Lymphocytes In Adipose Tissue Research Articles

B-1 lymphocytes in adipose tissue as innate modulators of inflammation linked to cardiometabolic disease.

Fat is stored in distinct depots with unique features in both mice and humans and B cells reside in all adipose depots. We have shown that B cells modulate cardiometabolic disease through activities in two of these key adipose depots: visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT). VAT refers to the adipose tissue surrounding organs, within the abdomen and thorax, and is comprised predominantly of white adipocytes. This depot has been implicated in mediating obesity-related dysmetabolism. PVAT refers to adipose tissue surrounding major arteries. It had long been thought to exist to provide protection and insulation for the vessel, yet recent work demonstrates an important role for PVAT in harboring immune cells, promoting their function and regulating the biology of the underlying vessel. The role of B-2 cells and adaptive immunity in adipose tissue biology has been nicely reviewed elsewhere. Given that, the predominance of B-1 cells in adipose tissue at homeostasis, and the emerging role of B-1 cells in a variety of disease states, we will focus this review on how B-1 cells function in VAT and PVAT depots to promote homeostasis and limit inflammation linked to cardiometabolic disease and factors that regulate this function.

Wnt10b knockdown regulates the relative balance of adipose tissue-resident T cells and inhibits white fat deposition.

Wnt10b is one of critical Wnt family members that being involved in networks controlling stemness, pluripotency and cell fate decisions. However, its role in adipose-resident T lymphocytes and further in fat metabolism yet remains largely unknown. In the present study, we demonstrated a distinctive effect for Wnt10b on the relative balance of T lymphocytes in adipose tissue by using a Wnt10b knockdown mouse model. Wnt10b knockdown led to a reduction of adipose-resident CD4+ T cells and an elevation of Foxp3+/CD4+ Treg cells. Wnt10b-knockdown mice fed with standard diet showed less white fat deposition owing to the suppressed adipogenic process. Moreover, under high fat diet conditions, Wnt10b knockdown resulted in an alleviated obesity symptoms, as well as an improvement of glucose homeostasis and hepatic steatosis. Collectively, we reveal an unexpected and novel function for Wnt10b in mediating the frequency of adipose-resident T cell subsets, that when knockdown skewing toward a Treg-dominated phenotype and further improving fat metabolism.

Adipose tissue lymphocytes and obesity.

Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.

Subclinical Inflammation and Adipose Tissue Lymphocytes in Pregnant Females With Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is accompanied by subclinical inflammation; however, little is known about local inflammation in adipose tissue and placenta. To analyze systemic and local subclinical inflammation and adipose tissue lymphocyte content and phenotype in pregnant women with and without GDM. Observational study. Academic hospital. Twenty-one pregnant women with GDM (GDM group), 16 pregnant women without GDM (non-GDM group) and 15 nonpregnant control women (N group). Serum samples taken at 28 to 32 (visit 1 [V1]) and 36 to 38 (V2) gestational weeks and 6 to 12 months after delivery (V3) in the GDM and non-GDM group and before elective gynecological surgery in the N group. Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained during cesarean delivery or surgery. Serum levels and adipose tissue expression of proinflammatory cytokines, adipose tissue lymphocyte content and phenotype (for a subset of GDM and non-GDM subjects). Accented proinflammatory state in GDM was documented by increased circulating tumor necrosis factor-α (TNF-α) levels. In both groups of pregnant females total lymphocytes were higher in VAT compared to SAT. In GDM subjects B cells and NKT cells were higher in SAT compared to VAT and T helper cells were increased relative to SAT of non-GDM group, while no intercompartmental adipose tissue differences were seen in non-GDM women. Pregnant females had higher total lymphocyte count in VAT relative to SAT regardless of GDM. In addition to increased systemic subclinical inflammation, GDM was associated with significant differences in lymphocyte composition between subcutaneous and visceral adipose tissue depots.

Oleacein Prevents High Fat Diet-Induced Adiposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice.

