The Response of White Adipose Progenitor Cells to Physiological and Genetic Changes

dc.contributor.advisorJohnson, Jane E
dc.contributor.committeeMemberMangelsdorf, David J
dc.contributor.committeeMemberOlson, Eric N
dc.contributor.committeeMemberGraff, Jonathan M
dc.creatorZeve, Daniel 2013
dc.description.abstractWe are in the midst of a dire, unprecedented and global epidemic of obesity and secondary sequelae, most prominently diabetes and hyperlipidemia. Underlying this epidemic are adipocytes and their inherent, dynamic ability to expand and renew. These abilities highlight a newly defined cell population within adipose tissue, the white adipose progenitor cell. These cells have the basic abilities that define a stem/progenitor cell, including the ability to proliferate and differentiate into mature adipocytes, opening up new studies into their involvement in both adipose development and growth. More specifically, interest lies in which physiological and genetic conditions can repress the adipogenic function of these cells, as these findings could lead to possible therapies for obesity and other metabolic diseases. We began our studies by examining the proliferative and adipogenic effect of both high fat diet and exercise on adipose progenitor cells. We found that while high fat diet increased adipose progenitor function, exercise dramatically reduced proliferation of the adipocyte progenitor in addition to diminishing new adipocyte formation during the exercise protocol. One physiological outcome of endurance exercise is the remodeling of skeletal muscle to more of a slow, oxidative fiber type composition. Thus, we hypothesized that type I skeletal muscle may also regulate the adipocyte progenitor. To directly test this hypothesis we analyzed the adipose progenitor cell in two, independent mouse lines that exhibit an increase of Type I fibers. These mice revealed that slow muscle fibers also reduce the activity of the adipocyte progenitor on normal chow and decrease adiposity while on high fat diet. Surprisingly, this effect may be due to non-nutritional factors, as the slow fiber mice exhibit no overt metabolic alterations on normal chow and conditioned media from muscle cell lines reduced pre-adipocyte function. These data suggest Type I fibers directly regulate the adipocyte progenitor cell, which may contribute to the reduced adiposity seen after exercise as well as the reduced adiposity of slow fiber mice in response to high fat diet. We next wanted to examine the genetics that control adipogenesis within the adipose progenitor cells. To do this, we activated Wnt signaling in either adipose progenitor cells or mature adipocytes. Wnt signaling is known to play a role in proliferation and differentiation in multiple stem cell lineages, including intestinal, bone and hematopoietic lineages, and thus we hypothesized that it may also play a role in in vivo adipogenesis and metabolism. Altering canonical Wnt signaling in mature fat tissues in mice had no discernable metabolic effects. In contrast, altering Wnt signaling in fat progenitors led to a depot-specific fate change and a paradoxical murine lipodystrophic syndrome that lacked the expected diabetes and ectopic fatty acid accumulation. Rather, muscle displayed increased glucose uptake and an insulin-independent increase in cell surface glucose transporters along with activation of AMPK and p38 MAPK. Muscle Wnt signaling was unaffected, indicating that these changes resulted from signals derived non-autonomously, which we found to be present in the serum of mutant mice. Thus, this model distinctively dissociates lipodystrophy from dysfunctional metabolism and uncovers a unique and potentially therapeutic method to lower blood glucose and improve metabolism.
dc.subjectStem Cell Niche
dc.titleThe Response of White Adipose Progenitor Cells to Physiological and Genetic Changes
dc.type.materialtext School of Biomedical Sciences and Development Southwestern Medical Center