Once considered an inert mass of stored energy, the past 2 decades have seen a surge in interest in the complexity of adipose tissue and its role in disease. In addition to serving as a site for energy storage, adipocytes secrete proteins involved in inflammation, appetite regulation, blood pressure control, and energy balance. Adipocytes are unique in their ability to store large quantities of lipids that can be rapidly released and used for energy by other organs, when necessary; however, excessive adipose tissue, particularly in the visceral adipose tissue depot, is associated with increased risk of insulin resistance, cardiovascular disease, and cancer. As such, adipose tissue is capable of extensive expansion or retraction depending on the energy balance or disease state of the host, a plasticity that is unparalleled in other organs. Expansion of adipose tissue is driven by both hypertrophy and hyperplasia of adipocytes, which can renew frequently to compensate for cell death, suggesting the necessity of adipocyte progenitor cells within the adipose tissue depot, that are capable of differentiating into mature and functional adipocytes.
Epidemiological studies estimate that more than one billion people worldwide are overweight and at least 400 million clinically obese. Therefore, in order to combat the global obesity pandemic, the origin and the molecular mechanisms controlling the development and expansion of adipocytes must be fully understood so that novel approaches to prevention and therapy can be developed.
KeywordsAdipose tissue Stem cells White adipose tissue Brown adipose tissue Obesity Cell differentiation Signaling Transcription factors
We apologize to our colleagues whose contributions could not be cited due to space limitations. We thank members of our lab for critically reading the manuscript and discussions. In particular, we thank Tatiana Golea for administrative and graphical support. Our work is supported by grants from the Deutsche Forschungsgemeinschaft, the European Foundation for the Study of Diabetes, the FP7 DIABAT consortium, the German Cancer Aid, and the Network Aging Research.
- Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, Cinti S. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab. 2010;298:E1244–53.PubMedCrossRefGoogle Scholar
- Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmuller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17(2):200–5.PubMedCrossRefGoogle Scholar
- Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8.PubMedCrossRefGoogle Scholar
- Bray GA, Wilson JF. In the clinic. Obesity. Ann Intern Med. 2008;149:ITC4-1-15; quiz ITC14-16.Google Scholar
- Bronnikov G, Bengtsson T, Kramarova L, Golozoubova V, Cannon B, Nedergaard J. beta1 to beta3 switch in control of cyclic adenosine monophosphate during brown adipocyte development explains distinct beta-adrenoceptor subtype mediation of proliferation and differentiation. Endocrinology. 1999;140:4185–97.PubMedCrossRefGoogle Scholar
- Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet. 2011;377:557–67.PubMedCrossRefGoogle Scholar
- Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, Gadde KM, Gupta AK, O’Neil P, Schumacher D, Smith D, Dunayevich E, Tollefson GD, Weber E, Cowley MA. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring). 2008;17(1):30–9.CrossRefGoogle Scholar
- Jia B, Madsen L, Petersen RK, Techer N, Kopperud R, Ma T, Doskeland SO, Ailhaud G, Wang J, Amri EZ, Kristiansen K. Activation of protein kinase A and exchange protein directly activated by cAMP promotes adipocyte differentiation of human mesenchymal stem cells. PLoS One. 2012;7:e34114.PubMedCrossRefGoogle Scholar
- Kang S, Bennett CN, Gerin I, Rapp LA, Hankenson KD, Macdougald OA. Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem. 2007;282:14515–24.PubMedCrossRefGoogle Scholar
- Lopez M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, Martinez de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Dieguez C, Vidal-Puig A. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010;16:1001–8.PubMedCrossRefGoogle Scholar
- Majka SM, Fox KE, Psilas JC, Helm KM, Childs CR, Acosta AS, Janssen RC, Friedman JE, Woessner BT, Shade TR, Varella-Garcia M, Klemm DJ. De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific. Proc Natl Acad Sci U S A. 2010;107:14781–6.PubMedCrossRefGoogle Scholar
- Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem. 2010;285:7153–64.PubMedCrossRefGoogle Scholar
- Pisani DF, Djedaini M, Beranger GE, Elabd C, Scheideler M, Ailhaud G, Amri EZ. Differentiation of human adipose-derived stem cells into “brite” (brown-in-white) adipocytes. Front Endocrinol (Lausanne). 2011;2:87.Google Scholar
- Rothwell NJ, Stock MJ. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin Sci (Lond). 1983;64:19–23.Google Scholar
- Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454:1000–4.PubMedCrossRefGoogle Scholar
- Vegiopoulos A, Muller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel Diaz M, Rozman J, Hrabe de Angelis M, Nusing RM, Meyer CW, Wahli W, Klingenspor M, Herzig S. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science. 2010;328:1158–61.PubMedCrossRefGoogle Scholar
- Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. American journal of physiology. Endocrinol Metab. 2012;302:E19–31.Google Scholar
- Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human. Cell. 2012;150(2):366–76.PubMedCrossRefGoogle Scholar
- Zhu Y, Qi C, Korenberg JR, Chen XN, Noya D, Rao MS, Reddy JK. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci U S A. 1995;92:7921–5.PubMedCrossRefGoogle Scholar