snapshot-Adipocyte Life Cycle

S n ap S h o t: A d ip o cy te L if e C yc le Yu w ei J ia ng , A -Y o un g J o , a nd J o na th an M . G ra ff D ep ar tm en t o f D ev el o p m en ta l B io lo g y, U ni ve rs ity o f Te xa s S o ut hw es te rn M ed ic al C en te r, D al la s, T X 7 53 90 , U S A 234 Cell 150, July 6, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.06.022 See online version for legend and references. 234.e1 Cell 150, July 6, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.06.022 SnapShot: Adipocyte Life Cycle Yuwei Jiang, A-Young Jo, and Jonathan M. Graff Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Adipose stem cells, which reside in a vascular niche, are essential to the development and maintenance of adipose tissue. Data from humans and rodents show that maintenance of adult adipose tissue is a dynamic process. Adipocyte turnover in young adult mice is estimated to be greater than 10% per month. The adipose stem cell niche is just as active, generating new adipocytes and replenishing the niche. This cycle occurs throughout life and responds to myriad environmental stimuli, including diet, pharmacological agents, and tissue injury. Adipose tissue deficiency (lipodystrophy) or excess (obesity) cause disease and serious secondary conditions, including diabetes, hypertension, hyper- lipidemia, and even cancer. It is therefore critical to understand the life cycle of adipose tissue and how it is regulated. In this SnapShot, we integrate a variety of studies—cell culture, animal model, human retrospective, and clinical trials—to summarize what is currently known about the molecular basis of adipose tissue formation, its stem cell niche, and the pathogenesis of obesity. Adipocyte Formation and Expansion: Key Events and Molecules Adipose depot and adipocyte formation are multistep processes, involving stem cell commitment, quiescence, and proliferation, as well as early (recruitment) and late (lipid filling) differentiation. These highly orchestrated processes involve many cell types in adipose tissue, including mature adipocytes and stromal-vascular cells (SVCs). The SVCs include fibroblasts, smooth muscle cells, pericytes, endothelial cells, and adipogenic stem/progenitor cells. The perivascular location of the stem cells places them in an appropriate position to help coordinate these interactions as well as respond to blood-borne signals, such as nutrients and drugs. Adipose Stem Cell Proliferation Stem cells are poised in a delicate balance between quiescence and division. Cell division may create additional stem cells or cells that are destined to differentiate. To maintain the appropriate balance of stem cells and various progeny, decisions are tightly regulated by an assortment of inhibitory and stimulatory factors, which can be subdivided into at least three groups (1): cell-cycle regulators (e.g., p21, Cyclin D1, Rb, and E2Fs), hormones (e.g., thyroid and growth hormones), and angiogenic factors (e.g., VEGF and HGF). Significant progress has been made toward identifying the origin, location, and niche of adipose stem cells, as well as their molecular signature. The expression of PPARγ marks the adipose stem compartment. Lineage-tracing studies based on the expression of PPARγ indicate a perivascular location of adipose stem cells and highlight the vasculature as a critical stem cell niche (Tang et al., 2008). Stem cells reside in this niche as mural cells (those which physically surround the endothelial cells to provide structural support to blood vessels and are essential for normal vascular development). These PPARγ-positive mural cells fulfill the standard stem criteria: they are quiescent cells that retain label, and they proliferate and lineage trace into adipocytes. Recent data indicate that a subset of the stem cell compartment may derive from endothelial cells, which are proposed to undergo an epithelial to mesenchymal transition, thus changing fate from endothelial to mural (Gupta et al., 2012; Tran et al., 2012). In addition to PPARγ, Sca-1, Zfp423, CD34, CD29, CD24, CD140a, and CD140b also appear to identify some adipose stem cells (Gupta et al., 2012; Rodeheffer et al., 2008; Tang et al., 2008). Ongoing studies are currently defining the molecular characteristics of the niche, the adipose stem cells, as well as their proliferative mechanisms and controls. This information will increase our understanding of how adipocytes form and expand under physiological and pathological conditions. Adipocyte Differentiation Adipose stem/progenitor cells differentiate into mature lipid-laden adipocytes. These cells have a characteristic morphology and stereotypic positions. They also express spe- cific markers. A complex network of signals regulates adipose differentiation (Rosen and MacDougald, 2006), such as transcription factors, cell-cycle regulators, extracellular signals, hormones, and small molecules, including widely prescribed therapies (2). Among these, PPARγ is a critical node, because it is necessary and sufficient for adipocyte formation. C/EBP family members and SREBP are also core transcriptional components. Multiple positive and negative regulators of the differentiation program converge upon PPARγ to influence the conversion of stem cells to mature adipocytes. For example, stimulatory signals, such as glucocorticoids, increase C/EBPβ and C/EBPδ function, and in turn these transcription factors activate PPARγ through regulation of KLF5. PPARγ in turn promotes C/EBPα expression, and together these molecules induce adipocyte dif- ferentiation, lipid storage (e.g., lipoprotein lipase, perilipin), and adipokine signaling (e.g., leptin). Adipocyte Turnover Adipocytes have a limited lifespan and are constantly