The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Carey N Lumeng - One of the best experts on this subject based on the ideXlab platform.
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properties and functions of Adipose Tissue Macrophages in obesity
Immunology, 2018Co-Authors: Lucia Russo, Carey N LumengAbstract:The expansion of Adipose Tissue (AT) in obesity is accompanied by the accumulation of immune cells that contribute to a state of low-grade, chronic inflammation and dysregulated metabolism. Adipose Tissue Macrophages (ATMs) represent the most abundant class of leukocytes in AT and are involved in the regulation of several regulatory physiological processes, such as Tissue remodeling and insulin sensitivity. With progressive obesity, ATMs are key mediators of meta-inflammation, insulin resistance and impairment of adipocyte function. While macrophage recruitment from blood monocytes is a critical component of the generation of AT inflammation, new studies have revealed a role for ATM proliferation in the early stages of obesity and in sustaining AT inflammation. In addition, studies have revealed a more complex range of macrophage activation states than the previous M1/M2 model, and the existence of different macrophage profiles between human and animal models. This review will summarize the current understanding of the regulatory mechanisms of ATM function in relation to obesity, type 2 diabetes, depot of origin, and to other leukocytes such as AT dendritic cells, with hopes of emphasizing the regulatory nodes that can potentially be targeted to prevent and treat obesity-related metabolic disorders.
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cd40 promotes mhc class ii expression on Adipose Tissue Macrophages and regulates Adipose Tissue cd4 t cells with obesity
PMC, 2016Co-Authors: David L Morris, Kanakadurga Singer, Kae Won Cho, Kelsie E Oatmen, Taleen Mergian, Jennifer L Delproposto, Carmella Evansmolina, Robert W Orourke, Carey N LumengAbstract:Obesity activates both innate and adaptive immune responses in Adipose Tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on Adipose Tissue Macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in Adipose Tissue Macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of conventional CD4(+) T cells (Tconv: CD3(+)CD4(+)Foxp3(-)) in visceral fat compared with wild-type mice. By contrast, the number of regulatory CD4(+) T cells (Treg: CD3(+)CD4(+)Foxp3(+)) in lean and obese fat was similar between wild-type and knockout mice. Adipose Tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on Adipose Tissue Macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity-induced insulin resistance in mice. In human Adipose Tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in Adipose Tissue Macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4(+) T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.
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flow cytometry analyses of Adipose Tissue Macrophages
PMC, 2014Co-Authors: Kae Won Cho, David L Morris, Carey N LumengAbstract:Within Adipose Tissue, multiple leukocyte interactions contribute to metabolic homeostasis in health as well as to the pathogenesis of insulin resistance with obesity. Adipose Tissue Macrophages (ATMs) are the predominant leukocyte population in fat and contribute to obesity-induced inflammation. Characterization of ATMs and other leukocytes in the stromal vascular fraction from fat has benefited from the use of flow cytometry and flow-assisted cell sorting techniques. These methods permit the immunophenotyping, quantification, and purification of these unique cell populations from multiple Adipose Tissue depots in rodents and humans. Proper isolation, quantification, and characterization of ATM phenotypes are critical for understanding their role in Adipose Tissue function and obesity-induced metabolic diseases. Here, we present the flow cytometry protocols for phenotyping ATMs in lean and obese mice employed by our laboratory.
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an mhc ii dependent activation loop between Adipose Tissue Macrophages and cd4 t cells controls obesity induced inflammation
Cell Reports, 2014Co-Authors: Kae Won Cho, David L Morris, Kanakadurga Singer, Jennifer L Delproposto, Robert W Orourke, Lynn M Geletka, Brian F Zamarron, Gabriel Martinezsantibanez, Kevin A Meyer, Carey N LumengAbstract:Summary An adaptive immune response triggered by obesity is characterized by the activation of Adipose Tissue CD4 + T cells by unclear mechanisms. We have examined whether interactions between Adipose Tissue Macrophages (ATMs) and CD4 + T cells contribute to Adipose Tissue metainflammation. Intravital microscopy identifies dynamic antigen-dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHC II) showed protection from diet-induced obesity. Deletion of MHC II expression in Macrophages led to an Adipose Tissue-specific decrease in the effector/memory CD4 + T cells, attenuation of CD11c + ATM accumulation, and improvement in glucose intolerance by increasing Adipose Tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c + ATMs in obese mice. These studies demonstrate the importance of MHCII-restricted signals from ATMs that regulate Adipose Tissue T cell maturation and metainflammation.
