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Creeping fat in Crohn’s disease: travelling in a creeper lane of research?
  1. A Schäffler,
  2. H Herfarth
  1. Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
  1. Correspondence to:
    Dr A Schäffler
    Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany; andreas.schaeffler{at}klinik.uni-regensburg.de

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Identification of a distinct secretion pattern of adipocytokines from creeping fat in Crohn’s disease and from mesenteric adipose tissue in chronic inflammatory bowel diseases (IBD) or mesenteric diseases can be considered as work in progress. Characterisation of visceral adipose tissue by its highly active secretory products may lead to the discovery of specific discrimination and activity markers in IBD and may provide future targets for drug therapy. In addition, the cellular compartment of macrophages residing within the mesenteric adipose tissue is becoming recognised as bearing pathophysiological relevance.

DR BURRIL B CROHN AND THE CREEPING FAT

The connective and adipose tissue changes observed in patients with Crohn’s disease (CD) have received only little attention from pathologists, although fat hypertrophy, fat wrapping (fat creeping upon the bowel), and creeping fat have long been recognised by surgeons as a phenomenon suitable for delineating the extent of active disease. Dr Burril B Crohn himself, who gave his name to this chronic inflammatory bowel disease, initially described the changes in the appearance of the mesenteric adipose tissue as a characteristic symptom of the disease.1 Sheehan and colleagues2 and others3 defined fat wrapping as present if more than 50% of the intestinal surface is covered by adipose tissue. Fat encroachment of the antimesenteric surface of the bowel displays a characteristic feature of CD, leading to complete enveloping of the antimesenteric surface and obliteration of the bowel-mesentery angle.3

To date, the pathophysiology of creeping fat has been investigated only sporadically2–5 and it seems to have fallen into oblivion.6

WHY DOES ADIPOSE TISSUE MATTER?

Adipose tissue has long been regarded as a passive type of connective tissue that stores energy as triglycerides and releases energy as free fatty acids. However, due to the wide variety of hormones, proteins, peptides, complement factors, cytokines, enzymes, and receptors expressed in and secreted by adipocytes, the total adipose tissue mass is currently being recognised as a real endocrine organ.7–11 Thus the term “adipocytokines”12 has been introduced for these highly active adipocyte derived cytokines, such as adiponectin, resistin, leptin, interleukin 6 (IL-6), tumour necrosis factor α (TNF-α), and many others. Macrophages infiltrating adipose tissue can transdifferentiate from local preadipocytes,13 suggesting the hypothesis that adipocytes and macrophages may be interconvertible. Charriere and colleagues13 demonstrated that stroma-vascular cells from adipose tissue or 3T3-L1 preadipocytes can transdifferentiate to macrophages and acquire phagocytic activity. As these preadipocytes express macrophage specific antigens such as F4/80, Mac-1, CD80, CD86, and CD45, preadipocytes and macrophages may not be too different.14 The observation that adipocytes can function as macrophage-like cells by expressing and secreting molecules related to inflammation and innate immunity directly brings the mesenteric adipose tissue into the focus of mesenteric diseases.

ADIPONECTIN, AN ANTI-INFLAMMATORY MEMBER OF THE C1Q/TNF SUPERFAMILY

Adiponectin, a new member of the C1q/TNF molecular superfamily,15 is abundantly present in human sera and circulates as monomer, trimer, and high molecular weight forms. Apart from full length adiponectin, globular adiponectin is also biologically active.16 Recently, two adiponectin receptors, hAdipoR1 and hAdipoR2, have been cloned.17 The signalling pathways are currently under investigation and phosphorylation of the insulin receptor, activation of the AMP activated protein kinase, activation of peroxisome proliferator activated receptor (PPAR)α, and modulation of nuclear factor kappa B (NFκB) activity have been described as involved.18–20 Besides its metabolic effects in the context of hepatic insulin resistance, type 2 diabetes mellitus, atherosclerosis, and fatty liver, it mainly exerts anti-inflammatory effects on macrophages and endothelial cells. Adiponectin can reduce secretion of TNF-α from monocyte/macrophages and attenuate the biological effects caused by TNF-α.21 Mice lacking adiponectin have high levels of TNF-α mRNA in adipose tissue,22 and viral mediated delivery of adiponectin reverses the increase in adipose tissue TNF-α mRNA. In contrast with leptin,23 adiponectin prevents the attachment of monocytes to TNF-α stimulated endothelial cells24,25 through downregulation of intracellular adhesion molecule 1, extracellular adhesion molecule 1, and E-selectin. Therefore, adiponectin may inhibit the migration of monocytes to the mesenteric adipose tissue and suppress local TNF-α driven proinflammatory pathways.

THE POTENTIAL ROLE OF ADIPONECTIN IN CROHN’S DISEASE

In this issue of Gut, Yamamoto and colleagues26 from the Osaka University School of Medicine, Japan, present an evaluation of adiponectin secretion from hypertrophied mesenteric adipose tissue of patients suffering from CD (see page 789).

They demonstrated that:

  1. tissue concentration and release of adiponectin (but not of IL-6) is significantly elevated in CD compared with patients suffering from ulcerative colitis (UC) or colon cancer,

  2. increased adiponectin secretion in CD is specifically related to inflamed and hypertrophied mesenteric adipose tissue (creeping fat) and not to normal adipose tissue in these patients, and

  3. hypertrophied adipose tissue in CD becomes infiltrated by large amounts of monocytes/macrophages.