Oleacein is one of the most abundant polyphenolic compounds of olive oil, which has been shown to play a protective role against several metabolic abnormalities, including dyslipidemia, insulin resistance, and glucose intolerance. Herein, we investigated the effects of oleacein on certain markers of adipogenesis and insulin-resistance in vitro, in 3T3-L1 adipocytes, and in vivo in high-fat diet (HFD)-fed mice. During the differentiation process of 3T3-L1 preadipocytes into adipocytes, oleacein strongly inhibited lipid accumulation, and decreased protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS), while increasing Adiponectin levels. In vivo, treatment with oleacein of C57BL/6JOlaHsd mice fed with HFD for 5 and 13 weeks prevented the increase in adipocyte size and reduced the inflammatory infiltration of macrophages and lymphocytes in adipose tissue. These effects were accompanied by changes in the expression of adipose tissue-specific regulatory elements such as PPARγ, FAS, sterol regulatory element-binding transcription factor-1 (SREBP-1), and Adiponectin, while the expression of insulin-sensitive muscle/fat glucose transporter Glut-4 was restored in HFD-fed mice treated with oleacein. Collectively, our findings indicate that protection against HFD-induced adiposity by oleacein in mice is mediated by the modulation of regulators of adipogenesis. Protection against HFD-induced obesity is effective in improving peripheral insulin sensitivity.

Coronary Artery Disease Is Associated with an Increased Amount of T Lymphocytes in Human Epicardial Adipose Tissue.

Immunocompetent cells including lymphocytes play a key role in the development of adipose tissue inflammation and obesity-related cardiovascular complications. The aim of the study was to explore the relationship between epicardial adipose tissue lymphocytes and coronary artery disease (CAD). To this end, we studied the content and phenotype of lymphocytes in peripheral blood, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT) in subjects with and without CAD undergoing elective cardiac surgery. Eleven subjects without CAD (non-CAD group) and 22 age-, BMI-, and HbA1C-matched individuals with CAD were included into the study. Blood, SAT, and EAT samples were obtained at the beginning of surgery. Lymphocyte populations were quantified as % of CD45+ cells using flow cytometry. Subjects with CAD had a higher total lymphocyte amount in EAT compared with SAT (32.24 ± 7.45 vs. 11.22 ± 1.34%, p = 0.025) with a similar trend observed in non-CAD subjects (29.68 ± 7.61 vs. 10.13 ± 2.01%, p = 0.067). T (CD3+) cells were increased (75.33 ± 2.18 vs. 65.24 ± 4.49%, p = 0.032) and CD3- cells decreased (21.17 ± 2.26 vs. 31.64 ± 4.40%, p = 0.028) in EAT of CAD relative to the non-CAD group. In both groups, EAT showed an elevated percentage of B cells (5.22 ± 2.43 vs. 0.96 ± 0.21%, p = 0.039 for CAD and 12.49 ± 5.83 vs. 1.16 ± 0.19%, p = 0.016 for non-CAD) and reduced natural killer (NK) cells (5.96 ± 1.32 vs. 13.22 ± 2.10%, p = 0.012 for CAD and 5.32 ± 1.97 vs. 13.81 ± 2.72%, p = 0.022 for non-CAD) relative to SAT. In conclusion, epicardial adipose tissue in subjects with CAD shows an increased amount of T lymphocytes relative to non-CAD individuals as well as a higher number of total and B lymphocytes and reduced NK cells as compared with corresponding SAT. These changes could contribute to the development of local inflammation and coronary atherosclerosis.

The Role of Epicardial Adipose Tissue Lymphocytes in Low-Grade Inflammation and Coronary Artery Disease

