The immune cells in adipose tissue.
TL;DR: The modulation of immune cell populations in adipose tissue is reviewed and regulatory processes implicated in controlling the interface between metabolism and immunologic function are discussed.
Abstract: Although the pathological role of the immune system in several metabolic disorders, including type 1 diabetes mellitus (T1DM) and Addison's disease, has long been recognized and studied, only in the last decade has it become apparent that the immune system plays a broad and more subtle role in local and systemic metabolism. It is now apparent that the immune system monitors and responds to specific metabolic cues in both pathologic and non-pathologic settings through a set of processes dubbed immunometabolism. Expansion of adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering thermogenesis all lead to the recruitment and activation of immune cells in key metabolic tissues. The responses are complex and not completely defined, and indeed, as is typical of rapidly evolving research areas, there are some conflicting reports, especially related to the metabolic consequences of manipulation of immune function. However, what is clear is the consensus that metabolic processes, especially obesity and obesity-related complications, activate both the innate and adaptive arms of the immune system. Canonical immune processes consist of discrete steps: surveillance, recognition, effector action and resolution. Over the last decade evidence for each part of the immune response has been found at the intersection of the immune system with metabolism. Although evidence for immune surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus and pancreas, immune cell function has been most intensively studied and best understood in adipose tissue where studies continue to provide insights into the intersection of the metabolic and immune systems. Here we review the modulation of immune cell populations in adipose tissue and discuss regulatory processes implicated in controlling the interface between metabolism and immunologic function.
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TL;DR: This review has focused on the various subsets of immune cells in AT and their role in the development of AT inflammation and obesity-induced insulin resistance.
Abstract: Adipose tissue (AT) lies at the crossroad of nutrition, metabolism, and immunity; AT inflammation was proposed as a central mechanism connecting obesity with its metabolic and vascular complications. Resident immune cells constitute the second largest AT cellular component after adipocytes and as such play important roles in the maintenance of AT homeostasis. Obesity-induced changes in their number and activity result in the activation of local and later systemic inflammatory response, marking the transition from simple adiposity to diseases such as type 2 diabetes mellitus, arterial hypertension, and ischemic heart disease. This review has focused on the various subsets of immune cells in AT and their role in the development of AT inflammation and obesity-induced insulin resistance.
438 citations
Cites background from "The immune cells in adipose tissue...."
...%) of all AT immune cells (Ferrante 2013)....
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TL;DR: This condition is proposed to be defined as "obese sarcopenia", to reflect the direction of the pathological pathway, and it is believed that AT inflammation dominates over skeletal muscle inflammation.
417 citations
Cites background from "The immune cells in adipose tissue...."
...…recently mainly in the context of its emergent and significant role in both local and systemic homeostasis, especially in the development of inflammaging, IR and T2DM (Febbraio, 2014; Ferrante, 2013; Osborn and Olefsky, 2012; Smitka and Marešová, 2015; Tsai et al., 2015a; Wensveen et al., 2015)....
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TL;DR: An overview of the impact that obesity and MetS parameters have on immune system function is presented, including the disruption of lymphoid tissue integrity; alterations in leukocyte development, phenotypes, and activity; and the coordination of innate and adaptive immune responses.
416 citations
Cites background from "The immune cells in adipose tissue...."
...50% of all cell types within the hypertrophic obese adipose tissue of mice and humans (79, 80), often taking on a proinflammatory phenotype (53, 81)....
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TL;DR: How adipose tissue becomes inflamed in obesity is described and key players and molecular mechanisms involved in adipose inflammation are summarized.
Abstract: Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation.
345 citations
Cites background from "The immune cells in adipose tissue...."
...This observation prompted an increased interest in the interplay between immune cells and metabolism and subsequently, different works revealed a growing list of multiple immune cell types including lymphocytes, eosinophils, neutrophils, mast cells and foam cells infiltrating the adipose tissue.(36) The initiating immune event remains unclear, but several studies suggest the infiltration of neutrophils,(37) others propose decreased number of T regulatory cells,(38) and others implicate rapid changes in the polarization of macrophages....
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TL;DR: Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved.
321 citations
References
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TL;DR: Transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob) found that the expression of 1,304 transcripts correlated significantly with body mass.
Abstract: Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.
8,902 citations
"The immune cells in adipose tissue...." refers background in this paper
...Adipose tissue macrophages (ATMs), originally identified in murine fat depots by the expression of the macrophage protein, F4/80 (EMR1), are the most abundant immune cell in adipose tissue, representing more than half of leucocytes in depots from lean and obese animals [1]....
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...In lean mice and humans, macrophages constitute ∼5% of cells in adipose tissue depots, but in the most obese rodents and humans macrophages make up as much as 50% of the cells in a depot [1,3]....
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...In lean individuals, ATMs are small and interspersed among adipocytes, but with the onset of obesity they aggregate and accumulate lipid, and some form multinucleated cells [1,11,12]....
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...The first direct evidence for a coherent immunometabolic system came from studies of adipose tissue in mice that varied in adiposity [1,2]....
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TL;DR: It is proposed that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue, and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.
Abstract: Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue
6,165 citations
"The immune cells in adipose tissue...." refers background in this paper
...The first direct evidence for a coherent immunometabolic system came from studies of adipose tissue in mice that varied in adiposity [1,2]....
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TL;DR: Diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
Abstract: Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
4,046 citations
"The immune cells in adipose tissue...." refers background in this paper
...The first antigenically distinct subpopulation identified was the ATMs that express the integrin CD11c/ITGAX [7,8]....
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TL;DR: It is suggested that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
Abstract: TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
3,301 citations
"The immune cells in adipose tissue...." refers background in this paper
...Indeed, toll-like receptors can bind saturated fatty acids and activate macrophage cell lines and bone marrow derived cells [42]....
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Book•
01 Jan 2007
TL;DR: The Evolution of the Immune System Appendix I Immunologists' Toolbox Appendix II CD Antigens Appendix III Cytokines and their Receptors Appendix IV Chemokinesand their Receptionors Appendix V Immunological Constants.
Abstract: Part I An Introduction to Immunobiology and Innate Immunity 1. Basic Concepts in Immunology 2. Innate Immunity Part II The Recognition of Antigen 3. Antigen Recognition by B-cell and T-cell Receptors 4. The Generation of Lymphocyte Antigen Receptors 5. Antigen Presentation to T Lymphocytes Part III The Development of Mature Lymphocyte Receptor Repertoires 6. Signaling Through Immune System Receptors 7. The Development and Survival of Lymphocytes Part IV The Adaptive Immune Response 8. T Cell-Mediated Immunity 9. The Humoral Immune Response 10. Dynamics of Adaptive Immunity 11. The Mucosal Immune System Part V The Immune System in Health and Disease 12. Failures of Host Defense Mechanism 13. Allergy and Hypersensitivity 14. Autoimmunity and Transplantation 15. Manipulation of the Immune Response Part VI The Origins of Immune Responses 16. Evolution of the Immune System Appendix I Immunologists' Toolbox Appendix II CD Antigens Appendix III Cytokines and their Receptors Appendix IV Chemokines and their Receptors Appendix V Immunological Constants
2,250 citations
"The immune cells in adipose tissue...." refers background in this paper
...In each of these diseases a breakdown in immune tolerance leads to a T-cell driven process that largely targets a specific cell or tissue [36]....
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