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1.
Genes Dev ; 33(23-24): 1657-1672, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727774

RESUMO

In obesity, adipose tissue undergoes dynamic remodeling processes such as adipocyte hypertrophy, hypoxia, immune responses, and adipocyte death. However, whether and how invariant natural killer T (iNKT) cells contribute to adipose tissue remodeling are elusive. In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese adipose tissue, iNKT cells were abundantly found nearby dead adipocytes. FasL-positive adipose iNKT cells exerted cytotoxic effects to eliminate hypertrophic and pro-inflammatory Fas-positive adipocytes. Furthermore, in vivo adipocyte-lineage tracing mice model showed that activation of iNKT cells by alpha-galactosylceramide promoted adipocyte turnover, eventually leading to potentiation of the insulin-dependent glucose uptake ability in adipose tissue. Collectively, our data propose a novel role of adipose iNKT cells in the regulation of adipocyte turnover in obesity.


Assuntos
Adipócitos/citologia , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Morte Celular/fisiologia , Ativação Linfocitária/fisiologia , Células T Matadoras Naturais/fisiologia , Obesidade/fisiopatologia , Células 3T3 , Adipócitos/imunologia , Adipócitos/metabolismo , Animais , Proliferação de Células , Proteína Ligante Fas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor fas/metabolismo
2.
J Biomed Sci ; 26(1): 62, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31470850

RESUMO

BACKGROUND: Loss of ovarian function, as in menopause or after ovariectomy (OVX), is closely associated with obesity and white adipose tissue (WAT) inflammation. Estrogen replacement protects against postmenopausal obesity but increases the risks of carcinogenesis. In the present study, we investigated the effects of long-term treatment of raloxifene (RAL), a selective estrogen receptor modulator, on the features of estrogen deficiency-induced obesity and explored the involvement of canonical and non-canonical Wnt regulation in vivo and in vitro. METHODS: Adult female rats received bilateral OVX and divided into 5 groups: (1) Sham, (2) OVX, (3) OVX + E2: OVX rats were administered with E2 (50 µg/kg, s.c., 3 times/week), (4) OVX + RAL: OVX rats were treated with RAL (gavage, 1 mg/kg/day) suspended in 0.8% carboxymethylcellulose (CMC), (5) OVX + CMC: 0.8% CMC as vehicle control. All treatments were given for 8 weeks beginning at 1 week after OVX. In 3 T3-L1 cells, the effects of RAL on adipogenesis and lipopolysaccharide (LPS)-induced inflammation were evaluated. RESULTS: Treatment with RAL significantly decreased body weight, visceral fat pad mass, adipocyte size and plasma levels of glucose but increased plasma adiponectin. RAL reduced the elevation of HIF-1α, VEGF-A and proinflammatory cytokines (MCP-1 and TNF-α) expression by inhibition of NF-κB p65 and JNK cascades in retroperitoneal WAT. This anti-inflammatory capacity of RAL may result from upregulation of secreted frizzle-related protein 5 (SFRP5), an adipokine that repressed Wnt5a signaling. Furthermore, RAL inhibited adipogenic factors such as PPAR-γ, C/EBP-α, and FABP4, and preserved canonical Wnt10b/ß-catenin protein expression. In 3 T3-L1 adipocytes, RAL (20 µM) diminished lipid accumulation and inhibited adipogenic factors accompanied with the induction of ß-catenin, which were effectively reversed by the ß-catenin inhibitor IWR-1-endo. In addition, RAL reduced LPS-induced NF-κB p65 and p-IκB expression as well as TNF-α secretion. Suppression of SFRP5 by small interfering RNA significantly abrogated the anti-inflammatory effects of RAL. CONCLUSIONS: Distinct activation of canonical ß-catenin on inhibition of adipogenesis and non-canonical SFRP5 on suppression of WAT inflammation may contribute to the beneficial effects of RAL. Therefore, this study provides a rationale for the therapeutic potential of RAL for postmenopausal obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Inflamação/induzido quimicamente , Cloridrato de Raloxifeno/farmacologia , Receptores Estrogênicos/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Proteínas Wnt/genética , Células 3T3-L1 , Tecido Adiposo/imunologia , Animais , Feminino , Regulação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Camundongos , Ovariectomia , Ratos , Ratos Wistar , Proteínas Wnt/metabolismo , Proteína Wnt1
3.
Nat Commun ; 10(1): 3650, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409776

