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.
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.
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.
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