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Adipose Tissue Macrophages function as antigen presenting cells and regulate Adipose Tissue cd4 t cells in mice
Diabetes, 2013Co-Authors: David Morris, Kanakadurga Singer, Kelsie E Oatmen, Jennifer L Delproposto, Lynn M Geletka, Gabriel Martinezsantibanez, Kae On W Cho, Carey N LumengAbstract:The proinflammatory activation of leukocytes in Adipose Tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains Adipose Tissue inflammation remains an unresolved question. We have examined the hypothesis that Adipose Tissue Macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4+ T cells in Adipose Tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ–producing CD4+ T cells in Adipose Tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II–restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific CD4+ T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.
Rinke Stienstra - One of the best experts on this subject based on the ideXlab platform.
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the role of uncoupling protein 2 in Macrophages and its impact on obesity induced Adipose Tissue inflammation and insulin resistance
Journal of Biological Chemistry, 2020Co-Authors: Xanthe A M H Van Dierendonck, Tiphaine Sancerni, Marieclotilde Alvesguerra, Rinke StienstraAbstract:The development of a chronic, low-grade inflammation originating from Adipose Tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The Adipose Tissue microenvironment drives specific metabolic reprogramming of Adipose Tissue Macrophages, contributing to the induction of Tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in Macrophages, and is upregulated in Macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced Adipose Tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2 ΔLysM), we found that Ucp2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2 ΔLysM Macrophages and their floxed controls. Furthermore, Ucp2 ΔLysM Macrophages show attenuated pro-inflammatory responses towards Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2 ΔLysM and Ucp2 fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in Adipose Tissue inflammation or insulin resistance was found between the two genotypes, Adipose Tissue Macrophages isolated from diet-induced obese Ucp2 ΔLysM mice showed decreased TNFα secretion after ex vivo LPS stimulation compared to their Ucp2 fl/fl littermates. Together, these results demonstrate that while UCP2 regulates both metabolism and the inflammatory response of Macrophages, its activity is not crucial in shaping macrophage activation in the Adipose Tissue during obesity-induced insulin resistance.
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hilpda uncouples lipid droplet accumulation in Adipose Tissue Macrophages from inflammation and metabolic dysregulation
Social Science Research Network, 2019Co-Authors: Xanthe A M H Van Dierendonck, Montserrat A De La Rosa Rodriguez, Anastasia Georgiadi, Frits Mattijssen, Wieneke Dijk, Michel Van Weeghel, Rajat Singh, Jan Willem Borst, Rinke Stienstra, Sander KerstenAbstract:Obesity leads to a state of chronic low-grade inflammation that features accumulation of lipid-laden Macrophages in Adipose Tissue. Here, we determined the role of macrophage lipid droplet accumulation in the development of obesity-induced Adipose Tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently-labeled fatty acids. Decreased lipid storage in HILPDA-deficient Macrophages could be rescued by inhibition of Adipose triglyceride lipase (ATGL) and was associated with increased oxidative metabolism. In diet-induced obese mice, HILPDA deficiency did not alter inflammatory and metabolic parameters, despite markedly reducing lipid accumulation in Macrophages. Overall, we find that HILPDA is a lipid-induced physiological inhibitor of ATGL-mediated lipolysis in Macrophages that uncouples lipid storage in Adipose Tissue Macrophages from inflammation and metabolic dysregulation. Our data question the contribution of lipid droplet accumulation in Adipose Tissue Macrophages in obesity-induced inflammation and metabolic dysregulation.
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unique metabolic activation of Adipose Tissue Macrophages in obesity promotes inflammatory responses
Diabetologia, 2018Co-Authors: Lily Boutens, Rinke Stienstra, Guido J E J Hooiveld, Sourabh Dhingra, Robert A Cramer, Mihai G NeteaAbstract:Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory Macrophages accumulate in Adipose Tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of Adipose Tissue Macrophages (ATMs) in lean and obese conditions. F4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific Hif1α−/− mice was used to examine the role of hypoxia-inducible factor-1α (HIF-1α) in ATMs part of obese Adipose Tissue. In vitro, bone marrow-derived Macrophages were co-cultured with Adipose Tissue explants to examine Adipose Tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of Macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production. Transcriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14+ cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal Macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed Macrophages. Instead, metabolic activation of Macrophages was dose-dependently induced by a set of Adipose Tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean Adipose Tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of Macrophages in obese Adipose Tissue. HIF-1α, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity. Our results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity. Microarray data of ATMs isolated from obese or lean mice have been submitted to the Gene Expression Omnibus (accession no. GSE84000).