RESUMO

The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA+ immune cells and that IgA is a critical immune regulator of glucose homeostasis. Obese mice have fewer IgA+ immune cells and less secretory IgA and IgA-promoting immune mediators. HFD-fed IgA-deficient mice have dysfunctional glucose metabolism, a phenotype that can be recapitulated by adoptive transfer of intestinal-associated pan-B cells. Mechanistically, IgA is a crucial link that controls intestinal and adipose tissue inflammation, intestinal permeability, microbial encroachment and the composition of the intestinal microbiome during HFD. Current glucose-lowering therapies, including metformin, affect intestinal-related IgA+ B cell populations in mice, while bariatric surgery regimen alters the level of fecal secretory IgA in humans. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease.


Assuntos
Imunoglobulina A/imunologia , Resistência à Insulina , Obesidade/imunologia , Tecido Adiposo/imunologia , Animais , Linfócitos B/imunologia , Estudos de Coortes , Fezes/microbiologia , Microbioma Gastrointestinal , Glucose/metabolismo , Humanos , Intestinos/imunologia , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/microbiologia
4.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443389

RESUMO

Alcohol exerts significant immunomodulatory effects on innate and adaptive immune responses, impairing host defense against infections. Gut-mucosa-derived dendritic cells (DCs) traffic to mesenteric lymph nodes (MLNs) through mesenteric lymphatic vessels (MLVs), contributing to intestinal antigen homeostasis. Previously, we demonstrated that acute alcohol administration to male rats induces MLV hyperpermeability resulting in perilymphatic adipose tissue (PLAT) inflammation and insulin signaling dysregulation. We hypothesized that alcohol-induced MLV hyperpermeability can lead to DC leakage to PLAT. DCs promote adipose tissue regulatory T cell (Treg) expansion, and this has been proposed as a mechanism underlying age-associated insulin resistance (IR). The aim of this study was to determine whether chronic alcohol consumption promotes DC leakage to PLAT and results in metabolic dysregulation. Male rats received a Lieber-DeCarli liquid diet containing 36% of calories from alcohol for 10 weeks. Time-matched control animals were pair-fed. PLAT, MLNs, and peripheral blood leukocytes (PBLs) were isolated for flow cytometry analyses. PLAT explants were used for determinations of insulin-induced glucose uptake. Chronic alcohol consumption decreased MLN CD4/CD8 ratio and Treg frequency in PBLs. Alcohol increased the frequency of DCs, CD4 T cells, and Tregs in PLAT. Lastly, alcohol decreased insulin-stimulated glucose uptake in PLAT. Collectively, these findings suggest that alcohol-induced immune cell deviation from the gut-MLN pathway is associated with PLAT immunometabolic dysregulation. Whether this immune cell deviation impacts induction of mucosal immunity warrants further investigation.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Etanol/farmacologia , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Consumo de Bebidas Alcoólicas , Animais , Relação CD4-CD8 , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Ratos , Circulação Esplâncnica , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Genet Epidemiol ; 43(8): 1018-1029, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31433079

RESUMO

Obesity is understood to be an inflammatory condition characterized in part by changes in resident immune cell populations in adipose tissue. However, much of this knowledge has been obtained through experimental animal models. Epigenetic mechanisms, such as DNA methylation may be useful tools for characterizing the changes in immune cell populations in human subjects. In this study, we introduce a simple and intuitive method for assessing cellular infiltration by blood into other heterogeneous, admixed tissues such as adipose tissue, and apply this approach in a large human cohort study. Associations between higher leukocyte infiltration, measured by evaluating a distance measure between the methylation signatures of leukocytes and adipose tissue, and increasing body mass index (BMI) or android fat mass (AFM) were identified and validated in independent replication samples for CD4 (pBMI = 0.009, pAFM = 0.020), monocytes (pBMI = 0.001, pAFM = 4.3 × 10-4 ), and dendritic cells (pBMI = 0.571, pAFM = 0.012). Patterns of depletion with increasing adiposity were observed for plasma B (pBMI = 0.430, pAFM = 0.004) and immature B (pBMI = 0.022, pAFM = 0.042) cells. CD4, dendritic, monocytes, immature B, and plasma B cells may be important agents in the inflammatory process. Finally, the method used to assess leukocyte infiltration in this study is straightforwardly extended to other cell types and tissues in which infiltration might be of interest.


