The rising incidence of obesity places an increasingly large number of individuals at a risk for developing cardiometabolic disorders. Interestingly, not all obese individuals develop metabolic disease; this has led to the notion that a state of relatively healthy obesity can exist. The mechanism of white adipose tissue (WAT) expansion has been proposed to be one critical determinant of cardiovascular disease and insulin resistance in the setting of obesity. In principle, the expansion of fat mass can occur by adipocyte hypertrophy (increased cell size) or adipocyte hyperplasia (increase in adipocyte number). Adipocyte hypertrophy is a defining feature of pathologic obesity. These overworked fat cells reach their storage capacity; this leads to the deleterious accumulation of lipids in the liver, skeletal muscle, pancreas, and heart. WAT expansion through adipocyte hyperplasia (de novo adipocyte formation, or adipogenesis) results in smaller, healthier fat cells within WAT depots, and is commonly observed in metabolically healthy obese individuals. Our laboratory focuses on the transcriptional mechanisms controlling the development and maintenance of healthy adipocytes in adult animals. Our previous work revealed that the transcription factor Zfp423 is a regulator of preadipocyte commitment, serving as an activator of Ppar?. In vivo, Zfp423 is expressed in mature adipocytes and a subset of peri-endothelial (or mural) cells that express the cell surface protein, Pdgfr (Pdgfr+). Our preliminary data reveal that Zfp423+;Pdgfr+ cells are a regulated population of committed preadipocytes; these cells are more abundant in WAT depots capable of adipocyte hyperplasia during high-fat diet feeding. The studies proposed here will utilize innovative mouse models that allow us to identify, localize, track, and manipulate adipocyte precursor cells. We propose to test the following hypotheses: Zfp423+;Pdgfr+ preadipocytes represent a novel subset of physiologically regulated adipose precursors that are highly committed to the adipose lineage (Aim 1). Zfp423 functions to commit Pdgfr+ cells to the adipose lineage; genetic ablation of Zfp423 in Pdgfr+ cells will impact adipocyte hyperplasia and insulin sensitivity during high-fat diet feeding (Aim 2). Zfp423 functions in mature adipocytes to maintain normal fat cell function (Aim 3). Successful completion of the experiments proposed here will 1) reveal a novel, physiologically regulated population of committed adipose precursors in adult WAT that influences the capacity for adipocyte hyperplasia and 2) identify a new cellular (mural cells) and molecular (Zfp423) determinant of healthy WAT expansion in obesity.
The rising incidence of obesity has increased the urgency of understanding the fundamental mechanisms controlling energy homeostasis, including those that drive fat tissue expansion in adults. The experiments described in this proposal will determine the identity and molecular properties of fat cell precursors, and begin to elucidate the mechanisms controlling adipocyte development in obesity. This knowledge will facilitate our attempts to manipulate fat tissue biology as a therapeutic treatment for obesity and metabolic disease.
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