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Hypothesis and Future Directions of Research

Dig Dis 2012;30:70–74 DOI: 10.1159/000335722

The Role of Visceral Fat

Arvind Batra Britta Siegmund

Charité – Universitätsmedizin Berlin, Medizinische Klinik I, Berlin , Germany

and M2 macrophages represents a prognostic marker for the disease course. In conclusion, the visceral fat tissue repre-sents a complex organ with multifaceted function linking the endocrine and the immune system.

Copyright © 2012 S. Karger AG, Basel

Introduction

The adipose tissue had originally been considered as being for energy storage with endocrine function. Emerg-ing data from the last decade suggest a multitude of ad-ditional regulatory tasks. In healthy subjects, the total adipose tissue can account for 10–20% of the body weight in males and 20–30% in females [1] . From a structural point of view, the so-called fat tissue includes far more than adipocytes and their precursors the preadipocytes. Depending on the surrounding milieu, fibroblasts, endo-thelial cells as well as infiltrating leukocytes and macro-phages build this complex compartment. The various in-filtrating cell populations as well as the adipocytes them-selves release a broad panel of mediators thus directly affecting metabolism and the immune system. With this review, we aim to outline the key functions of the viscer-al fat tissue considering the close proximity to the in-flamed site in diverticulitis.

Key Words

Visceral fat � Adipokines � Innate immune system

Abstract

Until a decade ago, fat tissue had been exclusively consid-ered as an endocrine organ. The emerging functional char-acterization of adipokines as well as adipocytes and preadi-pocytes suggested for the first time a close link between the endocrine and the immune system. This is emphasized by the changes of the expression pattern of adipokines when the fat tissue is adjacent to inflamed sites. In addition, adipo-kines are capable of regulating adaptive and acquired im-mune responses. Remarkably, adipocytes express functional pattern recognition receptors and can consequently re-spond to bacterial and viral antigens. This seems to be high-ly relevant for intestinal inflammation and here in particular transmural inflammation where bacteria or bacterial anti-gens translocalize into the mesenteric fat tissue. Besides phagocytosis of these antigens, adipocytes as well as pre-adipocytes can be activated resulting in a release of adipo-kines and chemokines mediating the infiltration of immune cells thus allowing for an immune response. Recent data sug-gest that the adipokine milieu of the fat tissue closely regu-lates the polarization of infiltrating immune cells. This is of increasing interest since the pattern of infiltrating cells al-lows for a characterization of the underlying disease. Thus, in obesity pro-inflammatory M1 macrophages dominate this site. Remarkably, in colorectal carcinoma the presence of M1

Britta Siegmund, MD Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin Medizinische Klinik I, Hindenburgdamm 30 DE–12200 Berlin (Germany) Tel. +49 30 8445 4039, E-Mail britta.siegmund   @   charite.de

© 2012 S. Karger AG, Basel0257–2753/12/0301–0070$38.00/0

Accessible online at:www.karger.com/ddi

The Role of Visceral Fat Dig Dis 2012;30:70–74 71

Visceral Fat

The localization of white adipose tissue within the body is heterogeneous. These different deposits exert various functions and are thus involved in the regulation of metabolic as well as inflammatory pathways. The white adipose tissue surrounding the viscera is named visceral fat and is the site of white adipose tissue studied in profound detail with regard to its implication in met-abolic and chronic inflammatory disorders. For in-stance, an augmentation of the visceral fat is closely as-sociated with an increased risk of developing a metabol-ic syndrome [2] . Remarkably, in Crohn’s disease, the visceral fat at the site of the inflamed small or large bow-el is not only characterized by a hypertrophy, which oc-curs by a fourfold increase in adipocyte number, but in addition covers the mesenteric site of the inflamed intes-tine. This phenomenon represents part of the initial dis-ease description by Burrill Crohn himself and has been formally confirmed by MRI studies a decade ago [3, 4] . These studies additionally revealed an increased expres-sion of the pro-inflammatory mediators TNF- � and the adipokine leptin in the visceral fat of Crohn’s disease pa-tients [4] . Due to these findings, the majority of studies focusing on the role of the visceral fat in intestinal in-flammation are based on this hallmark in patients with Crohn’s disease.

