCs. Various studies have substantiated the chances of obesity inducing accelerated aging. Therefore, it is essential to explore the potential effects of htNSC dysregulation in obesity and underlying pathways to develop strategies to address obesity-induced comorbidities associated with brain aging. This review will summarize hypothalamic neurogenesis associated with obesity and prospective NSC-based regenerative therapy for the treatment of obesity-induced cardiovascular conditions.
Hypothalamus is a major regulatory center in the brain responsible for various homeostasis processes. Distinct neurons and glial cells, including microglia support the cardiovascular functions in the hypothalamus. An important cardiovascular regulatory nucleus in the hypothalamus is the Paraventricular Nucleus (PVN). Previous studies from our laboratory showed evidence for cellular senescence in the PVN. Senescence is a state of irreversible growth arrest in proliferating cells, which has been implicated in several neurodegenerative diseases. Microglia, is the resident macrophage cells of the brain that can phagocytose and initiate local inflammatory responses. Upon chronic inflammatory signaling, microglia lose its phagocytic property and enters a state of activation and proliferation. We analyzed hypothalamus from young adult mice fed with either chow (6 kcal% fat) or High Fat Diet (HFD; 60 kcal% fat) for a period of 16 weeks. Cell sorting of activated microglia using a benchtop microfluidic cell sorter revealed an increase in activated microglia in the hypothalamus after chronic HFD feeding. Microglial activation has been associated with promotion of a senescence phenotype and induction of inflammation through senescence associated secretory phenotype (SASP). To investigate this, we analyzed senescence markers in the hypothalamus. Real-time PCR revealed elevated senescent markers p53, p21 and p16, along with a significant increase (P<0.05) in SASP factors such as IL1β, MCP1 and TNFα in the HFD group compared to controls. Immunofluorescence studies confirmed the presence of senescent Iba1+ microglial cells in the PVN of HFD mice compared to their chow counterparts. Taken together, these findings suggest that senescent microglia could play a central role in the hypothalamic inflammation in HFD-induced obesity and targeting microglia will help in developing novel preventive and treatment strategy for obesity associated cardiovascular diseases. National Heart, Blood and Lung Institute grant R15HL148844; American Heart Association Institutional Research Enhancement Award – 959725. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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