RESUMEN
Well known functions of adipose tissue include energy storage, regulation of thermogenesis, and glucose homeostasis-each of which are associated with the metabolic functions of fat. However, adipose tissues also have important immune functions. In this issue of Immunological Reviews, we present a series of articles that highlight the immune functions of adipose tissue, including the roles of specialized adipose-resident immune cells and fat-associated lymphoid structures. Importantly, immune cell functions in adipose tissues are often linked to the metabolic functions of adipocytes and vice versa. These reciprocal interactions and how they influence both immune and metabolic functions will be discussed in each article. In the first article, Wang et al.,11 discuss adipose-associated macrophages and how obesity and metabolism impact their phenotype and function. Several articles in this issue discuss T cells as either contributors to, or regulators of, inflammatory responses in adipose tissues. Valentine and Nikolajczyk12 provide insights into the role of T cells in obesity-associated inflammation and their contribution to metabolic dysfunction, whereas an article from Kallies and Vasanthakumar13 and another from Elkins and Li14 describe adipose-associated Tregs and how they help prevent inflammation and maintain metabolic homeostasis. Articles from Okabe35 as well as from Daley and Benezech15 discuss the structure and function of fat-associated lymphoid clusters (FALCs) that are prevalent in some adipose tissues and support local immune responses to pathogens, gut-derived microbes and fat-associated antigens. Finally, an article from Meher and McNamara16 describes how innate-like B1 cells in adipose tissues regulate cardiometabolic disease. Importantly, these articles highlight the physical and functional attributes of adipose tissues that are different between mice and humans, the metabolic and immune differences between various adipose depots in the body and the differences in immune cells, adipose tissues and metabolic functions between the sexes. At the end of this preface, we highlight how these differences are critically important for our understanding of anti-tumor immunity to cancers that metastasize to a specific example of visceral adipose tissue, the omentum. Together, these articles identify some unanswered mechanistic questions that will be important to address for a better understanding of immunity in adipose tissues.
Asunto(s)
Tejido Adiposo , Obesidad , Humanos , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Animales , Obesidad/inmunología , Obesidad/metabolismo , Homeostasis , Inflamación/inmunología , Macrófagos/inmunología , Adipocitos/inmunología , Adipocitos/metabolismo , Metabolismo Energético , InmunidadRESUMEN
UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).
Asunto(s)
Tejido Adiposo , Inflamación , Enfermedades Metabólicas , Obesidad , Humanos , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Obesidad/inmunología , Obesidad/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiología , Metabolismo Energético/fisiología , Adipocitos/metabolismo , Adipocitos/inmunología , Metabolismo de los Lípidos/fisiología , Animales , HomeostasisRESUMEN
White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.
Asunto(s)
Tejido Adiposo Blanco , Metabolismo Energético , Macrófagos , Obesidad , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/inmunología , Animales , Obesidad/inmunología , Obesidad/metabolismo , Adipocitos/metabolismo , Adipocitos/inmunología , HomeostasisRESUMEN
Metabolic syndrome poses a great worldwide threat to the health of the patients. Increased visceral adiposity is recognized as the main determinant of the detrimental clinical effects of insulin resistance. Inflammation and immune system activation in the adipose tissue (AT) have a central role in the pathophysiology of metabolic syndrome, but the mechanisms linking increased adiposity to immunity in the AT remain in part elusive. In this review, we support the central role of adipocyte overload and relative adipose failure as key determinants in triggering immune aggression to AT. This provides a mechanistic explanation of the relative metabolic wellness of metabolically normal obese people and the disruption in insulin signaling in metabolically obese lean people.
Asunto(s)
Adipocitos , Tejido Adiposo , Autoinmunidad , Humanos , Adipocitos/inmunología , Adipocitos/metabolismo , Autoinmunidad/inmunología , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Animales , Síndrome Metabólico/inmunología , Síndrome Metabólico/metabolismo , Resistencia a la Insulina/inmunología , Adiposidad/inmunologíaRESUMEN
Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1ß (IL-1ß). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1ß was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.
