Molecular Regulation of Brown Adipose Cell Fate in Somitic Stem Cells

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DESCRIPTION (Provided by the applicant) Abstract: Molecular Regulation of Brown Adipose Cell Fate in Somitic Stem Cells Obesity is now recognized as the most significant public health issue in the U.S. and in many other countries around the world. It is the predominant risk factor for a growing number of diseases including type 2 diabetes, heart disease, stroke and many cancers. Obesity is a genetic disease caused by an underlying defect in energy balance, where energy intake from food chronically exceeds energy expenditure. Brown adipose tissue (BAT) is highly adapted to expend chemical energy as heat and can therefore counteract obesity. A significant amount of this tissue has been recently identified in normal healthy adult humans raising the possibility that variation in its activity may influence propensity for weight gain. Importantly, manipulating the developmental pathways that control BAT formation may provide new therapeutic avenues to reduce obesity. We recently defined PRDM16 as a dominant transcriptional regulator of brown fat cell differentiation. Significantly, PRDM16 appears to act as a developmental switch in specifying brown fat cell fate from a common precursor for skeletal muscle and brown fat. This cell type, however, has not been identified in an in vivo context. In this proposal, we will characterize the stem/precursor cell population that gives rise to the brown fat cell lineage. To do this, we develop and utilize sophisticated genetic tools that enable us to mark and isolate brown adipose precursors from mouse embryos. Using the power of mouse genetics combined with stem cell biology approaches, we will identify genes and signaling pathways that control lineage commitment to the brown fat vs. skeletal muscle cell fate. This work has profound implications for our understanding of adipose and skeletal muscle biology. We hope that our findings can be translated into therapies that promote energy expenditure and reduce human obesity. Public Health Relevance: Obesity is the single most important public health issue that faces the U.S. and many other countries worldwide. It is imperative that we develop a better understanding of the genetic factors that drive weight gain. In this project, we will identify and characterize novel genes and pathways that control the development of brown adipose tissue, a key energy expending tissue that can counteract obesity.