Evidence of an anti-inflammatory toll-like receptor 9 (TLR 9) pathway in adipocytes

in Journal of Endocrinology
Correspondence should be addressed to T Karrasch: thomas.karrasch@innere.med.uni-giessen.de
Restricted access

Adipocytes express various pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and actively participate in anti-bacterial and anti-viral host defence. Obesity is associated with adipose tissue PRR expression. The potential role of Toll-like receptor 9 (TLR9) in adipocytes has not yet been investigated. Here, we evaluated TLR9 expression during adipocyte differentiation (AD) of 3T3-L1 adipocytes, in primary murine adipocytes and in different murine and human adipose tissue depots by real-time PCR, immunocytochemistry and immunohistochemistry. TLR9 expression was inhibited using specific siRNA-mediated knockdown, and TLR9 signaling was induced using specific class A, B and C agonistic CpG-oligodeoxynucleotide (ODN) treatment vs ODN controls in 3T3-L1 adipocytes and in primary murine adipocytes from Tlr9wt/wt vs Tlr9−/− mice. We found that TLR9 gene expression is induced during AD and that TLR9 protein is expressed in murine gonadal and human visceral adipocytes. AD depends on intact TLR9 expression. Tlr9−/− mice demonstrate significantly reduced adiponectin serum levels, while siRNA-mediated TLR9 knockdown led to reduced adiponectin mRNA expression in adipocytes. TLR9 ligands (CpG-ODNs) inhibit pro-inflammatory resistin secretion in mature 3T3-L1 adipocytes. Tlr9−/− as compared to Tlr9wt/wt adipocytes exhibit increased resistin and MCP1 secretion and reduced adiponectin secretion into cell culture supernatants, while TLR9 ligands (ODNs) show differential effects in Tlr9−/− vs Tlr9wt/wt primary murine adipocytes. TLR9 expression is significantly increased in visceral compared to subcutaneous adipose tissue depots in non-diabetic obese patients and correlates with systemic resistin levels in a compartment-specific manner. Thus, adipocytic TLR9 is a putative, new protective factor during (obesity-associated) adipose tissue inflammation.

 

      Society for Endocrinology

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 455 455 163
Full Text Views 54 54 5
PDF Downloads 26 26 3

Altmetrics

Related Articles

Figures

  • View in gallery

    Tlr9 gene expression is induced during adipocyte differentiation, and TLR9 protein is strongly expressed in murine gonadal and human visceral adipocytes. (A) Adipocyte differentiation was hormonally induced in murine 3T3-L1 pre-adipocytes in vitro. At the indicated time points, cells were lysed, mRNA was prepared from n = 17 wells each and reverse transcribed, and TLR9 mRNA in relation to GAPDH mRNA × 106 was analyzed by real-time PCR. TLR9 mRNA expression was not detectable in pre-adipocytes (d0); however, we found a stepwise and significant increase during differentiation into mature adipocytes (d3 through d9) with a maximum at day 9 (fully differentiated phenotype). The error bars indicate ± 1 × standard error of the mean (s.e.m.). (B) 3T3-L1 fibroblasts were differentiated into mature adipocytes and immunocytochemistry (ICC) for TLR9 protein was prepared on day 3 (B.1 and B.2) vs day 9 (B.3 and B.4) of differentiation. ICC demonstrated a significant induction of TLR9 protein expression during differentiation (d9, B.3), which was found predominantly within the cytoplasm of mature adipocytes (B.3). Representative images are shown. (C and D) Murine gonadal (mAT gon) (C) and human visceral (hAT vis) (D) adipose tissue was analysed for the expression of TLR9 protein by immunohistochemistry (IHC). IHC demonstrated a significant TLR9 expression in both murine gonadal and human visceral adipose tissue adipocytes, albeit slightly less intense in the latter. Representative images are shown. (E) Gonadal (gon) vs subcutaneous (sc) adipose tissue was harvested from n = 16 male C57BL/6 mice and the adipocyte (Adi) vs the stroma-vascular cell (SVC) fraction was prepared. Cells were lysed, mRNA was prepared and reverse transcribed, and TLR9 mRNA in relation to GAPDH mRNA × 106 was analyzed by real-time PCR. While the stroma-vascular cell fraction expectedly demonstrated a strong TLR9 expression signal, isolated adipocytes themselves also exhibited a lower but significant TLR9 expression. The error bars indicate ± 1 × standard error of the mean (s.e.m.).

