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Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity.

ABSTRACT: Obesity is a growing global concern in adults and youth with a parallel rise in associated complications, including cognitive impairment. Obesity induces brain inflammation and activates microglia, which contribute to cognitive impairment by aberrantly phagocytosing synaptic spines. Local and systemic signals, such as inflammatory cytokines and metabolites likely participate in obesity-induced microglial activation. However, the precise mechanisms mediating microglial activation during obesity remain incompletely understood. Herein, we leveraged our mouse model of high-fat diet (HFD)-induced obesity, which mirrors human obesity, and develops hippocampal-dependent cognitive impairment. We assessed hippocampal microglial activation by morphological and single-cell transcriptomic analysis to evaluate this heterogeneous, functionally diverse, and dynamic class of cells over time after 1 and 3 months of HFD. HFD altered cell-to-cell communication, particularly immune modulation and cellular adhesion signaling, and induced a differential gene expression signature of protein processing in the endoplasmic reticulum in a time-dependent manner.

SUBMITTER: Henn RE

PROVIDER: S-EPMC10006681 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity.

Henn Rosemary E RE Guo Kai K Elzinga Sarah E SE Noureldein Mohamed H MH Mendelson Faye E FE Hayes John M JM Rigan Diana M DM Savelieff Masha G MG Hur Junguk J Feldman Eva L EL

iScience 20230208 3

Obesity is a growing global concern in adults and youth with a parallel rise in associated complications, including cognitive impairment. Obesity induces brain inflammation and activates microglia, which contribute to cognitive impairment by aberrantly phagocytosing synaptic spines. Local and systemic signals, such as inflammatory cytokines and metabolites likely participate in obesity-induced microglial activation. However, the precise mechanisms mediating microglial activation during obesity r ...[more]

PMID: 36915697

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Project description:Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.

Project description:Background: Disturbance of immunometabolic signaling is a key process involved in the progression of obesity. Microglia-the resident immune cells in the brain, initiate local immune responses. It is known that hypercaloric diets lead to microglial activation. Previously, we observed that hypothalamic microglial cells from mice fed high-fat diet (HFD) lose their day/night rhythm and are constantly activated. However, little is known about daily rhythmicity in microglial circadian, immune and metabolic functions, either in lean or obese conditions. Therefore, we hypothesized that HFD disturbs microglial immunometabolism in a day/night-dependent manner. Methods: Obesity was induced in Wistar rats by feeding them HFD ad libitum for the duration of 8 weeks. Microglia were isolated from HFD- and chow-fed control animals at six time points during 24 h [every 4 h starting 2 h after lights on, i.e., Zeitgeber Time 2 (ZT2)]. Gene expression was evaluated using quantitative RT-PCR. JTK_Cycle software was used to estimate daily rhythmicity. Statistical analysis was performed with two-way ANOVA test. Results: Consumption of the obesogenic diet resulted in a 40 g significantly higher body weight gain in week 8, compared to chow diet (p < 0.0001), associated with increased adiposity. We observed significant rhythmicity of circadian clock genes in microglia under chow conditions, which was partially lost in diet-induced obesity (DIO). Microglial immune gene expression also showed time-of-day differences, which were disrupted in HFD-fed animals. Microglia responded to the obesogenic conditions by a shift of substrate utilization with decreased glutamate and glucose metabolism in the active period of the animals, and an overall increase of lipid metabolism, as indicated by gene expression evaluation. Additionally, data on mitochondria bioenergetics and dynamics suggested an increased energy production in microglia during the inactive period on HFD. Finally, evaluation of monocyte functional gene expression showed small or absent effect of HFD on peripheral myeloid cells, suggesting a cell-specific microglial inflammatory response in DIO. Conclusions: An obesogenic diet affects microglial immunometabolism in a time-of-day dependent manner. Given the central role of the brain in energy metabolism, a better knowledge of daily rhythms in microglial immunometabolism could lead to a better understanding of the pathogenesis of obesity.

Project description:BackgroundSince the emergence of COVID-19 at the end of 2019, the disease has led to widespread acute respiratory distress syndrome (ARDS), particularly among kidney transplant recipients (KTRs), who are at increased risk due to long-term immunosuppressive therapy. This study aims to explore the differences in immune responses between kidney transplant recipients and non-kidney transplant recipients in COVID-19-induced ARDS to identify potential therapeutic targets for improving outcomes. Single-cell RNA sequencing was performed on 108,320 cells derived from peripheral blood samples to construct a global single-cell map of COVID-19 induced ARDS in kidney transplant recipients(ARDSKT), COVID-19 induced ARDS in non transplant recipients(ARDSNKT), and healthy controls. Subsequently, using cellular clustering analysis, we obtained single-cell maps of different cell types. We employed enrichment analysis to determine the pathways involved in different subpopulations and focused on the role of key immune cells such as monocytes, megakaryocytes, B cells, and CD8+ T cells in the pathogenesis of ARDS. Significant immune differences were observed between ARDSKT and ARDSNKT. In ARDSKT, the S100A9+ MK subpopulation, which activates the NF-κB signaling pathway, was elevated, promoting inflammation. In contrast, the S100A12+ monocyte subpopulation that activates the chemokine signaling pathway was more abundant in ARDSNKT, reflecting a stronger inflammatory response, while its abundance was reduced in ARDSKT due to immunosuppression. The CXCR4+ B subpopulation, crucial for adaptive immunity, was significantly reduced in ARDSKT. Additionally, the XAF1+ Teff subpopulation, associated with apoptosis, was more abundant in ARDSKT, potentially impairing immune recovery. This study highlights the immune differences between ARDSKT and ARDSNKT, revealing the impact of immunosuppression on immune dysregulation. These findings suggest that targeting specific immune pathways can improve therapeutic strategies for ARDSKT.

Dataset Information

Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity.

Publications

Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity.

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