Biomarkers, Lineage Analysis--metabolic disease states

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DESCRIPTION (provided by applicant): Our overall objective is to elucidate the mechanisms that control formation of adipose tissues and to determine whether and how these processes are altered during metabolic diseases. The ability to store energy, primarily as fat, is a fascinating property that seems to be required for the life cycle of many higher organisms. Unfortunately, abnormalities in fat accumulation produce pathological states including lipodystrophy, diabetes, and obesity, which are major causes of morbidity and mortality throughout the world. Yet, the genes that regulate adipocyte development and physiology are not fully understood. Model organisms have proven to be powerful tools for gene discovery, for elucidating gene function, and for characterizing development. So, it would be great to exploit models to more fully characterize fat biology in healthy and unhealthy conditions. Surprisingly little is known about adipocyte development. The location and lineage of the cells that give rise to adipocytes remain unknown and the origin and identity of adipocyte stem cells are not established. Adipose tissues consist of at least three distinct types: brown fat, white mechanical fat, and white metabolic fat. Adipocytes are place in stereotypical positions dispersed throughout the body. The different types and depots of adipose cells differ morphologically and functionally, having different metabolic profiles with critical health ramifications. Yet, the mechanisms and developmental cues that control the morphogenesis, location, and functional differences are unknown. To begin to understand how diverse fat tissues are formed, patterned, regenerate, and are altered during metabolic diseases, we are systematically isolating molecules that mark different developmental stages and distinct depots. Further, we have and will continue to generate in vivo lineage tracers to mark, detect and isolate adipocytes and adipocyte progenitors at various developmental stages and from individual fat depots both in physiologic and pathophysiologic states. These studies are likely to shed light on the behavior of adipocytes and may allow for rational design of therapies for lipodystrophy, obesity, and diabetes. Aim I, to develop adipose biomarkers. Aim II, to trace the adipocyte lineage. Aim III, to determine whether and how expression of the biomarkers and lineage tracers generated in Aims I and II are altered in various abnormal metabolic states.