  • View in gallery

    Adipocyte differentiation is dependent on intact TLR9 expression. 3T3-L1 pre-adipocytes were repeatedly treated (at day 0, 3, 6, 8 for 3 h each) with TLR9 siRNA compared to non-targeting (nt) siRNA control during hormonally induced adipocyte differentiation. (A) Microscopic imaging as well as (B) Oil-red-O staining of intracellular lipid vacuoles revealed significantly inhibited intracellular lipid droplet formation as a hallmark of adipocyte differentiation in TLR9-siRNA-treated (TLR9 siRNA), differentiating adipocytes compared to control-treated (nt siRNA) cells. Representative images of n = 6 separate experiments are shown. (C) TLR9 siRNA-treatment vs nt siRNA-treatment of differentiating adipocytes demonstrated significantly reduced adiponectin mRNA accumulation as assessed by real-time PCR prepared from n = 6 wells each. The error bars indicate ± 1 × standard error of the mean (s.e.m.). (D) Healthy female Balb/c Tlr9wt/wt vs healthy Tlr9−/− (n = 5 per group; weighing 20–22 g) were sacrificed, and serum was harvested. Adiponectin serum levels were measured by ELISA. Tlr9−/− mice exhibited significantly reduced adiponectin serum levels as compared to healthy Tlr9wt/wt control mice. The error bars indicate ± 1 × standard error of the mean (s.e.m.).

  • View in gallery

    TLR9 ligand class A CpG-ODN (ODN 1585) inhibits resistin secretion, TLR9 ligand class B CpG-ODN (ODN 1826) inhibits resistin and partly adiponectin secretion and TLR9 ligand class C CpG-ODN (ODN 2395) inhibits resistin secretion into cell culture supernatants in mature 3T3-L1 adipocytes in vitro. Mature 3T3-L1 adipocytes were stimulated with increasing doses of class A ODN (ODN 1585; 1, 5, 20 µg/mL) vs class A control ODN (class A ctl ODN; 20 µg/mL; exhibiting a similar structure while missing the typical non-methylated CpG-motifs) vs solvent control (ctl). Resistin and adiponectin levels in cell culture supernatants from n = 6 wells each were assessed by ELISA measurements and were normalized to total cell protein content in each well. The error bars indicate ± 1 × standard error of the mean (s.e.m.). (A) Class A ODN induced a significant and dose-dependent inhibition of resistin protein secretion into cell culture supernatants. (B) Treatment with class A control ODN did not have an effect on resistin secretion. (C) Treatment with increasing doses of class A ODN did not impact on basal adiponectin protein secretion into cell culture supernatants. (D) Treatment with class A control ODN did not have an effect on basal adiponectin secretion. (E) Pre-incubation (1 h) of mature 3T3-L1 adipocytes with class A ODN (ODN 1585; 5, 20 µg/mL) followed by stimulation by LPS (10 ng/mL) led to a significant and dose-dependent inhibition of resistin protein secretion into cell culture supernatants as well. (F) Pre-incubation (1 h) of mature 3T3-L1 adipocytes with higher doses of class A ODN (ODN 1585; 20 µg/mL) followed by stimulation with LPS (10 ng/mL) led to a significant inhibition of adiponectin protein secretion into cell culture supernatants. (G, H, I, J, K and L) Similar experiments as reported for class A ODN were performed using class B ODN. Class B ODN had a similar impact on resistin and adiponectin secretion compared to class A ODN, albeit with an overall lesser effect size. (M, N, O, P, Q and R) Similar experiments as reported for class A ODN were performed using class C ODN. Class C ODN effects on adipocyte resistin secretion were comparable to class A ODN, although slightly less effective, while class C ODN did not impact on adiponectin at all. (light gray bars, resistin; dark gray bars, adiponectin; ns, not significant).

