scholarly journals Obesity-Induced Tumor Necrosis Factor Alpha Suppresses In Vivo and In Vitro Retinoic Acid Synthesis and Fatty Acid Oxidation in Adipose Tissue

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 955-955
Author(s):  
Seok-Yeong Yu ◽  
Zhenhua Liu ◽  
Soonkyu Chung ◽  
Young-Cheul Kim
Keyword(s):  
Adipose Tissue ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Acid Oxidation ◽  
Necrosis Factor Alpha ◽  
Raw264.7 Macrophages ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract Objectives Obese adipose tissue (AT) is characterized by decreased fatty acid oxidation (FAO) and overexpression of tumor necrosis factor alpha (TNFα), a potent proinflammatory mediator of AT dysfunction and metabolic diseases. Several studies have shown that biosynthesis of retinoic acid (RA) from retinol (vitamin A) is suppressed in obese AT. RA has been identified as an agonist for peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), a critical inducer of FAO. The present study aimed to identify a potential mediator of suppressing RA synthesis and thus metabolic dysregulation by (1) evaluating the role of TNFa in tissue RA synthesis and metabolism in vivo and (2) investigating the potential roles of all trans-RA (ATRA) against TNFa-induced AT dysfunction in vitro. We hypothesized that altered retinoid metabolism in obese AT leads to AT dysfunction by reducing PPARβ/δ expression in adipocytes and macrophages. Methods Wild-type (WT) or TNFa knockout (KO) mice were fed a high-fat diet (HFD) or a low-fat diet (LFD) for 16 weeks. Selected serum biochemical parameters as well as expression of genes related to FAO and retinol metabolism were assessed by qPCR and Western Blot analysis. 3T3-L1 adipocytes and RAW264.7 macrophages were also employed to evaluate the effect of TNFa and ATRA on RA synthesis and pro-inflammatory responses. Results We found that RA concentration was significantly attenuated in epididymal AT from HFD-fed TNFa KO group concomitant with the upregulation of genes for RA synthesis (RDH10 & RALDH1) and PPARβ/δ compared to HFD-fed WT group. In 3T3-L1 adipocytes, TNFa treatment significantly inhibited RA synthesis from retinol and downregulated the expression of RDH10 & RALDH1 genes and FAO makers (PPARβ/δ protein and CPT1 mRNA). Furthermore, ATRA treatment significantly increased the expression of PPARβ/δ protein and CPT1 mRNA in TNFα-treated cells. In addition, ATRA significantly suppressed adipocyte-conditioned medium-induced inflammatory responses in RAW264.7 macrophages by increasing PPARβ/δ expression. Conclusions These findings suggest that TNFα overexpressed in obesity mediates AT dysfunction by impairing RA synthesis and ATRA may confer protection against obesity-induced metabolic comorbidities. Funding Sources This project was partially supported by the US Department of Agricultural Experiment Station (MAS00503).

P-selectin glycoprotein ligand-1 supports rolling on E- and P-selectin in vivo

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3585-3591 ◽  
Author(s):  
Keith E. Norman ◽  
Andreas G. Katopodis ◽  
Gebhard Thoma ◽  
Frank Kolbinger ◽  
Anne E. Hicks ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Rolling Velocity ◽  
Selectin Ligand ◽  
Factor Alpha ◽  
Observable Event ◽  
Slow Rolling ◽  
Necrosis Factor

Abstract Selectin-dependent rolling is the earliest observable event in the recruitment of leukocytes to inflamed tissues. Several glycoproteins decorated with sialic acid, fucose, and/or sulfate have been shown to bind the selectins. The best-characterized selectin ligand is P-selectin glycoprotein-1 (PSGL-1) that supports P-selectin– dependent rolling in vitro and in vivo. In vitro studies have suggested that PSGL-1 may also be a ligand for E- and L-selectins. To study the in vivo function of PSGL-1, without the influence of other leukocyte proteins, the authors observed the interaction of PSGL-1–coated microspheres in mouse venules stimulated to express P- and/or E-selectin. Microspheres coated with functional recombinant PSGL-1 rolled in surgically stimulated and tumor necrosis factor alpha (TNFα)-stimulated mouse venules. P-selectin deficiency or inhibition abolished microsphere rolling in surgically and TNFα-stimulated venules, whereas E-selectin deficiency or inhibition increased microsphere rolling velocity in TNFα-stimulated venules. The results suggest that P-selectin–PSGL-1 interaction alone is sufficient to mediate rolling in vivo and that E-selectin–PSGL-1 interaction supports slow rolling.

scholarly journals Abnormal lymphokine production: a novel feature of the genetic disease Fanconi anemia. II. In vitro and in vivo spontaneous overproduction of tumor necrosis factor alpha

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1216-1225 ◽  
Author(s):  
F Rosselli ◽  
J Sanceau ◽  
E Gluckman ◽  
J Wietzerbin ◽  
E Moustacchi
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Fanconi Anemia ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract We have previously shown an unbalanced cytokine production in Fanconi anemia (FA) cells, ie, an underproduction of interleukin 6 (IL-6) during growth. Among a number of cytokines analyzed, the only other anomalies detected concern tumor necrosis factor alpha (TNF alpha). In comparison to normal cells, this cytokine is overproduced by FA lymphoblasts from the four genetic complementation groups. Indeed, up to an eight-fold increase in TNF alpha is observed in the growth medium of FA cells. Moreover, addition of anti-TNF alpha antibodies partially corrects the FA hypersensitivity to treatment by mitomycin C (MMC). Treatment of FA cells with IL-6, which partially restored an almost normal sensitivity to MMC of FA cells also reduces the TNF alpha overproduction in FA lymphoblasts. No anomalies at the molecular level (Southern and Northern blot analyses) are detected for the TNF alpha gene and its mRNA. We have investigated the in vivo situation by assaying TNF alpha levels in the serum from FA homozygotes and obligate heterozygotes. In contrast to normal healthy donors or to aplastic anemia patients in whom serum TNF alpha is present only in trace amounts, all 36 FA patients and 21 FA parents monitored show a significantly (P < .001) higher level of serum TNF alpha activity. Consequently, abnormal TNF alpha production seems to be associated with the FA genetic background.

scholarly journals Spontaneous production of tumor necrosis factor alpha by Kupffer cells of MRL/lpr mice.

