Tag Archives: Creeping fat

The Function of Creeping Fat in Crohn’s Disease

Creeping fat, the unusual increase of mesenteric fat deposition in Crohn’s disease (CD), is a common characteristic in CD patients. Even though it was described in the 1930s, scientists have only just begun study it. This is due to increased knowledge about obesity and the realization that it adipose tissue can influence inflammation. While scientists have yet to decipher its true role in CD pathogenesis, there are some interesting hints.

Adipose Tissue Is an Organ with Immune Functions

Early on biomedical scientists assumed that adipose tissue (AT) was passive, however, research in the 1990s changed this concept. It became clear that AT was composed of different cell types: adipocytes, preadipocytes, macrophages, endothelial cells, fibroblasts and leukocytes. These cells functioned together to exert metabolic and immune functions, and secreted various factors such as cytokines, chemokines and hormone factors called adipokines.

Crohn’s Disease with Creeping Fat Is not Obesity

At first glance, it’s obvious that obesity and CD with creeping fat are not the same. The clinical outlook of the two diseases is enormously different. CD is a problem dominated by severe inflammation in the intestines. Those with obesity have only minor issues with inflammation and are, instead, plagued by metabolic problems, such as diabetes and high cholesterol.

Creeping fat is found in more than half of the CD cases, but it doesn’t contribute greatly to body mass index (BMI). Obesity in CD patients is actually rare. This is because creeping fat is actually normal mesenteric fat that is behaving differently, extending from the mesenterium (see figure) to the small or large intestine. In extreme cases, it wraps around more than 50% of the intestinal circumference. It is correlated with increased severity including changes in tissue structure and cellular infiltration.

creeping fat
Creeping fat is an invasive form of mesenteric fat.

AT in obesity and creeping fat is strikingly dissimilar. In obesity, adipocytes grow large and stay the same in number (hypertrophy), while in creeping fat adipocytes have increased proliferation (hyperplasia). The size of creeping fat adipocytes is actually 75% smaller than normal adipocytes.

Obese Adipose Tissue is Inflammatory

While obese AT is not obviously associated with inflammation like creeping fat, it is obesity that introduced AT an immune organ. Studies show that obese patients suffer from what appears to be a low-grade inflammation and their fat has a high proportion of macrophages. This stimulated research into the functions of adipocytes beyond simple fat storage. Many of these findings can still be applied to creeping fat.

Researchers found that adipocytes (fat cells) have functions similar to macrophages. They are able to react to danger signals and secrete immune factors in response, encouraging inflammation and migration of immune cells into AT. Not only that, adipocyte precursors, called preadipocytes, have the ability to convert into macrophages.

Investigations uncovered a variety of factors secreted by adipocytes, which is together called the secretome. The adipocyte secretome included specialized factors like the adipokines leptin and adiponectin; typical pro-inflammatory cytokines like tumor necrosis factor alpha (TNFα), interleukin (IL)-6 and IL-8; chemokines such as CCL2 and CCL8; acute-phase proteins and even antimicrobial peptides.

The adipokine leptin initially was believed to be involved only in appetite suppression. However, later research revealed that it encourages the expression of important pattern-recognition receptors (PRR) that can recognize pathogens. Recent work with leptin has revealed that it can encourage dendritic cell migration to lymphoid tissues to stimulate adaptive immune responses. It also increases macrophage cytokine production and modulates CD4+ T cell polarization. Leptin secretion is proportional to total fat mass. Therefore, obese people secrete more of it and this likely supports their low-grade inflammation.

Another important player in adipocyte-controlled inflammation is adiponectin, which has anti-inflammatory properties. Its secretion is inversely proportional to total fat mass, meaning that lean individuals secrete more of it and obese individuals have less. It exerts its function by downregulating pro-inflammatory pathways initiated by PRRs and encouraging IL-10 secretion.

Interestingly, secreted factors were not the only reasons for mild inflammation in obese patients. It was found that those with the highest levels of pro-inflammatory cytokines in the blood also had high amounts of free fatty acids (FFA). It is believed that free fatty acids may trigger PRRs, like Toll-like receptor 4, and set off inflammatory pathways.

One suspicious observation by obesity researchers is the importance of intra-abdominal fat. They found that the body mass index (BMI) was not nearly so important for determining the risk of inflammation, as was the amount of intra-abdominal fat. Apparently, there’s something special about this area that promotes inflammation.