  • View in gallery

    TLR9 ligands (ODNs) inhibit MCP1, GLUT1 and GLUT4 mRNA accumulation in mature 3T3-L1 adipocytes in vitro. Mature 3T3-L1 adipocytes were stimulated with class A ODN (ODN 1585; 20 µg/mL), class B ODN (ODN 1826; 20 µg/mL) and class C ODN (ODN 2395; 20 µg/mL) vs the respective control ODNs (20 µg/mL; exhibiting a similar structure while missing the typical non-methylated CpG-motifs) vs solvent control (ctl). After isolation of mRNA, mRNA accumulation of murine MCP-1, GLUT1 and GLUT4 was quantified by reverse transcription and real-time PCR (RT-PCR) of the corresponding cDNA (A) Control ODN A, B and C significantly reduced basal MCP1 mRNA accumulation as compared to solvent control. Class A ODN reduced MCP1 expression even further compared to control ODN A, which was not observed with ODN B and C. (B, C) Class A ODN profoundly reduced both GLUT1 and GLUT4 mRNA accumulation as compared to class A control ODN treated cells. Class B and class C ODN did not have this effect. While class A, B and C control ODN themselves reduced GLUT1 mRNA accumulation compared to solvent treated controls, they did not impact on GLUT4 mRNA accumulation at all.

  • View in gallery

    Primary murine Tlr9−/− as compared to Tlr9wt/wt adipocytes exhibit increased resistin and MCP1 secretion and reduced adiponectin secretion into cell culture supernatants, while TLR9 ligands (ODNs) show differential effects in Tlr9−/− vs Tlr9wt/wt primary murine adipocytes. Primary pre-adipocytes were isolated from fresh subcutaneous (A; C, D and E) and gonadal (B) adipose tissue from Tlr9wt/wt- as compared to Tlr9−/−-mice as described in the Methods section. Adipocyte differentiation was hormonally induced in vitro, and mature adipocytes at day 11 of differentiation were stimulated with class A ODN (ODN 1585; 20 µg/mL), class B ODN (ODN 1826; 20 µg/mL) and class C ODN (ODN 2395; 20 µg/mL) vs the respective control ODNs (20 µg/mL; exhibiting a similar structure while missing the typical non-methylated CpG-motifs) vs solvent control (ctl). Resistin, MCP1 and adiponectin levels in cell culture supernatants from n = 6 wells each were assessed by ELISA measurements and were normalized to total cell protein content in each well. The error bars indicate ± 1 × standard error of the mean (s.e.m.). (A) Tlr9wt/wt-adipocytes demonstrate significantly increased basal resistin and MCP1 secretion and significantly reduced basal adiponectin secretion as compared to Tlr9−/−-adipocytes. (B) TLR4-dependent induction of MCP1-secretion stimulated by LPS-treatment (10 ng/mL) was intact in both Tlr9wt/wt- and Tlr9−/−-adipocytes, however, Tlr9−/−-adipocytes exhibited a significantly stronger induction of MCP1 by LPS as compared to Tlr9wt/wt-adipocytes. (C, D and E) Treatment of Tlr9wt/wt- vs Tlr9−/−-adipocytes with class A, B and C ODN vs control ODN had differential effects on resistin, MCP1 and adiponectin secretion into cell culture supernatants (compare text).

  • View in gallery

    TLR9 expression is significantly increased in visceral over subcutaneous adipose tissue depots in female non-diabetic obese patients undergoing bariatric surgery and correlates with systemic resistin levels in a compartment-specific manner. (A) Healthy female wild-type Balb/c mice (n = 11; weighing 20–22 g) were sacrificed, and adipose tissue specimen were collected from subcutaneous vs gonadal adipose tissue depots. Cells were lysed, mRNA was prepared and reverse transcribed, and TLR9 mRNA in relation to GAPDH mRNA × 106 was analyzed by real-time PCR. There were no differences in TLR9 mRNA expression levels in murine subcutaneous over gonadal adipose tissue depots. Data are given as box plots; the boundary of the box closest to zero indicates the 25th percentile, a line within the box marks the median, and the boundary of the box farthest from zero indicates the 75th percentile. Whiskers above and below the box indicate the highest/lowest values that are within 1.5 times the interquartile range (Tukey’s whiskers). (B) Human visceral and subcutaneous adipose tissue samples were obtained from 21 female patients not suffering from diabetes mellitus (mean age: 38.2 ± 2.5 years (range: 20–57 years); mean BMI: 52.0 ± 1.1 kg/m2 (range: 44.8–63.6 kg/m2)) undergoing bariatric surgery and were analyzed for TLR9 mRNA expression. TLR9 mRNA expression (as assessed relative to GAPDH mRNA expression × 106) was significantly increased in visceral adipose tissue depots as compared to subcutaneous adipose tissue depots. Data are given as box plots as described in (A). (C) Immunohistochemical analyses in three matched human subcutaneous and visceral adipose tissue specimen indicated that there is significant inter-individual variability in TLR9 protein accumulation between patients. (D and E) Human visceral and subcutaneous adipose tissue samples were obtained from 21 female patients undergoing bariatric surgery and were analyzed for TLR9 mRNA expression as described in (B). Serum samples from these 21 patients were collected before the bariatric operation, and resistin serum levels were measured by ELISA. Resistin serum levels were significantly correlated to adipose tissue TLR9 mRNA expression levels in a compartment-specific manner, demonstrating a negative correlation to subcutaneous adipose tissue TLR9 expression (D) and a positive correlation to visceral adipose tissue TLR9 expression (E).

