Macrophage Migration Inhibitory Factor in Acute Adipose Tissue Inflammation

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer binding protein (C/EBP)α, and C/EBPδ decreased with MIF siRNA transfection, but C/EBPβ expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1–3 d and from 14–20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPδ expression.

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Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance

Proceedings of The Nutrition Society ◽

10.1017/s0029665112000730 ◽

2012 ◽

Vol 71 (4) ◽

pp. 622-633 ◽

Cited By ~ 41

Author(s):

Orla M. Finucane ◽

Clare M. Reynolds ◽

Fiona C. McGillicuddy ◽

Helen M. Roche

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Metabolic Diseases ◽

Inhibitory Factor ◽

Low Grade ◽

Macrophage Migration ◽

Pharmacological Agents

High-fat diet (HFD)-induced obesity has emerged as a state of chronic low-grade inflammation characterised by a progressive infiltration of immune cells, particularly macrophages, into obese adipose tissue. Adipose tissue macrophages (ATM) present immense plasticity. In early obesity, M2 anti-inflammatory macrophages acquire an M1 pro-inflammatory phenotype. Pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β produced by M1 ATM exacerbate local inflammation promoting insulin resistance (IR), which consequently, can lead to type-2 diabetes mellitus (T2DM). However, the triggers responsible for ATM recruitment and activation are not fully understood. Adipose tissue-derived chemokines are significant players in driving ATM recruitment during obesity. Macrophage migration inhibitory factor (MIF), a chemokine-like inflammatory regulator, is enhanced during obesity and is directly associated with the degree of peripheral IR. This review focuses on the functional role of macrophages in obesity-induced IR and highlights the importance of the unique inflammatory cytokine MIF in propagating obesity-induced inflammation and IR. Given MIF chemotactic properties, MIF may be a primary candidate promoting ATM recruitment during obesity. Manipulating MIF inflammatory activities in obesity, using pharmacological agents or functional foods, may be therapeutically beneficial for the treatment and prevention of obesity-related metabolic diseases.

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The Role of Macrophage Migration Inhibitory Factor in Adipose-Derived Stem Cells Under Hypoxia

Frontiers in Physiology ◽

10.3389/fphys.2021.638448 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elena Hofmann ◽

Josefin Soppert ◽

Tim Ruhl ◽

Epameinondas Gousopoulos ◽

Simona Gerra ◽

...

Keyword(s):

Stem Cells ◽

Adipose Tissue ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Erk Signaling ◽

Macrophage Migration ◽

Adipose Derived Stem Cells ◽

Tissue Samples ◽

Healing Wounds

Background: Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue.Methods: Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody.Results: Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs.Conclusions: Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β.

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Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats

British Journal Of Nutrition ◽

10.1017/s0007114512005193 ◽

2013 ◽

Vol 110 (3) ◽

pp. 456-465 ◽

Cited By ~ 32

Author(s):

Nataša Veličković ◽

Ana Djordjevic ◽

Ana Vasiljević ◽

Biljana Bursać ◽

Danijela Vojnović Milutinović ◽

...

Keyword(s):

Adipose Tissue ◽

Mrna Expression ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Metabolic Inflammation ◽

High Fructose Diet ◽

High Fructose ◽

Tnf Α

High fructose consumption is commonly associated with insulin resistance, disturbed glucose homeostasis and low-grade inflammation. Increased glucocorticoid production within adipose tissue has been implicated in the pathogenesis of fructose-induced metabolic syndrome. Immunosuppressive actions of glucocorticoids can be counter-regulated by macrophage migration inhibitory factor (MIF), which is recognised as a key molecule in metabolic inflammation. In the present study, we hypothesised that coordinated action of glucocorticoids and MIF can mediate the effects of a high-fructose diet on adipose tissue and liver inflammation. We examined the effects of long-term consumption of a 10 % fructose solution on corticosterone (CORT) and MIF levels in rat blood plasma, liver and adipose tissue, as well as MIF and TNF-α mRNA expression and NF-κB activation in the same tissues. The high-fructose diet led to an increase in both CORT and MIF in the adipose tissue, and a highly significant positive correlation between their levels was observed. The attenuated NF-κB activation and unaltered TNF-α mRNA expression noticed in the adipose tissue could be interpreted as an outcome of the opposing actions of CORT and MIF. In contrast to adipose tissue, inflammation in the liver was characterised by NF-κB activation, an increased TNF-α mRNA level and unchanged levels of MIF protein, MIF mRNA and CORT. Overall, these findings suggest that a high-fructose diet differently affects the levels of glucocorticoids and MIF in the adipose tissue and liver, implicating that fructose over-consumption has tissue-specific effects on regulation of metabolic inflammation.

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