With regard to the focus of this review, we have to con-sider what impact these findings might have for diver-ticular disease. From an anatomic point of view the di-verticula are in close proximity to the visceral fat. The intra-abdominal view for the surgeon in chronic diver-ticulitis is characterized by adhesions of the colon to the surrounding tissue including the visceral fat. Thus, as outlined below, the results of various functional studies performed with regard to Crohn’s disease might equally apply to diverticulitis and in particular the chronic in-flammatory course ( fig. 1 ).

Diverticulitis, depending on the stage of disease, re-sults in the translocation of bacteria. Considering the an-atomical view described above translocalizing bacteria in diverticulitis will presumably be found in the surround-ing tissue including visceral fat. Consequently the ques-tion occurs of what might be the response of the visceral fat?

Recognition of Danger by Visceral Fat

The release of free fatty acids by adipocytes following LPS stimulation, and hence responsiveness of fat cells to bacterial components, is an effect detected over 30 years ago [5] . In the next step, the expression of the pattern rec-ognition receptors Toll-like receptors (TLR) 2 and 4 was detected on adipocytes generated from the 3T3L1 cell line [6] . Subsequent data from our group and others revealed that adipocytes as well as their precursors from mouse and man express a broad set of TLRs and that specific stimulation induces secretion of immune regulatory me-diators [7–9] . In addition, the expression of pattern rec-ognition receptors is not restricted to TLR, our group added evidence indicating that preadipocytes express the functional intracellular pattern recognition receptors nu-cleotide oligomerization domains (NOD) 1 and 2 [10] . Expression of NOD1 is regulated by TNF- � or LPS while expression of NOD2 by IFN- � [10] . Thus, one can assume that the visceral fat surrounding the inflamed diverticle is capable of ‘responding’ in case of bacterial translocal-ization. Responding implies the subsequent release of various mediators that are then capable of inducing an effector response within the visceral fat. The various fac-tors produced and the following effector response will be discussed in the next paragraph.

In addition, preadipocytes offer their own first line of defense for translocalizing antigens, demonstrating phagocytic and antimicrobial activity [11] . These find-ings indicate that preadipocytes share functional proper-

Gut microbiota

Inflamed diverticle

Visceral fat

Fig. 1. Anatomical considerations in diverticular disease. In di-verticlitis the intestinal wall gets leaky in areas of inflamed diver-ticles and thus facilitates the translocalization of bacteria. The bacteria then reach the visceral fat where they can actively stimu-late adipocytes as well as their precursors via receptors of the in-nate immune system. Alternatively, these antigens can directly be phagocytosed by preadipocytes.

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Dig Dis 2012;30:70–7472

ties with macrophages. This is further underlined by data showing that murine preadipocytes injected in the peri-toneum of nude mice rapidly acquired high phagocytic activity. Furthermore, 60–70% of the injected cells ex-pressed macrophage markers such as Mac-1, F4/80 and CD80 [12] . Consequently, the visceral fat cannot only re-spond to antigens by the secretion of mediators but can rather directly ‘fight against the harmful intruders’.

Adipokines

A panel of diverse mediators can be released by pre-adipocytes and adipocytes including cytokines such as IL-6, IL-10, or TNF- � , chemokines like MCP-1 (CCL2) or IL-8 (CXCL-8) in addition to adipokines including leptin and adiponectin [13] . While the possible role of chemo-kine production will be further discussed in the next paragraph, we will first focus on the role of adipokines with regard to the inflammatory signal. Since the most detailed data are available for leptin and adiponectin, the summary provided will be restricted to those two adipo-kines ( table 1 ).

Leptin This is the best characterized adipokine. Originally

described as hormone or satiety signal for the hypothala-mus [14] , increasing evidence over the last decade sug-gests a regulatory function in the innate as well as the acquired immune system. Remarkably, from a structural point of view leptin could be classified as a helical cyto-kine [15] . Leptin deficiency occurs rarely and is associ-ated with impaired T cell proliferation and an increased mortality in childhood due to infections [16, 17] . Animal studies offer an explanation: here, leptin could be identi-fied in vitro as well as in vivo as a critical factor for T cell proliferation and differentiation [18–20] . Of particular interest with regard to diverticular disease is the finding that leptin, originating from visceral fat, represents a crit-ical factor for the induction and maintenance of intesti-nal inflammation [21] . Thus, to allow for an appropriate T cell response leptin represents a critical mediator and one can only speculate that leptin is equally essential for the inflammatory process in diverticular disease.

