SELECTED SUMMARIES

Visceral Adipose Tissue in Crohn’s Disease:Satan or Samaritan?

Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, et al. Mesenteric fat as a source of C reactive protein and as atarget for bacterial translocation in Crohn’s disease. Gut. 2012;61:78–85.

T here is increasing evidence that visceral adipose tissue

is metabolically active and an important source of sev-

eral hormones and cytokines. Increased visceral adipose

tissue (VAT), called fat wrapping or creeping fat, has been

described as a hallmark of Crohn’s disease (CD) since its

initial description in 1937 by Burril B. Crohn et al.1 Sev-

eral recent studies exploring the significance and conse-

quences of VAT in CD have renewed interest in this

phenomenon.

Peyrin-Biroulet et al2 looked at the expression of C-

reactive protein (CRP) by VAT and inflammatory and bac-

terial triggers for its production by adipocytes. While the

liver is believed to be the exclusive source of CRP in

humans, adipocytes in VAT have previously been shown to

produce CRP in severely obese patients.3 CRP mRNA lev-

els in the mesenteric tissue of CD was 80 6 40 and 1450

6 750 times higher than those detected in the VAT of ul-

cerative colitis (UC) and controls, respectively. CRP

mRNA levels were significantly higher in VAT compared

to paired subcutaneous tissue of only CD patients, and not

UC and control subjects. The intestine was thought

unlikely to be a source of CRP, as similar levels of mRNA

expression were found in both inflamed and normal tissue

in CD and UC patients. Western blot analysis confirmed

this increased expression of CRP at the protein level.

Plasma CRP concentrations also positively correlated with

mesenteric CRP mRNA levels in CD but not UC or control

subjects.

Using the 3T3-L1 preadipocyte cell line the investi-

gators showed that treatment with tumor necrosis factor

alpha (TNF-a) and interleukin (IL)-6 significantly increased

CRP mRNA expression in differentiated adipocytes. CRP

biogenesis was strongly induced by Gram-negative bacteria

and lipopolysaccharide, which was enhanced synergistically

by TNFa. Bacterial translocation to mesenteric adipocytes

was shown to be increased in experimental mice models of

both dextran sodium sulfate (DSS) colitis and indometha-

cin-induced ileitis compared with control mice. Consistent

with the results from animal models, the rate of bacterial

translocation to mesenteric adipocytes was similar to that

in the mesenteric lymph nodes of the CD patients. While

numerically superior, translocation of bacteria to mesen-

teric adipocytes or mesenteric lymph nodes was not signifi-

cantly different between CD and non-CD patients.

COMMENTThis interesting study shows that VAT is a source of

raised CRP in CD, which was probably induced by bacte-

rial translocation to mesenteric adipocytes and circulating

proinflammatory cytokines. Questions remain as to whether

the process of mesenteric fat hyperplasia is a primary or

secondary phenomenon. The presence of increased CRP

mRNA transcript levels in adipose tissue relatively far

away from the diseased intestine is a point in favor of this

process being independent of tissue inflammation. Recent

data that the visceral to subcutaneous fat ratios were higher

in CD patients with more aggressive disease (stricture or

fistula),4 that CRP levels correlate with the amount of vis-

ceral fat,5 and increased intestinal permeability in healthy

women with higher visceral fat volume6 add credence to

the hypothesis that VAT could play a key pathophysiologi-

cal role in CD. However, the presence of elevated CRP

levels rather than the absolute value has been shown to be

associated with disease behavior and response to therapy

with biologics,7,8 suggesting that while some of the

increased CRP in active CD may be sourced from VAT,

further long-term studies are needed to confirm the biologi-

cal significance of this finding.

VAT adipocytes from CD patients have been shown

to be of smaller diameter than those from patients with

severe obesity with a higher expression of antiinflammatory

genes in VAT of CD compared with severe obesity.9 Small

adipocytes are believed to produce fewer proinflammatory

molecules than large adipocytes,10 treatment with inflixi-

mab has been shown to increase VAT by 27%,11 and levels

of adiponectin (which has strong antiinflammatory proper-

ties) are increased in VAT of CD patients,12 supporting a

possible protective role for VAT in CD.

