Obesity disrupts innate-adaptive immune network patterning in adipose tissue
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PROVIDER: PRJNA813399 | ENA |
REPOSITORIES: ENA
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Project description:Obesity drives significant changes in adipose tissue that precede development of tissue and systemic insulin resistance. Immune cell infiltration and inflammation are known contributors to these changes but there is limited understanding of their spatial context tissue-wide. We sought to identify spatial patterning in epididymal adipose tissue immune cells in a time course of diet-induced obesity in mice. Using spatial transcriptomics and single-cell RNA-sequencing, we identified dominant cell type signatures preserved in their anatomical context, quantified gene expression patterns at spots throughout adipose tissue, performed cell type network analysis, and investigated ligand-receptor colocalization. Our data support increased innate immune cells, including macrophages, monocytes, and innate lymphoid cells, with tissue-wide interspersion and dampened adaptive immune cell signatures with obesity. Network analysis identified increased heterogeneity in all major immune cell types, consistent with increased subtypes. To capture tissue dynamics at obesity onset, we draw on mathematical principles from linear algebra and spectral graph theory. We provide a framework for better understanding cell cooperation toward emergence of multicellular tissue function. Further, we adapt Turing's mathematical theory on morphogenesis to show lapse of emergence in adipose tissue.
2022-03-10 | GSE198012 | GEO
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Project description:Adult pancreatic β cells are refractory to proliferation, a roadblock for the treatment of insulin-deficient diabetes. Consumption of energy-dense Western or high-fat diet (HFD) triggers mild adaptive β cell mass expansion to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. Here we show that Toll-like receptors (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged islet mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and CDK4 in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.
2019-03-21 | GSE101392 | GEO
Project description:Three innate (B1-B, NKT, CD8aaT cells) and adaptive (B2-B, CD4T, CD8abT cells) cell-types were sorted by FACS. Three biological replicates for NKT, CD4T, CD8aaT, CD8abT cells and two biological replicates for B1 and B2 cells were generated and the expression profiles were determined using Affymetrix Mu74Av2 chip. Comparisons between the sample groups allow the identification of genes differentially expressed between the innate and adaptive cell-types. Keywords: cell type comparison, innate vs. adaptive
2006-01-31 | GSE3039 | GEO
Project description:Purpose: Interferon regulatory factor 3 (IRF3) is activated by pro-inflammatory cytokines, but its role in regulating adaptive thermogenesis and energy expenditure remains unclear. Here, we report that IRF3 as a negative transcription regulator of adaptive thermogenesis. Adipocyte-specific IRF3 knockout (FI3KO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that IRF3 suppresses adaptive thermogenesis through ISG15-mediated inhibition of glycolysis in adipocytes. Conversely, overexpression of IRF3 in adipocytes causes reduced thermogenesis gene expression, energy expenditure, and more persistent to HFD-induced obesity. Moreover, Isg15-/- increases adipose thermogenesis and protects mice from HFD-induced obesity and glucose intolerance. Taken together, these data indicate that IRF3 as a transcriptional regulator connecting between inflammatory signaling pathway and energy homeostasis Methods: primary adipocyte mRNA profiles of 8-week-old wild-type (WT) and FI3OE mice were generated by deep sequencing. The sequence reads that passed quality filters were analyzed at the transcript isoform level. qRT–PCR validation was performed using RT-PCR. Conclusions: Our study represents the first detailed analysis of adipocyte transcriptomes from WT and FI3OE iWAT, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that Irf3 adipocyte-speficic overrxpression markedly increases the expression of Isg15 and Herc6, which play important role in regulation of glycolysis.
2020-07-24 | GSE155019 | GEO
Project description: Not available
| S-EPMC4552860 | biostudies-literature
Project description:Drugs used to treat obesity and type 2 diabetes have limited efficacy in directly normalising muscle metabolism. The discovery of molecules mediating exercise adaptations, and drugs that modulate their activity, is a potential strategy to address this therapeutic gap. Here we show that genetic impairment of HDAC4 and 5 in mice regulated a subset of exercise responsive genes involved in metabolism and increased cell autonomous energy expenditure. Screening of HDAC inhibitors identified Scriptaid as a compound that also replicated aspects of the exercise adaptive response in vitro and in vivo. Treatment of obese mice with Scriptaid increased exercise performance, restored muscle insulin sensitivity and reduced muscle lipids. Scriptaid also increased oxygen consumption and normalised cardiac structure and function in obese mice. These data show that HDAC inhibition replicates aspects of the exercise adaptive response and that pharmacological HDAC inhibition could deliver more efficacious treatment to combat the metabolic diseases. Four-condition experiment, Empty, HDACs, Vehicle and Script-HDACs with five biological replicates for each condition. One replicate per array.
2015-01-28 | E-GEOD-54642 | biostudies-arrayexpress
Project description:Bone fractures, the most common musculoskeletal injuries, heal through three main phases: inflammatory, repair, and remodeling. Around 10% of fracture patients suffer from impaired healing that requires surgical intervention, a huge burden on the healthcare system. The rate of impaired healing increases with metabolic diseases such as obesity-associated hyperglycemia/type 2 diabetes (T2D), an increasing concern given the growing incidence of obesity/T2D. Immune cells play pivotal roles in fracture healing, and obesity/T2D is associated with defective immune-cell functions. However, there is a gap in knowledge regarding the stoichiometry of immune cells that populate the callus and how that population changes during different phases of healing. Here, we used complementary global and single-cell techniques to characterize the repertoire of immune cells in the fracture callus and to identify populations specifically enriched in the fracture callus relative to the unfractured bone or bone marrow. Our analyses identified two clear waves of immune-cell infiltration into the callus: the first wave occurs during the early inflammatory phase of fracture healing, while the second takes place during the late repair/early remodeling phase. Innate immune cells were activated during the early inflammatory phase, but in later phases they returned to homeostatic numbers and activation levels. Of the innate immune cells, distinct subsets of activated dendritic cells were particularly enriched in the inflammatory healing hematoma. In contrast to innate cells, lymphocytes, including B and T cells, were enriched and activated in the callus primarily during the late repair phase. The Diet-Induced Obesity (DIO) mouse, an established model of obesity-associated hyperglycemia and insulin resistance, suffers from multiple healing defects. Our data demonstrate that DIO mice exhibit dysregulated innate immune responses during the inflammatory phase, and defects in all lymphocyte compartments during the late repair phase. Taken together, our data characterize, for the first time, immune populations that are enriched/activated in the callus during two distinct phases of fracture healing and identify defects in the healing-associated immune response in DIO mice, which will facilitate future development of immunomodulatory therapeutics for impaired fracture healing.
2023-09-01 | GSE240390 | GEO