References

AbateNSallamHSRizzoMNikolicDObradovicMBjelogrlicPIsenovicER 2014 Resistin: an inflammatory cytokine. Role in cardiovascular diseases, diabetes and the metabolic syndrome. Current Pharmaceutical Design 20 49614969. (https://doi.org/10.2174/1381612819666131206103102)

AbdullahAWolfeRStoelwinderJUde CourtenMStevensonCWallsHLPeetersA 2011 The number of years lived with obesity and the risk of all-cause and cause-specific mortality. International Journal of Epidemiology 40 985996. (https://doi.org/10.1093/ije/dyr018)

AmarJChaboCWagetAKloppPVachouxCBermudez-HumaranLGSmirnovaNBergeMSulpiceTLahtinenSet al. 2011 Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Molecular Medicine 3 559572. (https://doi.org/10.1002/emmm.201100159)

ApostolopoulosVde CourtenMPStojanovskaLBlatchGLTangalakisKde CourtenB 2016 The complex immunological and inflammatory network of adipose tissue in obesity. Molecular Nutrition and Food Research 60 4357. (https://doi.org/10.1002/mnfr.201500272)

BachmeierMLofflerG 1994 Adipogenic activities in commercial preparations of fetuin. Hormone and Metabolic Research 26 9296. (https://doi.org/10.1055/s-2007-1000780)

BaeJRicciardiCJEspositoDKomarnytskySHuPCurryBJBrownPLGaoZBiggerstaffJPChenJet al. 2014 Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. American Journal of Physiology-Cell Physiology 306 C918C930. (https://doi.org/10.1152/ajpcell.00249.2013)

BamboatZMOcuinLMBalachandranVPObaidHPlitasGDeMatteoRP 2010 Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. Journal of Clinical Investigation 120 559569. (https://doi.org/10.1172/JCI40008)

BanchereauJPascualV 2006 Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25 383392. (https://doi.org/10.1016/j.immuni.2006.08.010)

BokarewaMNagaevIDahlbergLSmithUTarkowskiA 2005 Resistin, an adipokine with potent proinflammatory properties. Journal of Immunology 174 57895795. (https://doi.org/10.4049/jimmunol.174.9.5789)

BossallerLChristAPelkaKNundelKChiangPIPangCMishraNBustoPBonegioRGSchmidtREet al. 2016 TLR9 deficiency leads to accelerated renal disease and myeloid lineage abnormalities in pristane-induced murine lupus. Journal of Immunology 197 10441053. (https://doi.org/10.4049/jimmunol.1501943)

CappellanoGMorandiEMRainerJGrubwieserPHeinzKWolframDBernhardDLobenweinSPiererGPlonerC 2018 Human macrophages preferentially infiltrate the superficial adipose tissue. International Journal of Molecular Sciences 19 1404. (https://doi.org/10.3390/ijms19051404)

CaputoTGilardiFDesvergneB 2017 From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions. FEBS Letters 591 30613088. (https://doi.org/10.1002/1873-3468.12742)

CavallariJFFullertonMDDugganBMFoleyKPDenouESmithBKDesjardinsEMHenriksboBDKimKJTuinemaBRet al. 2017 Muramyl dipeptide-based postbiotics mitigate obesity-induced insulin resistance via IRF4. Cell Metabolism 25 1063.e10631074.e1063. (https://doi.org/10.1016/j.cmet.2017.03.021)