Lymphocytes play a role in the development of adipose tissue inflammation. Epicardial adipose tissue was shown to be a potential source of inflammatory mediators contributing to coronary atherosclerosis. The aim of the study was to assess lymphocyte content in peripheral blood, subcutaneous (SAT) and epicardial adipose tissue (EAT) in subjects with coronary artery disease (CAD) along with the effects of elective cardiac surgery. Twelve subjects without CAD (non-CAD group) and 24 age-, BMI- and HbA1C-matched subjects with CAD were included into the study. Blood, SAT and EAT samples were obtained before and at the end of elective cardiac surgery. Lymphocyte populations were quantified as percent of CD45+ cells using flow cytometry. Subjects with CAD had higher total lymphocyte (CD45+) amount in EAT compared to SAT (32.24±7.45 vs. 11.22±1.34%, p=0.025) with a similar trend observed in non-CAD subjects (29.68±7.61 vs. 10.13±2.01%, p=0.067). CD3+ cells were increased and CD3- cells decreased in EAT of CAD relative to non-CAD group with no difference between EAT and SAT. In both groups EAT showed reduced percentage of NK cells (CD15/56+CD3-) and elevated B cells (CD19+) relative to SAT (NK cells: 5.96±1.32 vs. 13.22±2.10%, p=0.012 for CAD and 5.32±1.97 vs. 13.81±2.72%, p=0.022 for non-CAD; B cells: 5.22±2.43 vs. 0.96±0.21%, p=0.039 for CAD and 12.49±5.83 vs. 1.16±0.19%, p=0.016 for non-CAD). CD8+ and NKT (CD16/56+CD3+) cells in EAT correlated positively with fasting glucose and HbA1C, while showing no association in SAT. Cardiac surgery decreased total lymphocytes in peripheral blood, SAT and EAT of both groups, while having only minor effects on lymphocyte subpopulations. To conclude, epicardial adipose tissue in subjects with CAD shows increased amount of total and CD3+ lymphocytes as compared with SAT or non-CAD subjects. These changes could contribute to the development of local inflammation and coronary atherosclerosis. Disclosure M. Mraz: None. A. Cinkajzlova: None. Z. Lacinov : None. J. Klouckova: None. H. Kratochvilova: None. M. Lips: None. P. Kopecky: None. M. Porizka: None. J. Lindner: None. M. Haluzik: None.

Inflammatory Pathways Regulated by Tumor Necrosis Receptor-Associated Factor 1 Protect From Metabolic Consequences in Diet-Induced Obesity.

The coincidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism. We have revisited the relationship between inflammation and metabolism by testing the role of TRAF (tumor necrosis receptor-associated factor)-1, an inhibitory adapter of inflammatory signaling of TNF (tumor necrosis factor)-α, IL (interleukin)-1β, and TLRs (toll-like receptors). Mice deficient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyperinflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated proinflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity. Unexpectedly, TRAF-1-/- mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance-an effect caused by increased lipid breakdown in adipocytes and UCP (uncoupling protein)-1-enabled thermogenesis. TRAF-1-dependent catabolic and proinflammatory cues were synergistically driven by β3-adrenergic and inflammatory signaling and required the presence of both TRAF-1-deficient adipocytes and macrophages. In human obesity, TRAF-1-dependent genes were upregulated. Enhancing TRAF-1-dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in diet-induced obesity. These findings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism.

Lymphocytes in atherosclerosis.

Atherosclerosis is the major cause of cardiovascular disease, and cardiovascular disease remains the primary cause of death in the United States. The primary complication for patients with type 2 diabetes mellitus (T2D) is cardiovascular disease.1–8 Because the incidences of T2D and obesity are drastically increasing in the United States and now worldwide, understanding how atherosclerosis is accelerated in these diseases becomes even more important to discern. Although many scientific advances in research on atherosclerosis have been made by multiple groups during the past 30 years, particularly about the function of endothelial and smooth muscle biology and macrophage foam cell formation in atherosclerotic plaque development, the roles of immune cells in regulating atherosclerosis onset and progression are still being elucidated. It was widely thought that immune cells played little part in atherogenesis until 1986, when Hansson et al9–12 reported the presence of lymphocytes within atherosclerotic lesions; yet it was many years later until it was widely accepted that immune cells play an important role in atherogenesis. Since 1986, the viewpoint has changed significantly, but details on lymphocyte subsets and mechanisms are still emerging. Moreover, controversy still exists on the roles that some lymphocyte subsets play in atherosclerosis. These discrepancies in findings are at least partly because of differences in mouse models used, diet composition, and length of time on diet for atherosclerosis measurements. However, despite a few ongoing controversies, there are many studies on immune cells in atherogenesis in mice that show clear findings.10,12–23 For example, CD4+ T lymphocytes have been shown to accelerate atherosclerosis.18,24–29 Activated CD4 T cells can be distinguished based on their phenotype, and the predominant CD4+ effector T cells studied to date in the context of atherosclerosis are Th1, …

The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance

Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis.

Erratum to: Adipose tissue lymphocytes: types and roles

Erratum to: Adipose tissue lymphocytes: types and roles

Adipose tissue lymphocytes: types and roles

Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development.

