Microglia Senescence Mediates Inflammation in the Hypothalamus of High-Fat Diet Induced Obese Mice

Abstract

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.