While TNF-α inhibits adipogenesis by downregulation of C/EBPα, PPARγ,27,28 and macrophage colony stimulating factor (MCSF),29 activation of PPARγ by synthetic (glitazones) and endogenous ligands (15d-PG-J2) reduces TNF-α and leptin expression and increases adiponectin expression in adipocytes.30 In detail, PPARγ agonists inhibit the expression of proinflammatory cytokines such as IL-1β, IL-2, IL-6, IL-8, monocyte chemoattractant protein (MCP-1), TNF-α, and matrix metalloproteases by transcriptional regulation and interference with signalling pathways such as NFkB (p65, p50), AP-1 (fos/jun), mitogen activated protein kinase cascade, and STAT-1/STAT-331,32 in monocytes/macrophages, endothelial cells, smooth muscle cells, and adipocytes. These data could provide the potential mechanism of an anti-inflammatory action of PPARγ ligands in the context of IBD and creeping fat31 and could potentially be used for both reducing the release of proinflammatory cytokines and increasing the release of anti-inflammatory cytokines such as adiponectin from visceral adipose tissue. In the case of PPARγ, recent data have pointed to this nuclear hormone receptor as a novel anti-inflammatory mediator with broad therapeutic potential in UC and CD.33–35

ADIPOCYTOKINES IN IBD: SECONDARY OR CAUSATIVE?

Sheehan and colleagues2 and Smedh and colleagues4 interpreted fat wrapping solely as a consequence of transmural inflammation and thus as a chronic feature of the disease, probably caused by cytokine release from adjacent lymphoid tissues.2 Similarly, Borley and colleagues5 interpreted the adipose tissue changes as related to the local effects of underlying chronic inflammatory infiltrates and released cytokines such as transforming growth factor β1 and TNF-α. Both cytokines have been discussed in relation to stimulating proliferation and activation of mesenchymal tissues.36–39 TNF-α and PPARγ mRNA expression is increased in mesenteric adipocytes contiguous with the involved intestine in patients with CD40 compared with adipocytes contiguous with healthy intestine or with controls.

However, specific overexpression of PPARγ,40 adiponectin, TNF-α,40 leptin,41 and MCSF42 in mesenteric adipocytes from patients with CD indicates that adipose tissue is an effector in the pathogenesis of CD. Taken together, mesenteric adipose tissue hypertrophy can be regarded as a cause of, or as a consequence of, intestinal inflammation in CD. The presence of mesenteric obesity at the onset of the disease, the axial polarity of inflammation, the association between connective tissue changes and transmural inflammation, and the release of highly active molecules from local adipocytes supports a more active role of adipose tissue in the pathogenesis of CD.

VISCERAL ADIPOSE TISSUE MACROPHAGES: A NEW THERAPEUTIC TARGET?

Xu and colleagues43 and Weisberg and colleagues44 reported that adipose tissue becomes infiltrated by significant amounts of macrophages (but not lymphocytes or granulocytes) in the context of obesity. They also demonstrated that proinflammatory cytokines are produced mainly by adipose tissue homed macrophages rather than by adipocytes. It has been estimated that the percentage of macrophages in adipose tissue ranges from <10% up to >50%,44,45 suggesting a high cellular plasticity of adipose tissue. MCP-1 and macrophage inflammatory protein 1α have been demonstrated to be secreted with increasing amounts from adipose tissue in response to TNF-α43,44,46 and could therefore function as chemoattractants directing macrophage precursors into stores of fat tissue.45,47 Subsequently, a permissive microenvironment created by adipose tissue secretion of MCSF42 could lead to a continuing process of differentiation, transdifferentiation, and maturation of preadipocytic and non-preadipocytic macrophage precursor cells. As the creeping fat in CD is becoming infiltrated by a significant amount of macrophages, the cellular compartment of macrophages residing within the mesenteric adipose tissue is becoming recognised as bearing pathophysiological relevance in IBD.

ADIPONECTIN AND ADIPOCYTOKINES IN GASTROENTEROLOGY

As adipose tissue hypertrophy is only seen in CD, secretory factors specifically expressed in adipose tissue could possibly serve as local or systemic activity markers for the disease or as discriminating markers for the diagnosis (for example, differential diagnosis between CD and UC). Release of highly active proinflammatory cytokines from fat cell necrosis in pancreatitis may explain the severe disease course. In addition, the pathophysiological role of adipocytokines in mesenteric panniculitis and gastrointestinal tumours (adipose tissue infiltration) has to be investigated. The future potential of adiponectin and adipocytokines in gastroenterological diseases is shown in table 1.

Table 1

 The future potential of adiponectin and adipocytokines in gastroenterology

Identification of a distinct secretion pattern of adipocytokines from creeping fat in Crohn’s disease and from mesenteric adipose tissue in chronic inflammatory bowel diseases (IBD) or mesenteric diseases can be considered as work in progress. Characterisation of visceral adipose tissue by its highly active secretory products may lead to the discovery of specific discrimination and activity markers in IBD and may provide future targets for drug therapy. In addition, the cellular compartment of macrophages residing within the mesenteric adipose tissue is becoming recognised as bearing pathophysiological relevance.

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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