Adiponectin Adiponectin serum concentrations are 5–10 � g/ml

making it the most abundant adipokine in the circula-tion. In contrast to other adipokines, adiponectin de-creases in obesity and vice versa. Adiponectin enhances

insulin sensitivity and decreases the expression of ad-hesion molecules in vascular walls, and therefore the artherogenic risk [22] . Adiponectin has a high affinity to form trimers that can further multimerize to polymers, resulting in various high and low molecular isoforms. The biological significance of the different high and low molecular forms is not completely understood at this point. However, anti-inflammatory properties on mono-cytes are exclusively mediated by the low molecular iso-form [23] . While generally adiponectin is considered as anti-inflammatory, the data in models of intestinal in-flammation are conflicting. While one group observed an increased susceptibility to the chemically induced model of dextran sulphate sodium (DSS) colitis, another reported protection against DSS- as well as trinitroben-zene sulphonic acid-induced colitis in adiponectin-defi-cient mice [24, 25] . In addition, a third study reported that adiponectin deficiency did not affect the outcome of dis-ease in IL-10-deficient mice that develop colitis sponta-neously [26] . Thus, at this point it is difficult to determine the definite role of adiponectin; however, there is no doubt that adiponectin does in fact modulate the im-mune response.

What are then the resulting consequences of adipo-cyte activation, adipokine, chemokine secretion, in other terms what is the ultimate result and thus the hypothe-sized impact for diverticular disease?

Consequences of Adipocyte Stimulation

Visceral fat represents a complex compartment con-sisting of adipocytes, preadipocytes, stromal cells, vascu-lar cells, macrophages, T cells and neutrophils. In health, only few cells can be found integrated in this compart-ment. In contrast, for example in obesity, an increased

Table 1. A dipokines released by visceral fat – implication for di-verticular disease

Adipokine Regulatory impact References

Leptin – T cell stimulation– Modulation of innate immune response– Pro-inflammatory role in models of

intestinal inflammation

[7, 10,18–20]

Adipo-nectin

– Anti-inflammatory– Contradictory results with regard to

intestinal inflammation

[24, 25]

The Role of Visceral Fat Dig Dis 2012;30:70–74 73

influx of macrophages into the adipose tissue has been observed. Here the number of adipose tissue macro-phages correlate with BMI and the increased production of chemokines and adipokines by these cells [27, 28] . Of interest, not only the number but also the phenotype of macrophages is changing towards a more pro-inflamma-tory so-called M1 type. These M1-type macrophages preferably release pro-inflammatory markers such as IL-6, TNF- � and IL-1. In sharp contrast, macrophages found within the visceral fat of lean individuals are char-acterized by the production of IL-10, IL-1Ra and TGF- � [29, 30] . The pro-inflammatory phenotype of M1 macro-phages includes the production of CXCL9 or CCL3/4 [31] . M2 macrophages express chemokines that attract acti-vated effector immune cells, but also CCL18 or CCL24 chemotactic for resting T cells, eosinophils and human Th2 cells [32–34] .

These data, in addition to unpublished data from our own group, suggest that the visceral fat compartment is strongly modulated and shaped by this process and is likely to significantly alter the disease course.

Conclusion

We suggest a working model as follows. Diverticular disease results in a bacterial translocation into the vis-ceral fat. This translocation is accompanied by a stimula-tion of adipocytes and preadipocytes via pattern recog-nition receptors resulting in the release of various me-diators including adipokines and chemokines. These mediators not only regulate the immune response in the intestinal wall but also influence the visceral fat com-partment and enhance defense against translocating bacteria.

Disclosure Statement

The authors declare that no financial or other conflict of inter-est exists in relation to the content of the article.

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