1988 ◽  
Vol 168 (2) ◽  
pp. 789-794 ◽  
Author(s):  
D B Magilavy ◽  
J L Rothstein
Keyword(s):  
Kupffer Cells ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Short Term ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Short Term Culture

We report that freshly isolated, unstimulated Kupffer cells (KC) from MRL/lpr female mice in short-term culture spontaneously produce high levels of TNF-alpha. TNF production was first detected in KC cultures at age 6 wk and increased with the age of the mice. Moreover, the levels of spontaneous TNF production by KC directly correlated with the age of the MRL/lpr mice. Although TNF production by KC could be induced with C. parvum in vivo or LPS in vitro in all nonautoimmune C3H/HeN, BALB/c, DBA/2, C57B16 mice, the only other strain in which spontaneous TNF production by KC was observed was MRL/++ mice greater than 10 mo old.

scholarly journals Differential Tumor Necrosis Factor Alpha Expression and Release from Peritoneal Mouse Macrophages In Vitro in Response to Proliferating Gram-Positive versus Gram-Negative Bacteria

2000 ◽  
Vol 68 (8) ◽  
pp. 4422-4429 ◽  
Author(s):  
Wei Cui ◽  
David C. Morrison ◽  
Richard Silverstein
Keyword(s):  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Gram Negative ◽  
E Coli ◽  
Tnf Α ◽  
Mouse Macrophages ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Viable Escherichia coli and Staphylococcus aureus bacteria elicited markedly different in vitro tumor necrosis factor alpha (TNF-α) responses when placed in coculture with peritoneal murine macrophages. These include quantitative differences in TNF-α mRNA expression and corresponding protein product secretion as well as kinetic differences in the profiles of the TNF-α responses. Further, lipopolysaccharide (from E. coli) is a major contributing factor to these differences, as revealed by comparative experiments with endotoxin-responsive (C3Heb/FeJ) and endotoxin-hyporesponsive (C3H/HeJ) macrophages. Nevertheless, the eventual overall magnitude of the TNF-α secretion of macrophages in response to S. aureus was at least equivalent to that observed with E. coli, while appearing at time periods hours later than the E. coli-elicited TNF-α response. Both the magnitude and kinetic profile of the TNF-α responses were found to be relatively independent of the rate of bacterial proliferation, at least to the extent that similar results were observed with both viable and paraformaldehyde-killed microbes. Nevertheless, S. aureus treated in culture with the carbapenem antibiotic imipenem manifests markedly altered profiles of TNF-α response, with the appearance of an early TNF-α peak not seen with viable organisms, a finding strikingly similar to that recently reported by our laboratory from in vivo studies (R. Silverstein, J. G. Wood, Q. Xue, M. Norimatsu, D. L. Horn, and D. C. Morrison, Infect. Immun. 68:2301–2308, 2000). In contrast, imipenem treatment of E. coli-cocultured macrophages does not significantly alter the observed TNF-α response either in vitro or in vivo. In conclusion, our data support the concept that the host inflammatory response of cultured mouse macrophages in response to viable gram-positive versus gram-negative microbes exhibits distinctive characteristics and that these distinctions are, under some conditions, altered on subsequent bacterial killing, depending on the mode of killing. Of potential importance, these distinctive in vitro TNF-α profiles faithfully reflect circulating levels of TNF-α in infected mice. These results suggest that coculture of peritoneal macrophages with viable versus antibiotic-killed bacteria and subsequent assessment of cytokine response (TNF-α) may be of value in clarifying, and ultimately controlling, related host inflammatory responses in septic patients.

Somnogenic, pyrogenic, and anorectic activities of tumor necrosis factor-alpha and TNF-alpha fragments

1992 ◽  
Vol 263 (3) ◽  
pp. R708-R715 ◽  
Author(s):  
L. Kapas ◽  
L. Hong ◽  
A. B. Cady ◽  
M. R. Opp ◽  
A. E. Postlethwaite ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

Exogenously administered tumor necrosis factor-alpha (TNF-alpha) elicits several symptoms of generalized infections such as fever, increased sleep, and anorexia. The aim of the present work was to localize these effects of TNF-alpha to specific amino acid sequences of the parent molecule by characterizing the in vivo and in vitro activities of several synthetic TNF-alpha fragments. Intracerebroventricular injection of TNF-alpha elicited dose-dependent fevers and increases in non-rapid-eye-movement sleep (NREMS) in rabbits. Four fragments also promoted NREMS and five elicited monophasic fevers. All of the somnogenic fragments share the amino acid sequence 31-36. In rats, TNF-alpha and one of the fragments [TNF-alpha-(69-100)] suppressed 12-h food intake. Furthermore, TNF-alpha increased the expression of the intercellular adhesion molecule-1 and enhanced interferon-gamma-induced HLA-DR expression in human glioblastoma cell line. In contrast, none of the fragments possessed these in vitro activities. Our in vivo results support the concept that there are biologically active regions in the TNF-alpha molecule.

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