Asunto(s)
Adipocitos , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Inflamación , Lactato Deshidrogenasa 5 , Ácido Láctico , Macrófagos , Adipocitos/inmunología , Tejido Adiposo/inmunología , Animales , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Resistencia a la Insulina/genética , Resistencia a la Insulina/inmunología , Resistencia a la Insulina/fisiología , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/inmunología , Lactato Deshidrogenasa 5/genética , Lactato Deshidrogenasa 5/inmunología , Ácido Láctico/inmunología , Macrófagos/inmunología , Ratones , Obesidad/genética , Obesidad/inmunología , Obesidad/patología , Procolágeno-Prolina Dioxigenasa/genética , Procolágeno-Prolina Dioxigenasa/inmunología , Prolil HidroxilasasRESUMEN
OBJECTIVE: Obesity is a recognized risk factor for the progression to severe forms of COVID-19, yet the mechanisms of the association are unclear. METHODS: Subcutaneous abdominal adipose tissue specimens of subjects deceased from COVID-19 (n = 23) were compared to those of controls dying abruptly from causes other than infectious (accidental trauma, sudden cardiac death). Alterations of lung parenchyma consistent with moderate to severe disease were detected in all COVID-19 cases, not in controls. Investigations included: histopathologic features, detection of virus antigens and genome, characterization of infiltrating leukocytes, transcription levels of immune-related genes. RESULTS: By RT-PCR, the SARS-CoV-2 genome was detected in the adipose tissue of 13/23 (56%) cases of the COVID-19 cohort. The virus nucleocapsid antigen was detected in the cytoplasm of 1-5% adipocytes in 12/12 COVID-19 cases that were virus-positive by PCR in the adipose tissue (one case could not be assessed due insufficient tissue). The adipose tissue of COVID-19 cases showed leukocyte infiltrates and upregulation of the interferon-alpha pathway. After adjusting for age and sex, the activation score of IFN-alpha was directly related with transcription levels of the ACE2 gene, a key entry factor of SARS-CoV-2. CONCLUSIONS: In lethal COVID-19 cases, the SARS-CoV-2 nucleocapsid antigen has been detected in a sizeable proportion of adipocytes, showing that the virus may directly infect the parenchymal cells of subcutaneous fat. Infection appears to activate the IFN alpha pathway and to attract infiltrating leukocytes. Due to the huge numbers of adipocytes in adults, the adipose tissue represents a significant reservoir for SARS-CoV-2 and an important source of inflammatory mediators.
Asunto(s)
Adipocitos , Tejido Adiposo , COVID-19 , Interferón-alfa , SARS-CoV-2 , Adipocitos/inmunología , Tejido Adiposo/inmunología , Adulto , COVID-19/diagnóstico , COVID-19/inmunología , COVID-19/virología , Humanos , Interferón-alfa/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificaciónRESUMEN
Chronic local inflammation of adipose tissue is an important feature of obesity. Serglycin is a proteoglycan highly expressed by various immune cell types known to infiltrate adipose tissue under obese conditions. To investigate if serglycin expression has an impact on diet-induced adipose tissue inflammation, we subjected Srgn +/+ and Srgn -/- mice (C57BL/6J genetic background) to an 8-wk high-fat and high-sucrose diet. The total body weight was the same in Srgn +/+ and Srgn -/- mice after diet treatment. Expression of white adipose tissue genes linked to inflammatory pathways were lower in Srgn -/- mice. We also noted reduced total macrophage abundance, a reduced proportion of proinflammatory M1 macrophages, and reduced formation of crown-like structures in adipose tissue of Srgn -/- compared with Srgn +/+ mice. Further, Srgn -/- mice had more medium-sized adipocytes and fewer large adipocytes. Differentiation of preadipocytes into adipocytes (3T3-L1) was accompanied by reduced Srgn mRNA expression. In line with this, analysis of single-cell RNA sequencing data from mouse and human adipose tissue supports that Srgn mRNA is predominantly expressed by various immune cells, with low expression in adipocytes. Srgn mRNA expression was higher in obese compared with lean humans and mice, accompanied by an increased expression of immune cell gene markers. SRGN and inflammatory marker mRNA expression was reduced upon substantial weight loss in patients after bariatric surgery. Taken together, this study introduces a role for serglycin in the regulation of obesity-induced adipose inflammation.
