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A main goal of the Rodeheffer lab is to determine how white adipose tissue (fat) mass is regulated in vivo. Determining how fat mass is regulated normally, and how that regulation is altered in obesity, is of particular relevance now as the prevalence of obesity has increased substantially in the United States and other developed countries in recent decades, along with the rates of type II diabetes and other obesity-related health problems. Despite the high incidence of obesity and the health risks associated with it, our understanding of the basic biology of fat tissue is limited.
In effort to better understand the regulation of fat mass we are currently addressing two major questions:
What is the identity of fat cell progenitor/stem cells in vivo?
What are the molecular mechanisms that regulate fat cell differentiation in vivo?
Fat Stem Cells
Obesity results from the excess accumulation of body fat that is accompanied by both an increase fat cell (adipocyte) size as well as an increase in the number of adipocytes compared to the normal adipose tissue. Since lipid-laden mature adipocytes cannot divide, the increase in cell number in obesity must come from differentiation of precursor cells in the tissue. We have previously identified a population of adipocyte precursor cells, derived from normal mouse adipose tissue, that are capable of reconstituting a functional fat pad in a fatless (lipodystrophic) mice. These progenitor cells are also capable of differentiation into other mesenchymal lineages, including cartilage and bone. We are currently expanding on our previous work in effort to identify bona fide adipocyte stem cells and to identify analogous cells from humans. Characterization of adipocyte stem cells will facilitate studies of how adipose tissue mass is regulated in vivo by allowing us to determine the pathways that control the proliferation and differentiation of the progenitor cells. In addition, human-derived adipocyte stem cells have a multitude of potential applications in regenerative medicine and tissue engineering.
Molecular Mechanisms Regulating Adipogenesis in vivo
The transcriptional cascade that regulates adipogenesis been well characterized in cell culture studies, but how adipogenesis is regulated in vivo is unknown. Normal adult adipose tissue is relatively quiescent, with a low rate of adipocyte turnover. In normal animals, the majority of adipogenesis occurs during the first few weeks of life when the adipose tissue is formed. How is the development of adipose tissue controlled? What are the molecular mechanisms that are altered in obesity that lead to an increase in fat mass? To address these questions we are employing a variety of proteomic and genomic approaches to study the development of adipose tissue through ontogeny and also to determine what pathways are altered in obesity and lipodystrophy. We are also using cell culture models to identify novel factors that control adipogenesis. Factors that are identified in these studies will ultimately be tested in adipose reconstitution assays and in transgenic mouse models to determine their role in the regulation of adipogenesis in vivo.
Selected Publications
Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. (2008) Cell. 135(2):240-9.
Zeigerer A, Rodeheffer MS, McGraw TE, Friedman JM. Insulin regulates leptin secretion from 3T3-L1 adipocytes by a PI 3 kinase independent mechanism. (2008) Exp Cell Res. 314(11-12):2249-56.
Bonawitz ND, Rodeheffer MS, Shadel GS. Defective mitochondrialgene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. (2006) Mol Cell Biol. 26(13):4818-29.
Rodeheffer MS, Shadel GS. Multiple interactions involving the amino-terminal domain of yeast mtRNA polymerase determine the efficiency of mitochondrial protein synthesis. (2003) J Biol Chem. 278(20):18695-701.
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