replenished with new adipocytes derived from the stem cell pool. The rate of this process is intermediate between epithelial cells and myocytes. In young adult mice, ?10%–15% of adipocytes are replaced every month (Rigamonti et al., 2011; Tang et al., 2011), and retrospective human studies also indicate a high turnover rate (Spalding et al., 2008). Under homeostatic conditions, the process is relatively constant, but it is sensitive to pharmacologic, physiologic, and dietary stimuli. For example, caloric excess accelerates various steps from stem cell division to adipocyte death. Cytokines, such as TNFα and interleukin (IL)-6, and pharmacologic agents appear to regulate adipocyte turnover (3). Notably, PPARγ is a target of the thiazolidinedione (TZD) class of diabetes treatments, and TZDs increase stem cell proliferation, stem cell self-renewal, and adipocyte formation, which is consistent with the expression of PPARγ in the stem cell compartment (Tang et al., 2011). Adipocyte Obesigenic Expansion Adipose tissues can expand from 2%–3% to 60%–70% of body weight in response to positive energy balance. The increase in adipose tissue mass involves several mechanisms, including stem cell proliferation, adipocyte hyperplasia (the recruitment of new cells from adipose stem cells), adipocyte hypertrophy (enlargement of existing adipocytes), and increased adipocyte turnover. Angiogenic factors, such as angiopoietins, HGF, and VEGF appear to regulate adipose tissue expansion, consistent with the stem cell perivascular microenvironment (4). The importance of angiogenesis or neovascularization in adipose tissue expansion is supported by observations that antiangiogenic drugs blunt adipose expansion in obese mice (Rupnick et al., 2002). During obesigenesis, several adipocyte extracellular signals, such as IGF-1, IGFBP, and TNFα, are elevated and appear to alter stem cell proliferation and adipocyte recruitment, suggesting mechanistic insights into the feed-forward interplay between adipocytes and stem cells (4) (Hausman et al., 2001). Exciting inroads into the adipocyte life cycle, including characterization of the stem compartment and appreciation of the dynamic nature of the adipose depot, have led inves- tigators to pose a number of new questions about adipose biology. We anticipate that an improved understanding of how different control mechanisms interact (e.g., signaling between adipocytes and stem cells) and a better appreciation of pathways that control adipose tissue expansion will further our ability to effectively treat patients suffering from adipose-related diseases and may offer new strategies in regenerative medicine. Abbreviations Sca-1, stem cell antigen-1; PPARγ, peroxisome proliferator-activated receptor gamma; Zfp423, zinc finger protein 423; SMA, α–smooth muscle actin; NG2/CSPG4, chondroitin sulfate proteoglycan 4; PDGFRβ, platelet-derived growth factor β; aP2, adipocyte protein 2; Glut4, glucose transport 4; perilipin/PLIN, lipid droplet-associated protein; LPL, lipo- protein lipase; resistin/ADSF, adipocyte secreted factor; PECAM-1, platelet endothelial cell adhesion molecule 1; VE-cadherin, vascular endothelial cadherin; VEGFR2, vascular endothelial growth factor receptor 2; ROS, reactive oxygen species; FFA, free fatty acids; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor. Acknowledgments The authors are grateful to artist Elizabeth Sumner. J.M.G is supported by NIH and NIDDK grants (R01 DK066556, R01 DK064261, and R01 DK088220). J.M.G. is a founder and shareholder of Reata Pharmaceuticals. SnapShot: Adipocyte Life Cycle Yuwei Jiang, A-Young Jo, and Jonathan M. Graff Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA RefeRences Gupta, R.K., Mepani, R.J., Kleiner, S., Lo, J.C., Khandekar, M.J., Cohen, P., Frontini, A., Bhowmick, D.C., Ye, L., Cinti, S., and Spiegelman, B.M. (2012). Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. 15, 230–239. Hausman, D.B., DiGirolamo, M., Bartness, T.J., Hausman, G.J., and Martin, R.J. (2001). The biology of white adipocyte proliferation. Obes. Rev. 2, 239–254. Rigamonti, A., Brennand, K., Lau, F., and Cowan, C.A. (2011). Rapid cellular turnover in adipose tissue. PLoS ONE 6, e17637. Rodeheffer, M.S., Birsoy, K., and Friedman, J.M. (2008). Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249. Rosen, E.D., and MacDougald, O.A. (2006). Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885–896. Rupnick, M.A., Panigrahy, D., Zhang, C.Y., Dallabrida, S.M., Lowell, B.B., Langer, R., and Folkman, M.J. (2002). Adipose tissue mass can be regulated through the vasculature. Proc. Natl. Acad. Sci. USA 99, 10730–10735. Spalding, K.L., Arner, E., Westermark, P.O., Bernard, S., Buchholz, B.A., Bergmann, O., Blomqvist, L., Hoffstedt, J., Näslund, E., Britton, T., et al. (2008). Dynamics of fat cell turnover in humans. Nature 453, 783–787. Tang, W., Zeve, D., Suh, J.M., Bosnakovski, D., Kyba, M., Hammer, R.E., Tallquist, M.D., and Graff, J.M. (2008). White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586. Tang, W., Zeve, D., Seo, J., Jo, A.Y., and Graff, J.M. (2011). Thiazolidinediones regulate adipose lineage dynamics. Cell Metab. 14, 116–122. Tran, K.V., Gealekman, O., Frontini, A., Zingaretti, M.C., Morroni, M., Giordano, A., Smorlesi, A., Perugini, J., De Matteis, R., Sbarbati, A., et al. (2012). The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab. 15, 222–229. 234.e2 Cell 150, July 6, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.06.022 SnapShot: Adipocyte Life Cycle Adipocyte Formation and Expansion: Key Events and Molecules Adipose Stem Cell Proliferation Adipocyte Differentiation Adipocyte Turnover Adipocyte Obesigenic Expansion Abbreviations Acknowledgments References