Asunto(s)
Adipocitos/inmunología , Inflamación/metabolismo , Macrófagos/inmunología , Obesidad/metabolismo , Proteoglicanos/metabolismo , ARN Mensajero/genética , Proteínas de Transporte Vesicular/metabolismo , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/inmunología , Proteoglicanos/genética , Proteínas de Transporte Vesicular/genética , Pérdida de Peso/inmunologíaRESUMEN
PURPOSE: Subjects with obesity may exhibit an increase in serum TSH concentrations. Several mechanisms have been proposed to explain this association, including the presence of a compensatory mechanism to counterbalance an accelerated turnover of thyroid hormones in subjects with obesity. This study aimed at evaluating whether the thyroids of subjects with obesity differs from those of normal-weight individuals regarding histology and gene expression profiling. METHODS: Ninety-eight patients were selected among those scheduled for thyroidectomy. At histology, thyroid tissue samples were investigated for the presence of adipocytes and/or lymphocyte infiltration. In a subset of patients, the expression at mRNA level of several genes involved in metabolic pathways and immune cell-related mechanisms was quantified by NanoString Technology. RESULTS: The presence of adipose cells was documented in thyroid specimens from 40% normal weight, 52.9% overweight and 73.5% patients with obesity. The number of infiltrating adipocytes was greater in specimens of patients with overweight or obesity compared to normal weight. The lymphocytes common antigen (CD45) and mast cell (MC) scores, and the number of CD3+ and CD8+ lymphocytes were higher in patients with overweight and obesity than in normal-weight subjects. Several genes involved in metabolic pathways were differently expressed in patients with overweight or obesity compared to normal weight, with upregulation of Leptin receptor and downregulation of Fatty Acid-Binding Protein 5. CONCLUSIONS: Increased BMI is associated with adipocyte and lymphocyte infiltration of the thyroid, not related to an autoimmune process, which might affect thyroid function in subjects with obesity. A differential gene expression profiling of metabolic and immune pathways in thyroid tissues of patients with obesity was also observed.
Asunto(s)
Proteínas de Unión a Ácidos Grasos/análisis , Obesidad , Receptores de Leptina/análisis , Subgrupos de Linfocitos T , Glándula Tiroides , Hormonas Tiroideas/metabolismo , Adipocitos/inmunología , Adipocitos/patología , Índice de Masa Corporal , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Inmunidad Celular , Masculino , Redes y Vías Metabólicas , Persona de Mediana Edad , Obesidad/diagnóstico , Obesidad/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Glándula Tiroides/metabolismo , Glándula Tiroides/patologíaRESUMEN
Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.
Asunto(s)
Interleucina-6/metabolismo , Metabolismo de los Lípidos/inmunología , Hígado/metabolismo , Músculos/metabolismo , Receptores de Interleucina-6/metabolismo , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Hígado/inmunología , Ratones , Músculos/inmunología , Transducción de Señal/inmunologíaRESUMEN
Epidemiological studies inversely associate BMI with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the 'local' environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI = 27 kg/m2) and obese (mean BMI = 44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory, and estrogen synthetic genes than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21 than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.
Asunto(s)
Tejido Adiposo/metabolismo , Mama/metabolismo , Epitelio/metabolismo , Interleucina-10/metabolismo , Fenotipo , Premenopausia/metabolismo , Adipocitos/inmunología , Adipocitos/metabolismo , Adiposidad , Adulto , Biomarcadores , Mama/patología , Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Citocinas/genética , Citocinas/metabolismo , Femenino , Expresión Génica , Hormonas Esteroides Gonadales/sangre , Hormonas Esteroides Gonadales/metabolismo , Humanos , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Obesidad/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Telómero/genética , Telómero/metabolismo , Adulto JovenRESUMEN
Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNF[alpha], MIP (macrophage inflammatory protein)-1[alpha], MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.
