Interaction of Mesenteric Adipose Tissue Physiology, Expansion, and Inflammation with Inflammatory Bowel Disease

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Project Summary Over the past two decades there has been a dramatic increase in the prevalence of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, coincident with the obesity epidemic. Obesity and adipose tissue inflammation are linked to whole-body metabolic disturbances as other organs cope with toxic levels of lipid, which would otherwise be safely stored in adipocytes. Of additional importance, adipose tissue is an active endocrine organ that secretes numerous adipokines including hormones and cytokines, regulating systemic glucose homeostasis, lipid metabolism, inflammation, and many other physiological processes. Many clinical and animal studies show a strong link between expansion of intra-abdominal fat, or visceral fat, and increased burden of IBD. The mesenteric visceral adipose tissue depot (MAT) surrounds and supports the gastrointestinal tract, dramatically expands during obesity, and is associated with unfavorable therapeutic outcomes for IBD. However, studying mesenteric adipose tissue is challenging as it is a highly lymphatic and cellularly heterogenous tissue. In this proposal I have applied methods that will isolate mature adipocytes, adipocyte progenitors, and immune cells so that I can study the unique way MAT remodels during obesity and how MAT inflammation affects the progression of IBD. The literature and our preliminary data suggest that during obesity MAT expansion and remodeling is different than other visceral adipose depots. Therefore, I hypothesize that during obesity, MAT undergoes maladaptive remodeling, initiating inflammatory cascades that exacerbates IBD in mice. The first Aim will define pathological MAT expansion during obesity using adipocyte and adipocyte progenitor lineage-tracing mouse models, in-depth characterization of the immune system, and single-cell RNA-sequencing methods. The second Aim will determine the importance of MAT inflammation to IBD progression. The gastrointestinal tract has understandably been the primary focus of study for several well-established mouse models that closely resemble human Crohn's disease. My general approach will be to focus on MAT biology and the role of mesenteric adipocyte inflammation at the intestinal interface. To study MAT/intestinal crosstalk during IBD, I will use mouse models to alter inflammation in MAT in an inducible manner and observe the effect on the severity of intestinal damage and inflammation. Currently, there is an unmet need for the treatment of IBD and no MAT-targeted treatments for IBD exist. Therefore, an understanding of mesenteric adipose tissue during obesity and its communication to the intestine may open up a fruitful area of research for new biomarkers and therapeutic strategies for IBD.