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Adipose Tissue Macrophages going off track during obesity
Diabetologia, 2016Co-Authors: Lily Boutens, Rinke StienstraAbstract:Inflammation originating from the Adipose Tissue is considered to be one of the main driving forces for the development of insulin resistance and type 2 diabetes in obese individuals. Although a plethora of different immune cells shapes Adipose Tissue inflammation, this review is specifically focused on the contribution of Macrophages that reside in Adipose Tissue in lean and obese conditions. Both conventional and Tissue-specific functions of Adipose Tissue Macrophages (ATMs) in lean and obese Adipose Tissue are discussed and linked with metabolic and inflammatory changes that occur during the development of obesity. Furthermore, we will address various circulating and Adipose Tissue-derived triggers that may be involved in shaping the ATM phenotype and underlie ATM function in lean and obese conditions. Finally, we will highlight how these changes affect Adipose Tissue inflammation and may be targeted for therapeutic interventions to improve insulin sensitivity in obese individuals.
Kanakadurga Singer - One of the best experts on this subject based on the ideXlab platform.
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frontline science rapid Adipose Tissue expansion triggers unique proliferation and lipid accumulation profiles in Adipose Tissue Macrophages
Journal of Leukocyte Biology, 2018Co-Authors: Lindsey A Muir, Kanakadurga Singer, Lynn M Geletka, Brian F Zamarron, Gabriel Martinezsantibanez, Samadhi Kiridena, Cameron Griffin, Jennifer B Delproposto, Hannah R Lucas, Robert W O RourkeAbstract:Obesity-related changes in Adipose Tissue leukocytes, in particular Adipose Tissue Macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white Adipose Tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3-56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation. ATMs, ATDCs, and ECs increased with rapid WAT expansion, with ATMs derived primarily from a CCR2-independent resident population. WAT expansion stimulated proliferation in resident ATMs and ECs, but not CD11c+ ATMs or ATDCs. ATM proliferation was unperturbed in Csf2- and Rag1-deficient mice with WAT expansion. Additionally, ATM apoptosis decreased with WAT expansion, and proliferation and apoptosis reverted to baseline with weight loss. Adipocytes reached maximal hypertrophy at 28 days of HFD, coinciding with a plateau in resident ATM accumulation and the appearance of lipid-laden CD11c+ ATMs in visceral epididymal WAT. ATM increases were proportional to Tissue expansion and adipocyte hypertrophy, supporting adipocyte-mediated regulation of resident ATMs. The appearance of lipid-laden CD11c+ ATMs at peak adipocyte size supports a role in responding to ectopic lipid accumulation within Adipose Tissue. In contrast, ATDCs increase independently of proliferation and may be derived from circulating precursors. These changes precede and establish the setting in which large-scale Adipose Tissue infiltration of CD11c+ ATMs, inflammation, and Adipose Tissue dysfunction contributes to insulin resistance.
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cd40 promotes mhc class ii expression on Adipose Tissue Macrophages and regulates Adipose Tissue cd4 t cells with obesity
PMC, 2016Co-Authors: David L Morris, Kanakadurga Singer, Kae Won Cho, Kelsie E Oatmen, Taleen Mergian, Jennifer L Delproposto, Carmella Evansmolina, Robert W Orourke, Carey N LumengAbstract:Obesity activates both innate and adaptive immune responses in Adipose Tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on Adipose Tissue Macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in Adipose Tissue Macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of conventional CD4(+) T cells (Tconv: CD3(+)CD4(+)Foxp3(-)) in visceral fat compared with wild-type mice. By contrast, the number of regulatory CD4(+) T cells (Treg: CD3(+)CD4(+)Foxp3(+)) in lean and obese fat was similar between wild-type and knockout mice. Adipose Tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on Adipose Tissue Macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity-induced insulin resistance in mice. In human Adipose Tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in Adipose Tissue Macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4(+) T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.
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an mhc ii dependent activation loop between Adipose Tissue Macrophages and cd4 t cells controls obesity induced inflammation
Cell Reports, 2014Co-Authors: Kae Won Cho, David L Morris, Kanakadurga Singer, Jennifer L Delproposto, Robert W Orourke, Lynn M Geletka, Brian F Zamarron, Gabriel Martinezsantibanez, Kevin A Meyer, Carey N LumengAbstract:Summary An adaptive immune response triggered by obesity is characterized by the activation of Adipose Tissue CD4 + T cells by unclear mechanisms. We have examined whether interactions between Adipose Tissue Macrophages (ATMs) and CD4 + T cells contribute to Adipose Tissue metainflammation. Intravital microscopy identifies dynamic antigen-dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHC II) showed protection from diet-induced obesity. Deletion of MHC II expression in Macrophages led to an Adipose Tissue-specific decrease in the effector/memory CD4 + T cells, attenuation of CD11c + ATM accumulation, and improvement in glucose intolerance by increasing Adipose Tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c + ATMs in obese mice. These studies demonstrate the importance of MHCII-restricted signals from ATMs that regulate Adipose Tissue T cell maturation and metainflammation.