ChoYLMinJKRohKMKimWKHanBSBaeKHLeeSCChungSJKangHJ 2015 Phosphoprotein phosphatase 1CB (PPP1CB), a novel adipogenic activator, promotes 3T3-L1 adipogenesis. Biochemical and Biophysical Research Communications 467 211217. (https://doi.org/10.1016/j.bbrc.2015.10.004)

CorneliusPMacDougaldOALaneMD 1994 Regulation of adipocyte development. Annual Review of Nutrition 14 99129. (https://doi.org/10.1146/annurev.nu.14.070194.000531)

CristanchoAGLazarMA 2011 Forming functional fat: a growing understanding of adipocyte differentiation. Nature Reviews Molecular Cell Biology 12 722734. (https://doi.org/10.1038/nrm3198)

DenouELolmedeKGaridouLPomieCChaboCLauTCFullertonMDNigroGZakaroff-GirardALucheEet al. 2015 Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Molecular Medicine 7 259274. (https://doi.org/10.15252/emmm.201404169)

FuriISiposFGermannTMKalmarATulassayZMolnarBMuzesG 2013 Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: clinico-pathogenic aspects. World Journal of Gastroenterology 19 41194126. (https://doi.org/10.3748/wjg.v19.i26.4119)

Garcia-AlonsoVClariaJ 2014 Prostaglandin E2 signals white-to-brown adipogenic differentiation. Adipocyte 3 290296. (https://doi.org/10.4161/adip.29993)

GhoshARBhattacharyaRBhattacharyaSNargisTRahamanODuttaguptaPRaychaudhuriDChen LiuCSRoySGhoshPet al. 2016 Adipose recruitment and activation of plasmacytoid dendritic cells fuel metaflammation. Diabetes 65 34403452. (https://doi.org/10.2337/db16-0331)

GrantRWStephensJM 2015 Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. American Journal of Physiology-Endocrinology and Metabolism 309 E205E213. (https://doi.org/10.1152/ajpendo.00053.2015)

GreenHKehindeO 1975 An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion. Cell 5 1927. (https://doi.org/10.1016/0092-8674(75)90087-2)

GreenHKehindeO 1979 Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. Journal of Cellular Physiology 101 169171. (https://doi.org/10.1002/jcp.1041010119)

GreenHMeuthM 1974 An established pre-adipose cell line and its differentiation in culture. Cell 3 127133. (https://doi.org/10.1016/0092-8674(74)90116-0)

GregorMFHotamisligilGS 2011 Inflammatory mechanisms in obesity. Annual Review of Immunology 29 415445. (https://doi.org/10.1146/annurev-immunol-031210-101322)

GuillereyCMouriesJPoloGDoyenNLawHKChanSKastnerPLeclercCDadaglioG 2012 Pivotal role of plasmacytoid dendritic cells in inflammation and NK-cell responses after TLR9 triggering in mice. Blood 120 9099. (https://doi.org/10.1182/blood-2012-02-410936)

HardyOTCzechMPCorveraS 2012 What causes the insulin resistance underlying obesity? Current Opinion in Endocrinology Diabetes and Obesity 19 8187. (https://doi.org/10.1097/MED.0b013e3283514e13)

HemmiHTakeuchiOKawaiTKaishoTSatoSSanjoHMatsumotoMHoshinoKWagnerHTakedaKet al. 2000 A Toll-like receptor recognizes bacterial DNA. Nature 408 740745. (https://doi.org/10.1038/35047123)

HofmannCDungerNDoserKLippertESillerSEdingerMFalkWObermeierF 2014 Physiologic TLR9-CpG-DNA interaction is essential for the homeostasis of the intestinal immune system. Inflammatory Bowel Diseases 20 136143. (https://doi.org/10.1097/01.MIB.0000436276.19755.c1)

HongCPYunCHLeeGWParkAKimYMJangMH 2015 TLR9 regulates adipose tissue inflammation and obesity-related metabolic disorders. Obesity 23 21992206. (https://doi.org/10.1002/oby.21215)

HutchesonJ 2015 Adipokines influence the inflammatory balance in autoimmunity. Cytokine 75 272279. (https://doi.org/10.1016/j.cyto.2015.04.004)

