Project Summary Our overall research goal is to understand the cellular and molecular mechanisms governing the adipose lineage and to understand how these mechanisms become dysfunctional in response to metabolic diseases. The worldwide epidemic of obesity and secondary negative health consequences such as type 2 diabetes and cardiovascular disease are a significant public health problem. Thus, there is an urgent need to better understand the mechanisms and molecules that control the formation of adipocytes and the expansion of white adipose tissue (WAT). WAT is highly plastic and can expand and shrink in response to various homeostatic cues, pharmacologic agents, and dietary stimuli. One way that WAT expands is through the formation of new adipocytes. New adipocytes emanate from a perivascular adipocyte precursor cell (APC) which appears to anatomically and genetically resemble a subset of mural cells (smooth muscle cells). However, during WAT organogenesis a distinct and lineage separate APC patterns and forms the tissues. These findings have led to the notion of two distinct APCs, developmental and adult. During the K01 award period, we discovered that adipose lineage specific disruption of platelet derived growth factor receptor beta (Pdgfrβ) signaling interferes with adult APC-niche interaction and communication and renders these APCs non-adipogenic. However, it was unclear if Pdgfrβ mediated adult APC lineage specification and WAT niche homing. Thus, our research objective is to understand the cellular and molecular differences between the APCs that develop WAT versus those that maintain the adult tissue. To answer this objective, we will use unique genetic models that target different APC populations to continue to probe the role of Pdgfrβ in the adult APC lineage. Our preliminary data herein suggest that Pdgfrβ is critical for the specification and determination of the adult adipose lineage. For instance, when Pdgfrβ is deleted within the adult APC population, they are no longer adipogenic and anatomically and genetically resemble macrophages. These data frame our hypothesis that Pdgfrβ is an adult adipose lineage determination factor. We propose to test the genetic requirement of Pdgfrβ and adult APCs in maintaining and expanding WAT (aim 1). Further we propose to explore the molecular mechanism(s) by which Pdgfrβ controls the adipose lineage and phenomenon by which APCs can form adipose tissue resident macrophages (aim 2). The successful completion of these studies will provide new inroads into how the adult APC lineage is specified and determined leading to healthy adipose tissue formation and expansion. Moreover, these insights into the mechanisms governing adipose lineage biology may lead to strategies to assist in counteracting obesity and type 2 diabetes.