Assuntos
Tecido Adiposo/citologia , Metilação de DNA , Leucócitos/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Adiposidade , Adulto , Animais , Linfócitos B/metabolismo , Índice de Massa Corporal , Movimento Celular , Estudos de Coortes , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Obesidade/imunologia
6.
Physiol Rev ; 99(4): 1701-1763, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339053

RESUMO

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.


Assuntos
Tecido Adiposo/fisiopatologia , Pressão Sanguínea , Diabetes Mellitus/fisiopatologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Adipocinas/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Adiposidade , Animais , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Hipertensão/epidemiologia , Hipertensão/imunologia , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Obesidade/epidemiologia , Obesidade/imunologia , Obesidade/metabolismo , Fenótipo , Medição de Risco , Fatores de Risco , Transdução de Sinais , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia
7.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357412

RESUMO

Obesity is considered to significantly increase the risk of the development of a vast range of metabolic diseases. However, adipogenesis is a complex physiological process, necessary to sequester lipids effectively to avoid lipotoxicity in other tissues, like the liver, heart, muscle, essential for maintaining metabolic homeostasis and has a crucial role as a component of the innate immune system, far beyond than only being an inert mass of energy storage. In pathophysiological conditions, adipogenesis promotes a pro-inflammatory state, angiogenesis and the release of adipokines, which become dangerous to health. It results in a hypoxic state, causing oxidative stress and the synthesis and release of harmful free fatty acids. In this review, we try to explain the mechanisms occurring at the breaking point, at which adipogenesis leads to an uncontrolled lipotoxicity. This review highlights the types of adipose tissue and their functions, their way of storing lipids until a critical point, which is associated with hypoxia, inflammation, insulin resistance as well as lipodystrophy and adipogenesis modulation by Krüppel-like factors and miRNAs.


Assuntos
Adipogenia , Tecido Adiposo/metabolismo , Adipócitos/metabolismo , Adipogenia/fisiologia , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Animais , Suscetibilidade a Doenças , Metabolismo Energético , Humanos , Lipogênese , Paniculite/etiologia , Paniculite/metabolismo , Paniculite/patologia
8.
Int Rev Immunol ; 38(4): 157-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31286783

RESUMO

Obesity predisposes the affected individuals to several metabolic, inflammatory, cardiovascular and malignant pathologies and is a top risk factor for premature mortality. It is now well known that inflammation has a major causative role in obesity-associated disease development and that obesity favors the establishment of a pro-inflammatory milieu at the level of adipose microenvironment. These inflammatory signals result in a disruption of normal cellular-crosstalk between adipose and non-adipose components leading to an altered metabolic and immunological status and a dysfunctional phenotype. Abnormal secretion of adipokines - small adipose-derived signaling molecules - can further assist in the inflammatory processes to offset the adipose tissue towards a dysfunctional state. Although adipokines have been recognized as the link between obesity and pathogenesis, studies are needed to fully understand their mechanism of action and underscore their therapeutic value. Here, we have reviewed obesity-induced metabolic and immunological changes at the level of vasculature and emphasize on the importance of adipokines, particularly leptin, vaspin and visfatin, for their therapeutic relevance.


Assuntos
Adipocinas/metabolismo , Células Endoteliais/imunologia , Mediadores da Inflamação/metabolismo , Obesidade/imunologia , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/metabolismo , Transdução de Sinais
9.
Nat Commun ; 10(1): 3254, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332184