Creeping Fat and IBD Inflammation

Like obese AT, mesenteric fat of CD patients secretes similar mediators such as pro-inflammatory cytokines, chemokines and acute phase proteins. One striking difference between mesenteric fat from obese individuals and CD patients is the secretion of adiponectin; it is higher in CD patients. Considering its anti-inflammatory function this could suggest that creeping fat may actually be trying to control inflammation instead of making it worse. In fact, a recent study suggests that it may mediate some of functions by supporting IL-10-secreting macrophages.

However, the situation is far too complex for snap hypotheses. Leptin is produced by creeping fat, and it is known from animal models that it causes severe colitis. Creeping fat adipocytes are also a major source of TNFα. Anti-TNF therapies are extremely helpful for lowering CD inflammation, and therefore, it is highly unlikely that creeping fat-derived TNFα would be desired.

PRRs appear to tether inflammation with obesity, and this may be the same for creeping fat. PRRs of the mesenteric fat tissue could be triggered either by FFA or pathogen associated molecules, such as bacterial cell wall components. One well-known gene associated with CD is NOD2. NOD2 recognizes bacterial products, and it is often non-functional in CD patients. Some scientists speculate that the loss of NOD2 function could allow bacteria leaking from the gut to reside in the mesenteric fat surrounding the intestines. This bacteria reservoir hypothesis would suggest that creeping fat develops secondary to an intestinal insult that allows bacteria to translocate from the intestinal lumen to the mesenteric AT depots.

Scientists have determined that, at least, in normal situations, bacterial translocation would lead to inflammatory reactions in the mesenteric fat. Using an animal model, they were able to measure increases in C-reactive protein after bacterial translocation. Furthermore, there is evidence that some immune reactivity is lost in CD patient mesenteric AT. Creeping fat from CD patients was non-responsive towards bacterial pathogens in an ex vivo test. However, there isn’t a complete loss of functionality. Peroxisome proliferator-activated response-gamma (PPAR-γ) is expressed after PRR triggering and it encourages adipocyte proliferation and differentiation. This factor is over expressed in the mesenteric fat of CD patients. Therefore, there may be continual signals from bacteria encouraging the proliferation of adipocytes without proper signals leading to their elimination.

Another hypothesis involves the brain-fat-gut axis. Studies into neuropeptides have given us interesting insights into the relationship between creeping fat and intestinal inflammation. Neuropeptides can be released in CD patients via the central or enteric nervous system. Neuropeptides can instruct adipocytes to release pro-inflammatory cytokines and increase neuropeptide receptor expression (leading to a positive feedback loop). This could increase local inflammation in the neighboring intestines and keep disease active. Moreover, neuropeptides are known to change fat depot physiology by increasing proliferation and reducing apoptosis, which might explain the large adipocyte numbers and unusual fat wrapping seen in creeping fat.

The Future

Creeping fat is an unusual characteristic of Crohn’s disease. New studies looking at the inflammatory potential of AT in obese individuals has set the stage for new interest in this phenomenon. Scientists need to find out if it’s a true participant in maintaining chronic inflammation, an initiator or a simple bystander. The most interesting avenues of research involve figuring out the factors that set the pro-inflammatory activities of AT in motion. Are they FFAs, bacteria, neuropeptides or a combination? It will also be interesting to determine if mesenteric AT can be an initiator of disease in some circumstances or if creeping fat can induce CD flares.

References

Creeping Fat in Crohn’s Disease Leads to Creeping Dendritic Cells

Creeping fat is a form of mesenteric fat that's found in Crohn's disease patients.
Creeping fat is a form of mesenteric fat that’s found in Crohn’s disease patients.

An article in Mucosal Immunology shows that the creeping fat factor, leptin, can cause dendritic cells to become more migratory in Crohn’s disease. Could this be the key to disease progression?

Visit my recent post to learn more about creeping fat.

For this post, there was certainly no lack of interesting options. The journal, Science, just posted an article on the long-term stability of gut microbiota and an article looking at the way that microbiota control regulatory T cell populations. Immunity hosted an article about RORγt innate lymphoid cells and three additional articles about how microbiota interact with and modulate the immune system. I appreciate all of the press that microbiota are now getting, but after my last post and the whole Nature Immunology series on microbiota, it’s time to think of something else. Mucosal Immunology had something different and interesting. In an article by Al-Hassi et al., is a story about Crohn’s disease, fat and dendritic cell migration.

