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.