RESUMO

Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood. Group 1 innate lymphoid cells (ILC1s) are effectors of innate immunity and enriched in inflamed tissues. Here we show that the number of adipose ILC1s increases in obese T2D patients and correlates with glycemic parameters and with the number of ILC1s in the blood; circulating ILC1 numbers decrease as a result of metabolic improvements after bariatric surgery. In vitro co-culture experiments show that human adipose ILC1s promote adipose fibrogenesis and CD11c+ macrophage activation. Reconstruction of the adipose ILC1 population in Prkdc-/-IL2rg-/- mice by adoptive transfer drives adipose fibrogenesis through activation of TGFß1 signaling; however, transfer of Ifng-/- ILC1s has no effect on adipose fibrogenesis. Furthermore, inhibiting adipose accumulation of ILC1s using IL-12 neutralizing antibodies attenuates adipose tissue fibrosis and improves glycemic tolerance. Our data present insights into the mechanisms of local immune disturbances in obesity-related T2D.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Imunidade Inata , Linfócitos/metabolismo , Obesidade/metabolismo , Adipócitos/citologia , Adipócitos/imunologia , Adipócitos/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Cirurgia Bariátrica , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Fibrose , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Ativação de Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/imunologia
10.
PLoS Pathog ; 15(6): e1007890, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220189

RESUMO

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.


Assuntos
Tecido Adiposo , Linfócitos T CD8-Positivos , Infecções por Herpesviridae , Hiperglicemia , Muromegalovirus/imunologia , Paniculite , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Tecido Adiposo/virologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Hiperglicemia/genética , Hiperglicemia/imunologia , Hiperglicemia/patologia , Hiperglicemia/virologia , Memória Imunológica , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Camundongos , Camundongos Knockout , Paniculite/genética , Paniculite/imunologia , Paniculite/patologia , Paniculite/virologia
11.
Mol Immunol ; 112: 223-232, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177059

RESUMO

The complement system is a major component of innate immunity playing essential roles in the destruction of pathogens, the clearance of apoptotic cells and immune complexes, the enhancement of phagocytosis, inflammation, and the modulation of adaptive immune responses. During the last decades, numerous studies have shown that the complement system has key functions in the biology of certain tissues. For example, complement contributes to normal brain and embryonic development and to the homeostasis of lipid metabolism. However, the complement system is subjected to the effective balance between activation-inactivation to maintain complement homeostasis and to prevent self-injury to cells or tissues. When this control is disrupted, serious pathologies eventually develop, such as C3 glomerulopathy, autoimmune conditions and infections. Another heterogeneous group of ultra-rare diseases in which complement abnormalities have been described are the lipodystrophy syndromes. These diseases are characterized by the loss of adipose tissue throughout the entire body or partially. Complement over-activation has been reported in most of the patients with acquired partial lipodystrophy (also called Barraquer-Simons Syndrome) and in some cases of the generalized variety of the disease (Lawrence Syndrome). Even so, the mechanism through which the complement system induces adipose tissue abnormalities remains unclear. This review focuses on describing the link between the complement system and certain forms of lipodystrophy. In addition, we present an overview regarding the clinical presentation, differential diagnosis, classification, and management of patients with lipodystrophy associated with complement abnormalities.


Assuntos
Complemento C3/imunologia , Lipodistrofia/imunologia , Tecido Adiposo/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Humanos , Imunidade Inata/imunologia
12.
Mediators Inflamm ; 2019: 5481725, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210749

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells contributing to regulation of lymphocyte immune response. DCs are divided into two subtypes: CD11c-positive conventional or myeloid (cDCs) and CD123-positive plasmacytoid (pDCs) DCs. The aim of the study was to assess DCs (HLA-DR+ lineage-) and their subtypes by flow cytometry in peripheral blood and subcutaneous (SAT) and epicardial (EAT) adipose tissue in subjects with (T2DM, n = 12) and without (non-T2DM, n = 17) type 2 diabetes mellitus undergoing elective cardiac surgery. Subjects with T2DM had higher fasting glycemia (8.6 ± 0.7 vs. 5.8 ± 0.2 mmol/l, p < 0.001) and glycated hemoglobin (52.0 ± 3.4 vs. 36.9 ± 1.0 mmol/mol, p < 0.001) and tended to have more pronounced inflammation (hsCRP: 9.8 ± 3.1 vs. 5.1 ± 1.9 mg/ml, p = 0.177) compared with subjects without T2DM. T2DM was associated with reduced total DCs in SAT (1.57 ± 0.65 vs. 4.45 ± 1.56% for T2DM vs. non-T2DM, p = 0.041) with a similar, albeit insignificant, trend in EAT (0.996 ± 0.33 vs. 2.46 ± 0.78% for T2DM vs. non-T2DM, p = 0.171). When analyzing DC subsets, no difference in cDCs was seen between any of the studied groups or adipose tissue pools. In contrast, pDCs were increased in both SAT (13.5 ± 2.0 vs. 4.6 ± 1.9% of DC cells, p = 0.005) and EAT (29.1 ± 8.7 vs. 8.4 ± 2.4% of DC, p = 0.045) of T2DM relative to non-T2DM subjects as well as in EAT of the T2DM group compared with corresponding SAT (29.1 ± 8.7 vs. 13.5 ± 2.0% of DC, p = 0.020). Neither obesity nor coronary artery disease (CAD) significantly influenced the number of total, cDC, or pDC in SAT or EAT according to multiple regression analysis. In summary, T2DM decreased the amount of total dendritic cells in subcutaneous adipose tissue and increased plasmacytoid dendritic cells in subcutaneous and even more in epicardial adipose tissue. These findings suggest a potential role of pDCs in the development of T2DM-associated adipose tissue low-grade inflammation.


