PROJECT SUMMARY
Obesity is rapidly becoming a global epidemic. Obesity drives inflammatory processes in the body's visceral
white fat. This inflammation acts systemically to promote “metabolic syndrome”, a confluence of clinical
manifestations including insulin resistance and high blood sugar, high levels of cholesterol and triglycerides in
the blood, hypertension, and cardiovascular disease progression. A white blood cell central to this process, the
invariant natural killer T cell (iNKT cell), interacts directly with fat cells to depress inflammation. iNKT cell
abundance in fat varies between genetically diverse mouse strains and between human patients. However, for
reasons not yet understood, these important immune regulatory cells are lost from white fat as individuals (both
mice and humans) transition from a lean to an obese state. Most of our knowledge of regulation of white fat
comes from studies of a single inbred mouse strain. To better understand the functioning of the immune
system of white fat, we will study fat cells in a mouse population (Collaborative Cross; CC) that models levels
of genetic diversity found in humans. We hypothesize that strain-dependent differences in fat iNKT cell
abundance affect the consequences of high fat diet-driven inflammation. To address this hypothesis, we will
create an unbiased, comprehensive cellular atlas of the white visceral fat in strains representing each of the
three subspecies that contributed ancestry to the CC (Aim 1). We will use cutting edge technology, single cell
RNA-Seq, to build this atlas, which will result in a catalog of the cells present in white visceral fat and an
understanding of the heterogeneity of each cell population. Furthermore, we will use the CC resource at The
Jackson Laboratory along with our cellular atlas of the visceral white fat to examine 36 genetically diverse CC
strains of mice fed either a normal or high fat diet. We will determine the effect of high fat diet on the immune
cell composition of white visceral fat in addition to examining mice for signs of metabolic syndrome (Aim 2).
Our focus will be on the role of iNKT cells as members of a complex immune cell network, where cells
communicate with each other and can influence the behavior of other cells. By correlating immune cell
abundance and indicators of metabolic disease, we will gain insight into the immune regulation of visceral fat.
Furthermore, this survey of 36 strains will yield strains where high fat diet-induced cellular changes diverge in
direction or magnitude from previously observed patterns, which would constitute valuable new models for
studying immunoregulatory mechanisms relevant to many diseases exacerbated by obesity. Overall, the
proposed project will lay the groundwork for future studies examining the detailed mechanisms through which
the immune system regulates visceral white fat and identifying potential therapeutic targets for the many
diseases associated with metabolic syndrome.