Asunto(s)
Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Linfocitos/metabolismo , Obesidad/metabolismo , Paniculitis/metabolismo , Factor 5 Asociado a Receptor de TNF/deficiencia , Adipocitos/inmunología , Adipocitos/patología , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Adiposidad , Adulto , Anciano , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Femenino , Humanos , Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Obesidad/genética , Obesidad/inmunología , Obesidad/patología , Paniculitis/genética , Paniculitis/inmunología , Paniculitis/patología , Transducción de Señal , Factor 5 Asociado a Receptor de TNF/genéticaRESUMEN
The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.
Asunto(s)
Inmunidad Adaptativa/inmunología , Adipocitos/inmunología , Tejido Adiposo/inmunología , Inmunidad Innata/inmunología , Obesidad/inmunología , Adipocitos/citología , Adipocitos/metabolismo , Adipoquinas/inmunología , Adipoquinas/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue-resident macrophages, controls lipid storage in adipocytes in a leptin receptor- and C-C chemokine receptor type 2-independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans.
Asunto(s)
Adipocitos/inmunología , Dieta Alta en Grasa , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Linfocinas/metabolismo , Macrófagos/inmunología , Obesidad/inmunología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Termogénesis , Tejido Adiposo Pardo/inmunología , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster , Femenino , Hemocitos/inmunología , Hígado/inmunología , Linfocinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Crecimiento Derivado de Plaquetas/genética , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The anti-inflammatory adipokine CTRP-3 might affect innate immune reactions such as NOD1. The impact of CTRP-3 on NOD1-mediated inflammation in adipocytes and monocytic cells as well as on NOD1 expression was investigated. Murine 3T3-L1 pre-adipocytes and adipocytes as well as human THP-1 monocyte-like cells were co-stimulated with the synthetic NOD1 agonist Tri-DAP and recombinant CTRP-3. Gonadal adipose tissue and primary adipocytes were obtained from a murine model carrying a knockout (KO) of CTRP-3 in adipocytes but not in stroma-vascular cells. Wildtype mice with lipopolysaccharide (LPS)-induced elevated NOD1 expression were treated with CTRP-3. Secreted inflammatory cytokines in cell supernatants were measured by ELISA and mRNA levels were quantified by RT-PCR. Pro-inflammatory chemokine and cytokine secretion (MCP-1, RANTES, TNFα) was induced by NOD1 activation in adipocytes and monocyte-like cells, and MCP-1 and RANTES release was effectively inhibited by pre-incubation of cells with CTRP-3. CTRP-3 also antagonized LPS-triggered induction of NOD1 gene expression in murine adipose tissue, whereas adipocyte CTRP-3 deficiency upregulated NOD1 expression in adipose tissue. CTRP-3 is an effective antagonist of peptidoglycan-induced, NOD1-mediated inflammation and of LPS-induced NOD1 expression. Since basal NOD1 expression is increased by adipocyte CTRP-3 deficiency, there have to be also inflammation-independent mechanisms of NOD1 expression regulation by CTRP-3.
Asunto(s)
Adipocitos/metabolismo , Adipoquinas/metabolismo , Grasa Intraabdominal/metabolismo , Proteína Adaptadora de Señalización NOD1/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Células 3T3-L1 , Adipocitos/inmunología , Adipoquinas/genética , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Mediadores de Inflamación/metabolismo , Grasa Intraabdominal/inmunología , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Adaptadora de Señalización NOD1/genética , Transducción de Señal , Grasa Subcutánea/inmunología , Grasa Subcutánea/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Células THP-1RESUMEN
Adipose tissue is comprised of heterogenous cell populations that regulate both energy metabolism and immune reactions. Macrophages play critical roles in regulating immunometabolic homeostasis or disorders through cooperation with adipocytes, adipose tissue-derived stem cells (ADSCs) or other cells in adipose tissue. Extracellular vesicles (EVs) are recently recognized as efficient messengers for intercellular communication. Emerging evidences have demonstrated that adipose EVs are actively involved in the mutual interactions of macrophages, adipocytes and ADSCs, which produce considerable influences on immunometabolism under healthy or obese conditions. Here, we will elaborate the production and the characteristics of adipose EVs that are related to macrophages under different metabolic demands or stresses, whilst discuss the roles of these EVs in regulating local or systemic immunometabolic homeostasis or disorders in the context of adipocyte-macrophage dialogue and ADSC-macrophage interaction. Particularly, we provide a profile of dynamic adipose microenvironments based on macrophages. Adipose EVs act as the messengers between ADSCs and macrophages to maintain the balance of metabolism and immunity, while drive a vicious cycle between hypertrophic adipocytes and inflammatory macrophages to cause immunometabolic imbalance. This review may provide valuable information about the physio- or pathological roles of adipose EVs and the application of adipose EVs in the diagnosis and treatment of metabolic diseases.