Assuntos
Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/metabolismo , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Tecido Adiposo/imunologia , Idoso , Doença da Artéria Coronariana/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/imunologia , Pericárdio/imunologia , Pericárdio/metabolismo , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo
13.
Nat Commun ; 10(1): 2375, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147543

RESUMO

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteína Semelhante a ELAV 1/genética , Intolerância à Glucose/genética , Hipercolesterolemia/genética , Resistência à Insulina/genética , Lipase/genética , Obesidade/genética , Adipócitos/patologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/imunologia , Animais , Crescimento Celular , Dieta Hiperlipídica , Proteína Semelhante a ELAV 1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hipertrofia , Inflamação/imunologia , Lipase/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Biossíntese de Proteínas , Estabilidade de RNA/genética , Gordura Subcutânea/metabolismo
14.
Nat Immunol ; 20(6): 701-710, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110314

RESUMO

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Caquexia/etiologia , Viroses/complicações , Viroses/imunologia , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia/diagnóstico por imagem , Caquexia/metabolismo , Caquexia/patologia , Doença Crônica , Citocinas/sangue , Citocinas/metabolismo , Feminino , Interferon Tipo I/metabolismo , Metabolismo dos Lipídeos , Lipólise , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Transdução de Sinais , Viroses/virologia
15.
Breast Cancer Res Treat ; 176(2): 387-394, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041685

RESUMO

PURPOSE: Circulating adipose stromal cells (CASC) are thought to be increased in obesity and facilitate angiogenesis, and tumor metastases. METHODS: CASC were identified from buffy coat peripheral blood mononuclear cells (PBMCs) by flow cytometry as CD34brightCD31- CD45- and CASC frequency was compared to adiposity measures in 33 women at increased risk for breast cancer. Feasibility of CASC as a response biomarker for a diet and exercise intervention in ten breast cancer survivors was then explored. RESULTS: For 33 high-risk women, median CASC frequency was 9.7 per million PBMCs and trended positively with body mass index, fat mass index (FMI), and percent android fat. Correlation was significant when BMI was dichotomized at > versus < 35 kg/m2 (p = 0.02). For ten breast cancer survivors with a median BMI of 37 kg/m2, median CASC frequency was 16.4 per million PBMCs. In univariate analyses, change in BMI, total fat and visceral fat were significantly correlated with change in CASC frequency. On multivariate analysis, change in visceral adipose had the strongest association with change in CASC frequency (p < 0.00078). CONCLUSIONS: The association between the reduction in visceral adipose tissue and the decrease in frequency of circulating adipose stromal cells suggests that the latter might be a useful biomarker in clinical trials of obese breast cancer survivors undergoing a weight loss intervention.


