Proper control of energy and nutrient homeostasis is crucial for growth, development, and the prevention of metabolic disease. Adipose tissue plays a critical role in the regulation of energy balance, functioning as a metabolic sensor that control energy storage, energy utilization, and food intake. Pathological adipose tissue distribution and adipocyte dysfunction are intimately linked to obesity and obesity-associated diseases such as type 2 diabetes, cardiovascular disease, and cancer. The growing epidemic of obesity and rising costs associated with treating metabolic disease has increased the urgency for understanding all aspects of adipose tissue biology, including how adipocytes are formed. My laboratory focuses on the adipocyte progenitor, or "preadipocyte". This is a cell type poorly defined, whose regulation is incompletely understood. The studies described in my funded K01 award led to the discovery that the preadipocyte determination factor, Zfp423, is actively expressed in a subset of peri-endothelial mesenchymal cells (pericytes) of adipose tissue blood vessels. In this R03 proposal, we will extend the findings from the K01-funded studies by testing the hypothesis that Zfp423+ perivascular cells represent a unique cell type, serving as developmental precursors in the adipocyte lineage.
In Specific Aim 1 we will perform functional and molecular analyses of isolated adipose- derived pericytes expressing Zfp423.
In Specific Aim 2 we will employ genetic lineage tracing to determine the precise role of these cells in the adipose lineage. Understanding the biology of adipose precursors will shed tremendous insight into the developmental origin of fat tissue and physiological regulation of adipose tissue distribution.
The rising incidence of obesity has increased the urgency of understanding the fundamental mechanisms controlling energy homeostasis, including those that drive fat tissue formation. The experiments described in this proposal will determine the identity and molecular properties of fat cell precursors. This knowledge will facilitate our attempts to manipulate fat tissue biology as a therapeutic treatment for obesity and metabolic disease.
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