JacksonSWScharpingNEKolhatkarNSKhimSSchwartzMALiQZHudkinsKLAlpersCELiggittDRawlingsDJ 2014 Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. Journal of Immunology 192 45254532. (https://doi.org/10.4049/jimmunol.1400098)

KarraschTSchafflerA 2016 Adipokines and the role of visceral adipose tissue in inflammatory bowel disease. Annals of Gastroenterology 29 115. (https://doi.org/10.20524/aog.2016.0077)

KarraschTSchmidAKoppAObermeierFHofmannCSchafflerA 2015 Impact of toll-like-receptor-9 (TLR9) deficiency on visceral adipose tissue adipokine expression during chronic DSS-induced colitis in mice. Experimental and Clinical Endocrinology and Diabetes 123 8087. (https://doi.org/10.1055/s-0034-1398502)

KimSJChoiYChoiYHParkT 2012 Obesity activates toll-like receptor-mediated proinflammatory signaling cascades in the adipose tissue of mice. Journal of Nutritional Biochemistry 23 113122. (https://doi.org/10.1016/j.jnutbio.2010.10.012)

KoppABuechlerCBalaMNeumeierMScholmerichJSchafflerA 2010 Toll-like receptor ligands cause proinflammatory and prodiabetic activation of adipocytes via phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase but not interferon regulatory factor-3. Endocrinology 151 10971108. (https://doi.org/10.1210/en.2009-1140)

KriegAM 2006 Therapeutic potential of Toll-like receptor 9 activation. Nature Reviews Drug Discovery 5 471484. (https://doi.org/10.1038/nrd2059)

KumagaiYTakeuchiOAkiraS 2008 TLR9 as a key receptor for the recognition of DNA. Advanced Drug Delivery Reviews 60 795804. (https://doi.org/10.1016/j.addr.2007.12.004)

KwonHLaurentSTangYZongHVemulapalliPPessinJE 2014 Adipocyte-specific IKKbeta signaling suppresses adipose tissue inflammation through an IL-13-dependent paracrine feedback pathway. Cell Reports 9 15741583. (https://doi.org/10.1016/j.celrep.2014.10.068)

LancasterGILangleyKGBerglundNAKammounHLReibeSEstevezEWeirJMellettNAPernesGConwayJRWet al. 2018 Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metabolism 27 1096.e10951110.e1095. (https://doi.org/10.1016/j.cmet.2018.03.014)

LarsenCMFaulenbachMVaagAVolundAEhsesJASeifertBMandrup-PoulsenTDonathMY 2007 Interleukin-1-receptor antagonist in type 2 diabetes mellitus. New England Journal of Medicine 356 15171526. (https://doi.org/10.1056/NEJMoa065213)

LeeJMoJHKatakuraKAlkalayIRuckerANLiuYTLeeHKShenCCojocaruGShenoudaSet al. 2006 Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biology 8 13271336. (https://doi.org/10.1038/ncb1500)

MacDougaldOALaneMD 1995 Transcriptional regulation of gene expression during adipocyte differentiation. Annual Review of Biochemistry 64 345373. (https://doi.org/10.1146/annurev.bi.64.070195.002021)

MiuraKKodamaYInokuchiSSchnablBAoyamaTOhnishiHOlefskyJMBrennerDASekiE 2010 Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139 323.e327334.e327. (https://doi.org/10.1053/j.gastro.2010.03.052)

NakatsujiTChiangHIJiangSBNagarajanHZenglerKGalloRL 2013 The microbiome extends to subepidermal compartments of normal skin. Nature Communications 4 1431. (https://doi.org/10.1038/ncomms2441)

NickersonKMChristensenSRShupeJKashgarianMKimDElkonKShlomchikMJ 2010 TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. Journal of Immunology 184 18401848. (https://doi.org/10.4049/jimmunol.0902592)

NishimotoSFukudaDHigashikuniYTanakaKHirataYMurataCKim-KaneyamaJRSatoFBandoMYagiSet al. 2016 Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. Science Advances 2 e1501332. (https://doi.org/10.1126/sciadv.1501332)

OhashiKParkerJLOuchiNHiguchiAVitaJAGokceNPedersenAAKalthoffCTullinSSamsAet al. 2010 Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. Journal of Biological Chemistry 285 61536160. (https://doi.org/10.1074/jbc.M109.088708)