Assuntos
Tecido Adiposo/imunologia , Biomarcadores/sangue , Neoplasias da Mama/sangue , Obesidade/terapia , Tecido Adiposo/citologia , Idoso , Antígenos CD34/metabolismo , Neoplasias da Mama/imunologia , Sobreviventes de Câncer , Estudos Transversais , Dietoterapia , Terapia por Exercício , Feminino , Humanos , Antígenos Comuns de Leucócito/metabolismo , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/imunologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pós-Menopausa , Pré-Menopausa , Células Estromais/citologia , Células Estromais/imunologia
16.
BMC Musculoskelet Disord ; 20(1): 199, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077169

RESUMO

BACKGROUND: Chronic inflammation with aging contributes to sarcopenia. Previous studies have suggested that the accumulation of adipose tissue in skeletal muscle, referred to as intermuscular adipose tissue (IMAT), increases with age and is associated with inflammation. However, the mechanism governing ectopic inflammation in skeletal muscle due to aging is not fully understood. Leptin, an adipocytokine derived from adipose tissue, is an important mediator of inflammatory processes. We examined changes in leptin levels with age and whether leptin contributes to ectopic inflammation. METHODS: To evaluate ectopic inflammation in skeletal muscle, we measured alterations to the expression of inflammatory cytokine genes (Il1b, Il6, and Tnfa) and muscle break down-related gene (MuRF1 and Atrogin1) in the quadricep muscles of young (10 weeks) and aged (48 weeks) female rats using quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR). Histological examination was performed to identify the extent of IMAT. Leptin mRNA and leptin protein expression were examined using Q-RT-PCR and enzyme-linked immunosorbent assay, respectively. The effect of leptin on the mRNA expression of Il1b, Il6, and Tnfa in quadricep muscle-derived cells was also examined by stimulating the cells with 0 (control), 1, or 10 µg/mL rat recombinant leptin using Q-RT-PCR. RESULTS: Aged rats had significantly higher Il6, MuRF1, and Atrogin1 but not Il1b and Tnfa, expression and greater levels of IMAT in their quadricep muscles than young rats. Aged rats also had significantly higher leptin expression and leptin protein concentration in their quadricep muscles than young rats. The addition of exogenous leptin to quadricep muscle-derived cells significantly increased the gene expression of Il1b and Il6 but not Tnfa. CONCLUSIONS: Our results suggest that elevated leptin levels due to aging cause ectopic inflammation through IL-6 in the skeletal muscle of aged rats.


Assuntos
Tecido Adiposo/metabolismo , Envelhecimento/metabolismo , Interleucina-6/metabolismo , Leptina/metabolismo , Músculo Esquelético/metabolismo , Tecido Adiposo/imunologia , Envelhecimento/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Modelos Animais , Músculo Esquelético/imunologia , Ratos , Ratos Sprague-Dawley , Sarcopenia/imunologia
17.
Cells ; 8(5)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096722

RESUMO

Multipotent mesenchymal stromal cells (MSCs) have emerged as potent therapeutic agents for multiple indications. However, recent evidence indicates that MSC function is compromised in the physiological post-injury milieu. In this study, bone marrow (BM)- and adipose-derived (AD)-MSCs were preconditioned in hypoxia with or without inflammatory mediators to potentiate their immunotherapeutic function in preparation for in vivo delivery. Human MSCs were cultured for 48 hours in either normoxia (21% O2) or hypoxia (2% O2) with or without the addition of Cytomix, thus creating 4 groups: 1) normoxia (21%); 2) Cytomix-normoxia (+21%); 3) hypoxia (2%); and 4) Cytomix-hypoxia (+2%). The 4 MSC groups were subjected to comprehensive evaluation of their characteristics and function. Preconditioning did not alter common MSC surface markers; nonetheless, Cytomix treatment triggered an increase in tissue factor (TF) expression. Moreover, the BM-MSCs and AD-MSCs from the +2% group were not able to differentiate to chondrocytes and osteoblasts, respectively. Following Cytomix preconditioning, the metabolism of MSCs was significantly increased while viability was decreased in AD-MSCs, but not in BM-MSCs. MSCs from both tissues showed a significant upregulation of key anti-inflammatory genes, increased secretion of IL-1 receptor antagonist (RA), and enhanced suppression of T-cell proliferation following the Cytomix treatment. Similarly, following a lipopolysaccharide challenge, the Cytomix-treated MSCs suppressed TNF-α secretion, while promoting the production of IL-10 and IL-1RA. These preconditioning approaches facilitate the production of MSCs with robust anti-inflammatory properties. AD-MSCs preconditioned with Cytomix under normoxia appear to be the most promising therapeutic candidates; however, safety concerns, such as thrombogenic disposition of cells due to TF expression, should be carefully considered prior to clinical translation.