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diet induced obesity promotes myelopoiesis in hematopoietic stem cells
Molecular metabolism, 2014Co-Authors: Kanakadurga Singer, Kae Won Cho, Taleen Mergian, Lynn M Geletka, Brian F Zamarron, David Morris, Jennifer B Delproposto, Nidhi Maley, Perla Subbaiah, Lindsey A MuirAbstract:Obesity is associated with an activated macrophage phenotype in multiple Tissues that contributes to Tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic Tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in Macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c+ Adipose Tissue Macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c+ Adipose Tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to Adipose Tissue inflammation.
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Adipose Tissue Macrophages function as antigen presenting cells and regulate Adipose Tissue cd4 t cells in mice
Diabetes, 2013Co-Authors: David Morris, Kanakadurga Singer, Kelsie E Oatmen, Jennifer L Delproposto, Lynn M Geletka, Gabriel Martinezsantibanez, Kae On W Cho, Carey N LumengAbstract:The proinflammatory activation of leukocytes in Adipose Tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains Adipose Tissue inflammation remains an unresolved question. We have examined the hypothesis that Adipose Tissue Macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4+ T cells in Adipose Tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ–producing CD4+ T cells in Adipose Tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II–restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific CD4+ T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.
Lynn M Geletka - One of the best experts on this subject based on the ideXlab platform.
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frontline science rapid Adipose Tissue expansion triggers unique proliferation and lipid accumulation profiles in Adipose Tissue Macrophages
Journal of Leukocyte Biology, 2018Co-Authors: Lindsey A Muir, Kanakadurga Singer, Lynn M Geletka, Brian F Zamarron, Gabriel Martinezsantibanez, Samadhi Kiridena, Cameron Griffin, Jennifer B Delproposto, Hannah R Lucas, Robert W O RourkeAbstract:Obesity-related changes in Adipose Tissue leukocytes, in particular Adipose Tissue Macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white Adipose Tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3-56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation. ATMs, ATDCs, and ECs increased with rapid WAT expansion, with ATMs derived primarily from a CCR2-independent resident population. WAT expansion stimulated proliferation in resident ATMs and ECs, but not CD11c+ ATMs or ATDCs. ATM proliferation was unperturbed in Csf2- and Rag1-deficient mice with WAT expansion. Additionally, ATM apoptosis decreased with WAT expansion, and proliferation and apoptosis reverted to baseline with weight loss. Adipocytes reached maximal hypertrophy at 28 days of HFD, coinciding with a plateau in resident ATM accumulation and the appearance of lipid-laden CD11c+ ATMs in visceral epididymal WAT. ATM increases were proportional to Tissue expansion and adipocyte hypertrophy, supporting adipocyte-mediated regulation of resident ATMs. The appearance of lipid-laden CD11c+ ATMs at peak adipocyte size supports a role in responding to ectopic lipid accumulation within Adipose Tissue. In contrast, ATDCs increase independently of proliferation and may be derived from circulating precursors. These changes precede and establish the setting in which large-scale Adipose Tissue infiltration of CD11c+ ATMs, inflammation, and Adipose Tissue dysfunction contributes to insulin resistance.
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an mhc ii dependent activation loop between Adipose Tissue Macrophages and cd4 t cells controls obesity induced inflammation
Cell Reports, 2014Co-Authors: Kae Won Cho, David L Morris, Kanakadurga Singer, Jennifer L Delproposto, Robert W Orourke, Lynn M Geletka, Brian F Zamarron, Gabriel Martinezsantibanez, Kevin A Meyer, Carey N LumengAbstract:Summary An adaptive immune response triggered by obesity is characterized by the activation of Adipose Tissue CD4 + T cells by unclear mechanisms. We have examined whether interactions between Adipose Tissue Macrophages (ATMs) and CD4 + T cells contribute to Adipose Tissue metainflammation. Intravital microscopy identifies dynamic antigen-dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHC II) showed protection from diet-induced obesity. Deletion of MHC II expression in Macrophages led to an Adipose Tissue-specific decrease in the effector/memory CD4 + T cells, attenuation of CD11c + ATM accumulation, and improvement in glucose intolerance by increasing Adipose Tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c + ATMs in obese mice. These studies demonstrate the importance of MHCII-restricted signals from ATMs that regulate Adipose Tissue T cell maturation and metainflammation.
