The ability to sense nutrient availability and regulate energy homeostasis is an ancient and fundamental process that when disturbed leads to many pervasive human diseases. Fat storing tissues play a central role in energy balance, responding to and regulating the metabolic state. Fat tissues also control growth, development, reproduction, and lifespan, and when fat stores are altered (e.g., obesity) diabetes, cardiovascular disease, infertility, and even cancers ensue. The intertwined epidemics of obesity and diabetes have led to a public health crisis affecting hundreds of millions that demands an improved understanding of fat biology and metabolism.
We integrate multiple experimental systems, ranging from invertebrates to mice to humans, to unravel the mechanisms that underlie the formation and function of adipose tissues. Depending on the nature of the question explored, we exploit powers inherent in each experimental system, and then focus on molecules conserved across species using an "Evo-Physio" approach. For example, we performed genetic screens in C. elegans (worms) and D. melanogaster (flies) and generated several hundred mutant lines including a host of "skinny flies", "fat flies", "diabetic flies", etc. From this collection we identified hundreds of genes important in metabolism, including novel conserved genes, transcription factors, and signaling cascade components. We then investigate the role that these genes play in mammalian metabolism with biochemical, molecular, and cellular studies, as well as with knockout and transgenic mice. Notably many genes play a conserved role in invertebrate and mammalian metabolism. For example, the Adipose (Adp) gene has anti-obesity and anti-diabetes functions in worms, flies, and mammals. Thus Adp regulates an ancient metabolic pathway and our mechanistic studies indicate it does so by regulating signaling, transcription and chromatin structure. These and other data indicate that insights derived from these Evo-Physio studies will increase our understanding of metabolism and could lead to novel obesity and/or diabetes therapies.
Understanding the development of the adipose lineage is the second major aspect of our research program. Though we know that adipocytes form throughout life, the current understanding of adipose lineage formation is rudimentary. For example, the identity, origins, and location of embryonic and adult adipocyte stem cells are not established. As a step for developmental characterization, we identified genes that specifically mark the adipose lineage progenitors at multiple steps during the adipocyte life cycle. Based upon these insights, we developed in vivo tools to trace the murine adipose lineage and to identify the adipogenic stem cell. With these genetically marked mice, we isolated proliferating and renewing adipogenic progenitors that ultimately give rise to adult adipose tissues. These stem-like cells form adipocytes both after isolation and upon transplantation into recipient mice. Surprisingly, these progenitors reside in close proximity to the adipose depot vasculature but not in vessels of other tissues. The localization of the adipocyte progenitor to the vessel wall indicates the presence of a therapeutically-accessible vascular niche. Further, these adipose progenitors provide the basis for several therapies for obesity, diabetes, and may be an excellent resource for regenerative medicine and tissue engineering.
SELECTED REFERENCES
Graff JM. Embryonic Patterning: To BMP or not to BMP, that is the question. Cell 89, 171-174, 1997.
Zhu Y, Richardson JA, Parada LF, and Graff JM. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703-714. 1998.
Peters JM, McKay RM, McKay JP, and Graff JM. Casein Kinase I transduces Wnt signals. Nature, 401, 345-350, 1999.
LeSueur JA, Fortuno III ES, McKay RM, and Graff JM. Smad10 is required for formation of the frog nervous system Developmental Cell 2, 771-783, 2002.
McKay RM, McKay JP, Avery L, and Graff JM. C. elegans: a model for exploring the genetics of fat storage. Developmental Cell 4, 131-142, 2003.
Suh, JM, Gao X, McKay JP, McKay RM, Salo Z, and Graff JM. Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metabolism 3, 25-34, 2006.
McKay RM, McKay JP, Suh JM, Avery L, and Graff JM. Tripeptidyl peptidase II promotes fat formation in a conserved fashion. EMBO Reports 8, 1183-1189 2007.
Suh JM, Zeve D, McKay RM, Seo J, Salo Z, Li R, Wang M, and Graff JM. Adipose is a conserved dosage-sensitive anti-obesity gene. Cell Metabolism 6, 195-207, 2007.
Suh JM, Stenesen D, Peters JM, Inoue A, Cade A, and Graff JM. An RGS-containing sorting nexin controls Drosophila lifespan. PLoSONE 14, e2152, 2008.
Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer R, Tallquist MD, Graff JM White Fat Originate Progenitors Reside in the Adipose Vasculature Science In Press 2008
RESEARCH INTERESTS
Fat Biology
Stem Cell
Metabolism
Evolution
RECENT PUBLICATIONS
Peters JM, McKay RM, McKay JP, and Graff JM, "Casein Kinase I transduces Wnt signals" Nature, 401:345-350, 1999
Zhu, Y, Richardson, JA, Parada, LF, and Graff, JM, "Smad3 mutant mice develop metastatic colorectal cancer" Cell, 94:703-714, 1998
McKay RM, McKay JP, Avery L, and Graff JM, "C. elegans: a model for exploring the genetics of fat storage." Developmental Cell, 4:131-142, 2003
Suh JM, Zeve D, McKay RM, Seo J, Salo Z, Li R, Wang M, and Graff JM, "Adipose is a conserved dosage-sensitive anti-obesity gene." Cell Metabolism, Vol 6:195-207, 2007
Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer R, Tallquist MD, Graff JM, "White Fat Progenitors Reside in the Adipose Vasculature" Science, 2008
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