Innate Immunity Modulates Adipokines in Humans

Anderson, Paul D.; Mehta, Nehal N.; Wolfe, Megan L.; Hinkle, Christine; Pruscino, Leticia; Comiskey, L.; Tabita‐Martinez, Jennifer; Sellers, Kimberly F.; Rickels, Michael R.; Ahima, Rexford S.; Reilly, Muredach P.

doi:10.1210/jc.2006-2545

Cited by 175 publications

(172 citation statements)

References 41 publications

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“…Furthermore, the ability of 12 PPAR␥-binding regions tested to function as enhancer elements was independent of distance to the nearest gene in the context of a minimal promoter. Similar results have been reported for other nuclear receptors such as vitamin D (Kim et al 2007), estrogen , and glucocorticoid receptors (Anderson et al 2007). To explain the abundance of distal binding sites, it has been proposed that transcription factors bound to distal sites direct DNA looping such that coactivators and chromatin remodelers at the distal enhancers are brought in proximity to TSS of target genes, facilitating the recruitment of polymerase (West and Fraser 2005).…”

Section: Discussionsupporting

confidence: 87%

PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

Lefterova¹,

Zhang²,

Steger³

et al. 2008

Genes Dev.

721

693

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Peroxisome proliferator-activated receptor ␥(PPAR␥), a nuclear receptor and the target of anti-diabetic thiazolinedione drugs, is known as the master regulator of adipocyte biology. Although it regulates hundreds of adipocyte genes, PPAR␥ binding to endogenous genes has rarely been demonstrated. Here, utilizing chromatin immunoprecipitation (ChIP) coupled with whole genome tiling arrays, we identified 5299 genomic regions of PPAR␥ binding in mouse 3T3-L1 adipocytes. The consensus PPAR␥/RXR␣ "DR-1"-binding motif was found at most of the sites, and ChIP for RXR␣ showed colocalization at nearly all locations tested. Bioinformatics analysis also revealed CCAAT/enhancer-binding protein (C/EBP)-binding motifs in the vicinity of most PPAR␥-binding sites, and genome-wide analysis of C/EBP␣ binding demonstrated that it localized to3350 of the locations bound by PPAR␥. Importantly, most genes induced in adipogenesis were bound by both PPAR␥ and C/EBP␣, while very few were PPAR␥-specific. C/EBP␤ also plays a role at many of these genes, such that both C/EBP␣ and ␤ are required along with PPAR␥ for robust adipocyte-specific gene expression. Thus, PPAR␥ and C/EBP factors cooperatively orchestrate adipocyte biology by adjacent binding on an unanticipated scale.[Keywords: PPAR␥; C/EBP; adipocyte; genome wide; ChIP-chip] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionsupporting

confidence: 87%

PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

Lefterova¹,

Zhang²,

Steger³

et al. 2008

Genes Dev.

721

693

View full text Add to dashboard Cite

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“…Complementary estimates of IR and ␤-cell function, the homeostasis model assessment for IR (HOMA-IR) index [glucose (mmol/l) ϫ insulin (U/ml)/22.5], and the HOMA for ␤-cell function (HOMA-B) index [insulin (U/ml) ϫ 20/glucose (mmol/l) Ϫ 3.5] were calculated using fasting glucose and insulin values at 24 h and 5 min before and 24 h after LPS. Plasma biomarkers and lipoprotein measurement was described previously (10) and is outlined in the online appendix.…”

Section: Results-endotoxemia Induced Systemic Ir As Demonstratedmentioning

confidence: 99%

Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

et al. 2009

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OBJECTIVE-An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS-We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults (n ϭ 20, 50% male, 80% Caucasian, aged 27.3 Ϯ 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index (S i ). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS-Endotoxemia induced systemic IR as demonstratedby a 35% decrease in S i (3.17 Ϯ 1.66 to 2.06 Ϯ 0.73 ϫ 10 Ϫ4 [U ⅐ ml Ϫ1 ⅐ min Ϫ1 ], P Ͻ 0.005), while there was no effect on pancreatic ␤-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems.CONCLUSIONS-We demonstrate, for the first time in humans, that acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.

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“…The two cohorts were well matched with respect to age, gender, and severity of infection based on a sepsis-associated organ failure assessment (SOFA) score at the day of enrollment in the study (STSS: median 11.50, range 6 -19; G-negative cohort: median 13.00, range [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Analyses of systemic resistin levels confirmed our previous finding (5) that septic shock patients have markedly elevated levels (28-fold higher) as compared with healthy controls ( p Ͻ 0.0001) (Fig.…”

Section: Persistent Systemic Hyperresistinemia In Stss Patientsmentioning

confidence: 99%

Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections

Johansson

Linnér

Sundén-Cullberg

et al. 2009

The Journal of Immunology

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The concept of neutrophil activation and degranulation as important contributors to disease pathology in invasive group A streptococcal infections has recently been emphasized. This study focuses on two of the most severe streptococcal manifestations, toxic shock syndrome and necrotizing fasciitis, and the newly described proinflammatory molecule resistin, known to derive from adipocytes and monocytes. We demonstrate for the first time that these conditions are characterized by hyperresistinemia in circulation as well as at the local site of infection. Importantly, analyses of patient tissue biopsies and whole blood revealed that neutrophils represent a novel and dominant source of resistin in bacterial septic shock. This was confirmed by the identification of resistin within neutrophil azurophilic granules. In vitro assays using primary neutrophils showed that resistin release was readily triggered by streptococcal cell wall components and by the streptococcal M1 protein, but not by the potent streptococcal superantigens. This is the first report demonstrating that resistin is released from neutrophils in response to microbial stimuli, which adds resistin to the neutrophil granule proteins that are likely to contribute to the pathologic inflammatory responses associated with severe streptococcal infections.

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Innate Immunity Modulates Adipokines in Humans

Cited by 175 publications

References 41 publications

PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections

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