The plasticity that fat cells demonstrate between dif-

ferent depots in the body13 could very well imply that adi-

pocytes could be pro or antiinflammatory based on the

Received for publication October 24, 2011; Accepted December 7,

2011.

Copyright VC 2011 Crohn’s & Colitis Foundation of America, Inc.

DOI 10.1002/ibd.22869

Published online in Wiley Online Library (wileyonlinelibrary.com).

Inflamm Bowel Dis 1

physiological state of the cells in the body. Long-term fol-

low up studies looking at changes in visceral adipose tissue

volumes and biology with time, disease activity, and treat-

ment are needed to make firm conclusions on the role of

this intriguing phenomenon in the pathophysiology of CD.

Venkataraman Subramanian, MD, DM, MRCP (UK)Leeds Gastroenterology Institute

Leeds Teaching Hospital NHS Trust

Leeds Institute of Molecular Medicine

St James University Hospital

University of Leeds

Leeds, UK

REFERENCES1. Crohn BB, Ginzburg L, Oppenheimer GD. Landmark article Oct 15,

1932. Regional ileitis. A pathological and clinical entity. By Burril B.Crohn, Leon Ginzburg, and Gordon D. Oppenheimer. JAMA. 1984;251:73–79.

2. Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, et al. Mesenteric fat as asource of C reactive protein and as a target for bacterial translocationin Crohn’s disease. Gut. 2012;61:78–85.

3. Anty R, Bekri S, Luciani N, et al. The inflammatory C-reactive pro-tein is increased in both liver and adipose tissue in severely obesepatients independently from metabolic syndrome, Type 2 diabetes, andNASH. Am J Gastroenterol. 2006;101:1824–1833.

4. Erhayiem B, Dhingsa R, Hawkey CJ, et al. Ratio of visceral to subcu-

taneous fat area is a biomarker of complicated Crohn’s disease. ClinGastroenterol Hepatol. 2011;9:684–687.

5. Desreumaux P, Ernst O, Geboes K, et al. Inflammatory alterations inmesenteric adipose tissue in Crohn’s disease. Gastroenterology. 1999;117:73–81.

6. Gummesson A, Carlsson LM, Storlien LH, et al. Intestinal permeabil-ity is associated with visceral adiposity in healthy women. Obesity(Silver Spring). 2011;19:2280–2282.

7. Henriksen M, Jahnsen J, Lygren I, et al. C-reactive protein: a predictivefactor and marker of inflammation in inflammatory bowel disease. Resultsfrom a prospective population-based study. Gut. 2008;57:1518–1523.

8. Jurgens M, Mahachie John JM, Cleynen I, et al. Levels of C-reactiveprotein are associated with response to infliximab therapy in patientswith Crohn’s disease. Clin Gastroenterol Hepatol. 2011;9:421–427.

9. Zulian A, Cancello R, Micheletto G, et al. Visceral adipocytes: oldactors in obesity and new protagonists in Crohn’s disease? Gut. 2012;61:86–94.

10. Skurk T, Alberti-Huber C, Herder C, et al. Relationship between adi-pocyte size and adipokine expression and secretion. J Clin EndocrinolMetab. 2007;92:1023–1033.

11. Parmentier-Decrucq E, Duhamel A, Ernst O, et al. Effects of inflixi-mab therapy on abdominal fat and metabolic profile in patients withCrohn’s disease. Inflamm Bowel Dis. 2009;15:1476–1484.

12. Yamamoto K, Kiyohara T, Murayama Y, et al. Production of adipo-nectin, an anti-inflammatory protein, in mesenteric adipose tissue inCrohn’s disease. Gut. 2005;54:789–796.

13. Tchkonia T, Tchoukalova YD, Giorgadze N, et al. Abundance of twohuman preadipocyte subtypes with distinct capacities for replication,adipogenesis, and apoptosis varies among fat depots. Am J PhysiolEndocrinol Metab. 2005;288:E267–E277.

Inflamm Bowel DisSubramanian

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