This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is a strong risk factor for atherosclerosis. As fat stores expand, they become increasingly inflamed, releasing inflammatory cytokines, which then negatively affect blood vessel functioning. However, the underlying cause of inflammation during the expansion of adipose tissue is currently unknown. One prominent event is the infiltration of macrophages, though it is still unclear why this happens, and what these macrophages do. Recent studies with mice have suggested that macrophage infiltration occurs relatively late during experimental obesity, which suggests that there are earlier inflammatory events preceding, and perhaps causing macrophage infiltration. We have observed that intestinal fat absorption is associated with the intestinal absorption of antigens from gut microflora. The absorbed antigen was associated with newly secreted chylomicrons, which are the large lipoprotein particles that transport dietary fat via mesenteric lymph into the body proper. Since chylomicrons are prominently cleared in adipose tissue, we will test in the current project the hypothesis that gut antigens are deposited into adipose tissue in a chylomicron-dependent manner. Increased fat feeding would then lead to increased adipose antigen enrichment, followed by lymphocyte infiltration. Our preliminary data suggest that chylomicron formation promotes intestinal absorption and adipose deposition of dietary ovalbumin (OVA), a prototypical experimental T-cell antigen. Our preliminary data also show that adipose enrichment with such T-cell antigens is rapidly followed by T-cell infiltration, which may be an important initial event in adipose inflammation, and which may subsequently recruit macrophages. If our hypothesis is correct, it would not only put the spotlight on the adaptive immune system as an important contributor to adipose inflammation, but also on the intestinal microflora and dietary antigens as potential sources for inflammation in fat tissue, and in many other tissues. It may well be that individuals with reduced tolerance to bacterial or dietary antigens, and who thus would respond to these antigens if they make their way into the body proper, are especially sensitive to obesity-associated inflammation. Moreover, the novel link between fat absorption and gut antigen absorption may profoundly affect our thinking on the way the gut microflora affects our body.
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