Interplay Between Human Adipocytes and T Lymphocytes in Obesity

Adipose tissue (AT) plays a major role in the low-grade inflammatory state associated with obesity. The aim of the present study was to characterize the human AT lymphocytes (ATLs) and to analyze their interactions with adipocytes. Human ATL subsets were characterized by flow cytometry in subcutaneous ATs from 92 individuals with body mass index (BMI) ranging from 19 to 43 kg/m(2) and in paired biopsies of subcutaneous and visceral AT from 45 class II/III obese patients. CD3(+) ATLs were composed of effector and memory CD4(+) helper and CD8(+) cytotoxic T cells. The number of ATLs correlated positively with BMI and was higher in visceral than subcutaneous AT. Mature adipocytes stimulated the migration of ATLs and released the chemokine CCL20, the receptor of which (CCR6) was expressed in ATLs. The expression of adipocyte CCL20 was positively correlated with BMI and increased in visceral compared to subcutaneous adipocytes. ATLs expressed inflammatory markers and released interferon gamma (IFN gamma). Progenitor and adipocyte treatment with ATL-conditioned media reduced the insulin-mediated upregulation of lipogenic enzymes, an effect involving IFN gamma. Therefore, crosstalk occurs between adipocytes and lymphocytes within human AT involving T cell chemoattraction by adipocytes and modulation of lipogenesis by ATLs.

Adipose Tissue Lymphocytes and Macrophages in Obesity and Insulin Resistance

Obesity, and more specifically accumulation of adipose tissue in the visceral and subcutaneous abdominal locations, is a major risk factor for the development of cardiovascular pathologies including hypertension and atherosclerosis, as well as metabolic disorders such as type 2 diabetes. During recent years, “metaflammation” or metabolically-triggered inflammation1 has emerged as a key process involved in the clustering of those conditions. Although several metabolically active organs such as the liver, muscle, and, recently, the intestine2 certainly play major roles, the white adipose tissue appears as a central and primary player as both a source and site of inflammation. Accumulation of adipose tissue macrophages (ATMs) has been well-described in obese conditions in mice and humans.3–5 Moreover, the ATM proinflammatory phenotype has been linked to the development of insulin resistance in mice,4 although the exact nature of the proinflammatory myeloid cells, ie, macrophages or dentritic cells, remains to be determined.6 Nevertheless, the causal link between inflammation and insulin resistance was further strengthened by the specific knock-out of the inflammation coordinator IkappaB kinase beta of myeloid cells, which gave protection against insulin resistance.7 The study of Kintscher and al in this issue8 extends those original observations to cells of adaptative immunity. The authors suggest that the accumulation of T-lymphocytes, assessed mainly through gene expression analyses and immunohistochemistry, occurs in the perigonadal adipose tissue of mice on …

Abstract 3592: Early Detection Of CD4-positive Lymphocytes In Adipose Tissue During The Development Of Insulin Resistance

Background: Adipose tissue inflammation may play a critical role in the pathogenesis of insulin resistance (IR) and arteriosclerosis. Previous work has mainly focused on the role of macrophages in human adipose tissue, but little is known about pro-inflammatory T-lymphocytes. Therefore the present study examined the role of CD4-positive lymphocytes in adipose tissue inflammation and IR. Results: Both, CD4-positive lymphocytes and macrophages are present in human visceral adipose tissue as determined by immunohistochemical staining. Most macrophages were HLA-DR positive, reflecting activation through IFNγ, a cytokine released from CD4-positive lymphocytes. Furthermore, SDF-1α, a T-cell chemotactic protein, was also detectable in human adipose tissue. RT-PCR analyses confirmed the expression of IFNγ and SDF1α in visceral adipose tissue. Freshly isolated human adipocytes as well SGBS adipocyte cells express SDF-1α with a down regulation of its expression during adipocyte differentiation in both cell types. In a mouse model of IR, high fat diet induced IR already after 5 weeks which was associated with a marked lymphocyte infiltration in visceral adipose tissue as determined by immunohistochemical staining and RT-PCR. In contrast, macrophages were absent after 5 weeks of diet but could be detected at week 10, suggesting early infiltration of lymphocytes during the development of IR. Conclusion: Pro-inflammatory T-lymphocytes are present in visceral adipose tissue and may contribute to local inflammatory cell activation before the appearance of macrophages. These data suggest that lymphocytes may play an important role in the initiation and perpetuation of adipose tissue inflammation as well as the development of insulin resistance.