Asunto(s)
Tejido Adiposo/inmunología , Vesículas Extracelulares/inmunología , Homeostasis/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Adipocitos/citología , Adipocitos/inmunología , Tejido Adiposo/citología , Comunicación Celular , Humanos , Macrófagos/citología , Obesidad/patología , Transducción de Señal , Células Madre/citología , Células Madre/inmunologíaRESUMEN
Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.
Asunto(s)
Adipocitos/metabolismo , Neoplasias de la Mama/metabolismo , Transducción de Señal , Adipocitos/inmunología , Adipocitos/patología , Adipoquinas/inmunología , Adipoquinas/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Humanos , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/metabolismoRESUMEN
White adipose tissue (WAT) is an essential regulator of energy storage and systemic metabolic homeostasis. Regulatory networks consisting of immune and structural cells are necessary to maintain WAT metabolism, which can become impaired during obesity in mammals. Using single-cell transcriptomics and flow cytometry, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of healthy lean and obese human WAT. We report new subsets and developmental trajectories of adipose-resident innate lymphoid cells, dendritic cells and monocyte-derived macrophage populations that accumulate in obese WAT. Analysis of cell-cell ligand-receptor interactions and obesity-enriched signaling pathways revealed a switch from immunoregulatory mechanisms in lean WAT to inflammatory networks in obese WAT. These results provide a detailed and unbiased cellular landscape of homeostatic and inflammatory circuits in healthy human WAT.
Asunto(s)
Inmunidad Innata , Obesidad/inmunología , Grasa Subcutánea Abdominal/inmunología , Abdominoplastia , Adipocitos/inmunología , Adipocitos/metabolismo , Adulto , Comunicación Celular/inmunología , Línea Celular , Células Dendríticas Foliculares/inmunología , Células Dendríticas Foliculares/metabolismo , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Linfocitos/inmunología , Linfocitos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Obesidad/patología , Obesidad/cirugía , RNA-Seq , Transducción de Señal/inmunología , Análisis de la Célula Individual , Grasa Subcutánea Abdominal/patología , Grasa Subcutánea Abdominal/cirugíaRESUMEN
To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-κB pathway in human adipose tissue. The circadian clock function is impaired in omental fat from obese patients. ChIP-seq analyses reveal that the core clock activator, BMAL1 binds to several thousand target genes. NF-κB competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-κB consensus motifs. Obesity relocalizes BMAL1 occupancy genome-wide in human omental fat, thereby altering the transcription of numerous target genes involved in metabolic inflammation and adipose tissue remodeling. Eventually, clock dysfunction appears at early stages of obesity in mice and is corrected, together with impaired metabolism, by NF-κB inhibition. Collectively, our results reveal a relationship between NF-κB and the molecular clock in adipose tissue, which may contribute to obesity-related complications.