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diet induced obesity promotes myelopoiesis in hematopoietic stem cells
Molecular metabolism, 2014Co-Authors: Kanakadurga Singer, Kae Won Cho, Taleen Mergian, Lynn M Geletka, Brian F Zamarron, David Morris, Jennifer B Delproposto, Nidhi Maley, Perla Subbaiah, Lindsey A MuirAbstract:Obesity is associated with an activated macrophage phenotype in multiple Tissues that contributes to Tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic Tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in Macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c+ Adipose Tissue Macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c+ Adipose Tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to Adipose Tissue inflammation.
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Adipose Tissue Macrophages function as antigen presenting cells and regulate Adipose Tissue cd4 t cells in mice
Diabetes, 2013Co-Authors: David Morris, Kanakadurga Singer, Kelsie E Oatmen, Jennifer L Delproposto, Lynn M Geletka, Gabriel Martinezsantibanez, Kae On W Cho, Carey N LumengAbstract:The proinflammatory activation of leukocytes in Adipose Tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains Adipose Tissue inflammation remains an unresolved question. We have examined the hypothesis that Adipose Tissue Macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4+ T cells in Adipose Tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ–producing CD4+ T cells in Adipose Tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II–restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific CD4+ T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.
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the protein kinase ikkepsilon regulates energy balance in obese mice
Cell, 2009Co-Authors: Shian Huey Chiang, Carey N Lumeng, Lynn M Geletka, Merlijn Bazuine, Jonathan Mowers, Nicole M A White, Jing Tyan, Jie Zhou, Daniel J WestcottAbstract:Summary Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here, we show that high-fat diet can increase NF-κB activation in mice, which leads to a sustained elevation in level of IκB kinase ɛ (IKKɛ) in liver, adipocytes, and Adipose Tissue Macrophages. IKKɛ knockout mice are protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKɛ knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKɛ may represent an attractive therapeutic target for obesity, insulin resistance, diabetes, and other complications associated with these disorders.
Jongsoon Lee - One of the best experts on this subject based on the ideXlab platform.
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Adipose Tissue Macrophages in the development of obesity-induced inflammation, insulin resistance and type 2 Diabetes
Archives of Pharmacal Research, 2013Co-Authors: Jongsoon LeeAbstract:It has been increasingly accepted that chronic subacute inflammation plays an important role in the development of insulin resistance and type 2 Diabetes in animals and humans. Particularly supporting this is that suppression of systemic inflammation in type 2 Diabetes improves glycemic control; this also points to a new potential therapeutic target for the treatment of type 2 Diabetes. Recent studies strongly suggest that obesity-induced inflammation is mainly mediated by Tissue resident immune cells, with particular attention being focused on Adipose Tissue Macrophages (ATMs). This review delineates the current progress made in understanding obesity-induced inflammation and the roles ATMs play in this process.
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inflammation and Adipose Tissue Macrophages in lipodystrophic mice
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Laura Herrero, Hagit Shapiro, Ali Nayer, Jongsoon Lee, Steven E ShoelsonAbstract:Lipodystrophy and obesity are opposites in terms of a deficiency versus excess of Adipose Tissue mass, yet these conditions are accompanied by similar metabolic consequences, including insulin resistance, dyslipidemia, hepatic steatosis, and increased risk for diabetes and atherosclerosis. Hepatic and myocellular steatosis likely contribute to metabolic dysregulation in both states. Inflammation and macrophage infiltration into Adipose Tissue also appear to participate in the pathogenesis of obesity-induced insulin resistance, but their contributions to lipodystrophy-induced insulin resistance have not been evaluated. We used aP2-nSREBP-1c transgenic (Tg) mice, an established model of lipodystrophy, to ask this question. Circulating cytokine elevations suggested systemic inflammation but even more dramatic was the number of infiltrating Macrophages in all white and brown Adipose Tissue depots of the Tg mice; in contrast, there was no evidence of inflammatory infiltrates or responses in any other Tissue including liver. Despite there being overt evidence of Adipose Tissue inflammation, antiinflammatory strategies including salicylate treatment and genetic suppression of myeloid NF-κB signaling that correct insulin resistance in obesity were ineffective in the lipodystrophic mice. We further showed that Adipose Tissue Macrophages (ATMs) in lipodystrophy and obesity are very different in terms of activation state, gene expression patterns, and response to lipopolysaccharide. Although ATMs are even more abundant in lipodystrophy than in obesity, they have distinct phenotypes and likely roles in Tissue remodeling, but do not appear to be involved in the pathogenesis of insulin resistance.