Assuntos
Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Células da Medula Óssea/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Células-Tronco Mesenquimais/imunologia , Tromboplastina/metabolismo , Células da Medula Óssea/citologia , Hipóxia Celular/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Humanos , Mediadores da Inflamação/imunologia , Interleucina-10/metabolismo , Células-Tronco Mesenquimais/citologia , Fator de Necrose Tumoral alfa/metabolismo
18.
Horm Mol Biol Clin Investig ; 39(2)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31136298

RESUMO

Background Inflammation, induced by excessive adiposity, links obesity to disease risk yet little attention has been devoted to the lymphoid tissues embedded within adipose tissue depots. Lymph nodes are the primary site for the development of protective immunity, hence any disease process that affects these tissues will also directly impact immunity. Here we examined how obesity alters secondary lymphatic tissue structure and encapsulated immune cells. Materials and methods Four-month-old C57BL/6 male mice were fed standard rodent chow or a Western high fat diet (HFD) for 6 months. Center regions of visceral and subcutaneous lymph nodes (SQLNS) were observed via transmission electron microscopy (TEM). Results Compared with chow, HFD-induced obesity deleteriously modified the structural microarchitecture and immune cell morphology of visceral and SQLNs. In HFD mice, fibroblastic reticular cells (FRCs) were dysregulated while laying among excessive amounts of disorganized collagen (C). In addition HFD lymph nodes contained a disproportionate amount of cellular debris from damaged or dead cells, increased sinus spacing and decreased immune cell interactions. Specifically, dendritic cells (DCs) that are necessary for adaptive immune response where embedded among extracellular debris with decreased pseudopodia. Similarly, the extraneous fibrous extracellular matrix (ECM) in HFD mice limited contact between lymphocytes (LCs) causing their microvilli extensions to decrease. Discussion Overall, excessive C production within lymph nodes, driven by diet-induced obesity, creates a physical barrier that impedes proper lymph flow and cellular communication. Obesity-induced disorganization of the immune cell guidance network interrupts immune cell adhesion and consequently inhibits travel within cortex regions needed for cell interactions, survival and proliferation.


Assuntos
Tecido Adiposo/imunologia , Linfonodos/imunologia , Obesidade/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Comunicação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose , Imunidade , Inflamação/imunologia , Inflamação/metabolismo , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/patologia
19.
Curr Protein Pept Sci ; 20(6): 505-524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30950347

RESUMO

α1-acid glycoprotein (orosomucoid, AGP) is an Acute Phase Protein produced by liver and peripheral tissues in response to systemic reaction to inflammation. AGP functions have been studied mostly in human, cattle and fish, although the protein has been also found in many mammalian species and birds. AGP fulfils at least two set of functions, which are apparently different from each other but in fact intimately linked. On one hand, AGP is an immunomodulatory protein. On the other hand, AGP is one of the most important binding proteins in plasma and, beside modulating pharmacokinetics and pharmacodynamics of many drugs, it is also able to bind and transport several endogen ligands related to inflammation. The focus of this review is the immunomodulatory activity of AGP. This protein regulates every single event related to inflammation, including binding of pathogens and modulating white blood cells activity throughout the entire leukocyte attacking sequence. The regulation of AGP activity is complex: the inflammation induces not only an increase in AGP serum concentration, but also a qualitative change in its carbohydrate moiety, generating a multitude of glycoforms, each of them with different, and sometimes opposite and contradictory, activities. We also present the most recent findings about the relationship between AGP and adipose tissue: AGP interacts with leptin receptor and, given its immunomodulatory function, it may be included among the potential players in the field of immunometabolism.


Assuntos
Fatores Imunológicos/imunologia , Orosomucoide/imunologia , Proteínas da Fase Aguda/metabolismo , Tecido Adiposo/imunologia , Animais , Quimiotaxia , Citocinas/biossíntese , Humanos , Fatores Imunológicos/metabolismo , Imunomodulação , Inflamação/imunologia , Inflamação/metabolismo , Orosomucoide/química , Orosomucoide/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional , Receptores para Leptina/metabolismo
20.
Nat Immunol ; 20(5): 581-592, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962591

RESUMO

Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/genética , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética , Ácido Succínico/imunologia , Ácido Succínico/metabolismo , Ácido Succínico/farmacologia , Células THP-1
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