Asunto(s)
Factores de Transcripción ARNTL/metabolismo , Relojes Circadianos/inmunología , Grasa Intraabdominal/patología , FN-kappa B/metabolismo , Obesidad/complicaciones , Adipocitos/inmunología , Adipocitos/metabolismo , Adiponectina/genética , Adulto , Animales , Biopsia , Estudios de Casos y Controles , Células Cultivadas , Secuenciación de Inmunoprecipitación de Cromatina , Relojes Circadianos/genética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Inflamación/inmunología , Inflamación/patología , Grasa Intraabdominal/inmunología , Masculino , Células Madre Mesenquimatosas , Ratones Transgénicos , Persona de Mediana Edad , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patología , Epiplón/inmunología , Epiplón/patología , Proteínas Circadianas Period/genética , Cultivo Primario de Células , Transcripción GenéticaRESUMEN
In our previous study, we constructed Schwann cells (SCs) that stably express Simian virus 40 T antigen (SV40T-SCs). SV40T-SCs functions and markers are similar to those of neural crest cells. There we used bone morphogenetic protein 9 (BMP9) to induce SV40T-SCs differentiation in vitro and in vivo and study possible related mechanism. SV40T-SCs differentiation was induced by BMP9 conditioned medium. The lipogenic differentiation of SV40T-SCs was assessed by Oil Red O staining. Alizarin red and Alcian blue staining, and alkaline phosphatase (ALP) assays were used to evaluate the SV40T-SCs osteogenic differentiation. The expression of adipocyte differentiation (c/EBPα and c/EBPß) and osteoblast differentiation markers (OSX and RUNX2) were detected by quantitative polymerase chain reaction (qPCR). To study possible mechanism related to SV40T-SCs differentiation, the P53 and E2F1 activity were assessed by luciferase reporter plasmid, and Slug and E-cadherin expression by qPCR. In vivo, SV40T-SCs infected by Ad-BMP9 or Ad-GFP were injected under the skin of nude mice. After 4-6 W, the mice were euthanized and subcutaneously mass formed at injecting sites was collected for pathological analysis. After SV40T-SCs were cultured in BMP9 conditioned medium, lipid droplets were formed in the cytoplasm of these cells. Alizarin red and Alcian blue staining were positive, and ALP activity of SV40T-SCs increased significantly. The expression of adipocyte differentiation (c/EBPα and c/EBPß) and osteoblast differentiation markers (OSX and RUNX2) in SV40T-SCs was upregulated by BMP9. SV40T significantly increased Slug expression and decreased E-cadherin expression. SV40T-SCs infected with Ad-BMP9 were able to differentiate into adipose tissue and form a small bone matrix under the nude mice skin. SV40T-SCs have the ability to differentiate into adipocytes and osteoblasts in vivo and in vitro. SV40T can upregulate the Slug expression and downregulate the E-cadherin expression to produce endothelial-to-mesenchymal transition (EMT). The multidirectional differentiation ability of SV40T-SCs may be related to EMT.
Asunto(s)
Adipocitos/citología , Antígenos Virales de Tumores/inmunología , Factor 2 de Diferenciación de Crecimiento/metabolismo , Osteoblastos/citología , Osteogénesis , Células de Schwann/citología , Virus 40 de los Simios/inmunología , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Antígenos Virales de Tumores/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Desnudos , Osteoblastos/inmunología , Osteoblastos/metabolismo , Células de Schwann/inmunología , Células de Schwann/metabolismo , Virus 40 de los Simios/metabolismoRESUMEN
In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized. We studied the contribution of adipose tissue to uremic inflammation in-vitro, in-vivo and in human samples. Exposure to uremic serum resulted in activation of inflammatory pathways including NFκB and HIF1, upregulation of inflammatory cytokines/chemokines and catabolism with lipolysis, and lactate production. Also, co-culture of adipocytes with macrophages primed by uremic serum resulted in higher inflammatory cytokine expression than adipocytes exposed only to uremic serum. Adipose tissue of end stage renal disease subjects revealed increased macrophage infiltration compared to controls after BMI stratification. Similarly, mice with kidney disease recapitulated the inflammatory state observed in uremic patients and additionally demonstrated increased peripheral monocytes and inflammatory polarization of adipose tissue macrophages (ATMS). In contrast, adipose tissue in uremic IL-6 knock out mice showed reduced ATMS density compared to uremic wild-type controls. Differences in ATMS density highlight the necessary role of IL-6 in macrophage infiltration in uremia. Uremia promotes changes in adipocytes and macrophages enhancing production of inflammatory cytokines. We demonstrate an interaction between uremic activated macrophages and adipose tissue that augments inflammation in uremia.