Dendritic cells (DCs) are the scouts of the immune system. They hide out in the peripheral regions of the body, detecting and collecting information on invaders. Once they have collected this information, they become activated and travel to local lymph nodes and alert T cells. This activation process includes the expression of receptors that allow them to detect the signals produced by lymph nodes. C-C motif chemokine receptor 7 (CCR7) is the most important of these receptors, and it recognizes three different ligands produced by lymph nodes and the lymphatic endothelia: CCL19 and two variants of CCL21.

Al-Hassi et al. noted that in Crohn’s disease (CD), there is an increase of mesenteric fat that surrounds the inflamed intestines. This fat is called “creeping fat,” and its adipocytes secrete large amounts of inflammatory mediators, including a mediator called leptin. Leptin is well-known for its ability to modulate DC behavior and encourage a T helper type 1 (Th1) response via leptin receptors (LepRs). Furthermore, leptin encourages the expression of CCR7 on DCs and prolongs their lifespan. The researchers hypothesized that creeping fat via leptin could control DC responses in CD, increasing their ability to travel to local lymph nodes and initiate pro-inflammatory responses.

They first looked at the expression of CCR7 and LepRb on DCs isolated from the colons of healthy individuals. LepRb distinguishes itself from other LepRs by being the only one that can activate the transcription factor, STAT3, which is important for initiating pro-inflammatory gene expression and preventing apoptosis. They found that DCs isolated from the small intestine of healthy individuals expressed both these receptors, but not DCs from the colon. However, in the CD patient DCs, this was different. DCs from CD colons also expressed the receptors too.

Looking at the maturation status between DCs collected from both healthy and patient intestinal samples. They found no real difference indicating that the increased expression of CCR7 and LepRb was not related to the activation status of the DCs themselves. They then performed experiments of a more mechanistic nature, by exposing colon DC from healthy donors to leptin. They found that this led to extensive CCR7 expression (10% to 60%) and the migratory capacity was also sharply increased towards CCL19.

To give the same experiment a more physiological swing, they collected culture supernatant from CD biopsies and added this to isolated, healthy colonic DCs. This also caused the upregulation of CCR7, and the addition of a LepR blocking antibody eliminated the effect, indicating that the likely factor controlling the CCR7 upregulation was the leptin secreted into the supernatant from the CD biopsies.

Although this is a small study, it has a strong message, and one that will probably lead to even more exciting studies. In the discussion, they consider that the difference of expression between small and large intestinal DC may have something to do with increased traffic for the transport of self-antigen to lymph nodes to perpetrate oral tolerance in local T cell populations, which could very well be true. Furthermore, they note that creeping fat does appear early in CD giving it an even better chance to affect CD progression in the long-term.

However, Gut published an article about macrophage populations in creeping fat in June. These researchers found that mediators secreted by the creeping fat adipocytes actually encouraged the M2 macrophage type, which is associated with IL-10 production and an anti-inflammatory function. They speculated that this would indicate a protective role for creeping fat in CD, not a story that fits with the ideas of Al-Hassi et al.

Which leaves us with a lot of questions. While I am convinced of the good intentions of the macrophages in the aforementioned study, I am not convinced about the innocence of the creeping fat. Adipocytes of creeping fat produce many more pro-inflammatory factors besides leptin, and TNFα is one of them. My opinion is that the anti-inflammatory nature of the creeping fat macrophages is more a response to being bathed consistently with pro-inflammatory factors. Their response would then be somewhat similar to the myeloid suppressor cell phenomenon.

Experiments need to be done that look at how dangerous leptin-exposed, CCR7+ DC are in CD patients and examine the real role of creeping fat. Is it the initiator, a propagator or protector in CD?

Thanks for reading. Please let me know what you think about creeping fat in IBD! If you need a bit more background in immunology, visit my basic immunology page.

References:

Al-Hassi, H. O., Bernardo, D., Murugananthan, A. U., Mann, E. R., English, N. R., Jones, A., et al. (2012). A mechanistic role for leptin in human dendritic cell migration: differences between ileum and colon in health and Crohn’s disease. Mucosal Immunology, 6(4), 751–761. doi:10.1038/mi.2012.113

Fink, C., Karagiannides, I., Bakirtzi, K., & Pothoulakis, C. (2012). Adipose Tissue and Inflammatory Bowel Disease Pathogenesis. Inflammatory Bowel Diseases, 18(8), 1550–1557. doi:10.1002/ibd.22893

Kredel, L. I., Batra, A., Stroh, T., Kuhl, A. A., Zeitz, M., Erben, U., & Siegmund, B. (2013). Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut, 62(6), 852–862. doi:10.1136/gutjnl-2011-301424

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