ReveloXSGhazarianMChngMHLuckHKimJHZengKShiSYTsaiSLeiHKenkelJet al. 2016 Nucleic acid-targeting pathways promote inflammation in obesity-related insulin resistance. Cell Reports 16 717730. (https://doi.org/10.1016/j.celrep.2016.06.024)

SchafflerAScholmerichJBuchlerC 2005 Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in nonalcoholic fatty liver disease. Nature Reviews Gastroenterology and Hepatology 2 273280. (https://doi.org/10.1038/ncpgasthep0186)

SchafflerAMuller-LadnerUScholmerichJBuchlerC 2006 Role of adipose tissue as an inflammatory organ in human diseases. Endocrine Reviews 27 449467. (https://doi.org/10.1210/er.2005-0022)

SchafflerAScholmerichJSalzbergerB 2007 Adipose tissue as an immunological organ: toll-like receptors, C1q/TNFs and CTRPs. Trends in Immunology 28 393399. (https://doi.org/10.1016/j.it.2007.07.003)

ShamseddeenHGettyJZHamdallahINAliMR 2011 Epidemiology and economic impact of obesity and type 2 diabetes. Surgical Clinics of North America 91 11631172 vii. (https://doi.org/10.1016/j.suc.2011.08.001)

ShiHKokoevaMVInouyeKTzameliIYinHFlierJS 2006 TLR4 links innate immunity and fatty acid-induced insulin resistance. Journal of Clinical Investigation 116 30153025. (https://doi.org/10.1172/JCI28898)

StienstraRJoostenLAKoenenTvan TitsBvan DiepenJAvan den BergSARensenPCVosholPJFantuzziGHijmansAet al. 2010 The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metabolism 12 593605. (https://doi.org/10.1016/j.cmet.2010.11.011)

TakeshitaFSuzukiKSasakiSIshiiNKlinmanDMIshiiKJ 2004 Transcriptional regulation of the human TLR9 gene. Journal of Immunology 173 25522561. (https://doi.org/10.4049/jimmunol.173.4.2552)

TakeuchiOAkiraS 2010 Pattern recognition receptors and inflammation. Cell 140 805820. (https://doi.org/10.1016/j.cell.2010.01.022)

TilgHMoschenAR 2006 Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 6 772783. (https://doi.org/10.1038/nri1937)

Varela-GuruceagaMMilagroFIMartinezJAde MiguelC 2018 Effect of hypoxia on caveolae-related protein expression and insulin signaling in adipocytes. Molecular and Cellular Endocrinology 473 257267. (https://doi.org/10.1016/j.mce.2018.01.026)

Vijay-KumarMAitkenJDCarvalhoFACullenderTCMwangiSSrinivasanSSitaramanSVKnightRLeyREGewirtzAT 2010 Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328 228231. (https://doi.org/10.1126/science.1179721)

WagnerH 2001 Toll meets bacterial CpG-DNA. Immunity 14 499502. (https://doi.org/10.1016/S1074-7613(01)00144-3)

WeisbergSPMcCannDDesaiMRosenbaumMLeibelRLFerranteAWJr 2003 Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation 112 17961808. (https://doi.org/10.1172/JCI200319246)

WelnerRSPelayoRNagaiYGarrettKPWuestTRCarrDJBorghesiLAFarrarMAKincadePW 2008 Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection. Blood 112 37533761. (https://doi.org/10.1182/blood-2008-04-151506)

Wernstedt AsterholmITaoCMorleyTSWangQADelgado-LopezFWangZVSchererPE 2014 Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metabolism 20 103118. (https://doi.org/10.1016/j.cmet.2014.05.005)

YuLYanKLiuPLiNLiuZZhuWChenYHanD 2014 Pattern recognition receptor-initiated innate antiviral response in mouse adipose cells. Immunology and Cell Biology 92 105115. (https://doi.org/10.1038/icb.2013.66)

ZaitsuHSerreroG 1990 Pedersen fetuin contains three adipogenic factors with distinct biochemical characteristics. Journal of Cellular Physiology 144 485491. (https://doi.org/10.1002/jcp.1041440316)

ZhangLJGuerrero-JuarezCFHataTBapatSPRamosRPlikusMVGalloRL 2015 Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347 6771. (https://doi.org/10.1126/science.1260972)

PubMed

Google Scholar