Journal of Molecular Cell Biology Advance Access published online on October 12, 2009
Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjp035
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The Engineering of Brown Fat
Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London W12 0NN, UK
* Correspondence to: Malcolm G. Parker, E-mail: m.parker{at}imperial.ac.uk
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The developmental origins of brown adipose tissue and white adipose tissue are distinct, with brown adipocytes being derived from muscle precursors. PR domain containing 16, together with C/EBPβ, forms a lineage-switching transcriptional complex which promotes brown fat differentiation and suppresses muscle cell differentiation.
Adipose tissue has a pivotal role in the regulation of energy balance both as a fat storage depot and as an endocrine tissue. Energy homeostasis is crucial since excess fat storage leads to obesity and negatively impacts the body's metabolic health with associated predisposition to diseases including diabetes. There are two types of adipocytes, white for the storage of triglyceride and brown for the oxidation of fat by a process called thermogenesis. Despite similarities in the signalling pathways responsible for the generation of brown and white adipocytes, recent work indicates that they have distinct developmental origins.
Following the identification of the zinc finger protein PR domain containing 16 (PRDM16) enriched in brown adipocytes which plays a key role in brown fat determination, Seale et al. (2008) demonstrated that brown, but not white, adipocytes are derived from myogenic factor 5 (Myf5)-expressing muscle precursor cells under the control of the PRDM16 switch. Conversely, myogenin is responsible for the development of muscle cells from these precursors. Although the discovery that brown adipocytes and muscle cells are derived from common progenitors was unexpected, with the benefit of hindsight it should not have been surprising that brown and white adipocytes might have a distinct developmental origin, not least because of their opposing functions. Moreover, a link between brown fat and skeletal muscle had already been recognized in gene expression profiling experiments which indicated they shared many mRNAs (Timmons et al., 2007).
Adipogenesis is controlled by a number of hormones and cytokines including bone morphogenic proteins (BMPs). Tseng et al. (2008) have shown that BMP2 and 4 promote the development of white adipocytes and BMP7 promotes the development of brown adipocytes. Importantly, BMP7 induces the expression of PRDM16 which functions in a cell autonomous manner to promote brown fat gene expression and suppress the white fat programme. PRDM16 seems to function in conjunction with a number of key adipocyte transcription factors and cofactors.
Initial studies indicated that PRDM16 is a cofactor for both PPAR
and its coactivators PGC-1
and PGC-1β, acting to facilitate the expression of brown fat-selective genes, including UCP1, Cidea and PGC1a. In addition, PRDM16 is capable of blocking the white fat programme by suppressing the expression of genes such as the adipokines, resistin and angiotensinogen. This is achieved by the recruitment of the CtBP corepressor to their promoters through binding to PRDM16 (Kajimura et al., 2008). The binding of PGC-1 and CtBP to PRDM16 is mutually exclusive, but the mechanisms that determine which will bind are unknown.
Work reported by Kajimura et al. (2009) in Nature now demonstrates that PRDM16 functions as a brown fat switch by forming a transcriptional complex with C/EBPβ and that this in turn leads to the expression of both key regulators of the brown fat programme, including PPARg and PGC1a, and characteristic brown fat genes such as UCP1, Cidea, Cox7a1 and Cox8b (Figure 1). A fully functional engineered brown fat depot was achieved by expressing both PRMD16 and C/EBPβ in mouse fibroblasts and transplanting of these cells into mice. Only the cells that expressed both factors together developed into UCP1-positive fat cells. Positron-emission tomography (PET) scans using the tracer 18F-fluorodeoxyglucose detected the metabolically active engineered brown fat depot, which acts as a sink for the labelled glucose. In contrast, an engineered white adipose depot derived from fibroblasts expressing PPAR was not detected by the PET scan. Surprisingly, the engineered brown fat depot contained UCP1-expressing adipocytes that morphologically resembled either multilocular brown adipocytes or unilocular white adipocytes. The multilocular appearance of brown adipocytes is considered to rely on a high degree of sympathetic innervation which is unlikely to occur within the experimental time frame. Alternatively, the unilocular appearance may result from elevated expression of lipid storage proteins such as CIDEC/Fsp27, which preferentially promotes the formation of unilocular droplets (Nishino et al., 2008).
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Brown adipose tissue is highly metabolically active due to the expression of UCP1 which is a mitochondrial proton transporter that uncouples electron transport from ATP production, enabling energy dissipation. Exposure to cold induces UCP1, in this highly innervated tissue, via the sympathetic nervous system and in vitro this pathway is bypassed with agents that increase intracellular levels of cAMP. Unlike differentiated brown adipocytes which respond to cAMP with a massive increase in UCP1, the PRMD16-C/EBPβ-induced brown fat cells express very high levels of UCP1 without stimulus and show only a small additional increase with cAMP treatment. Many brown adipocyte selective genes, including UCP1 and Cidea, are regulated by the important metabolic co-regulator PGC-1
. The high basal levels of UCP1 may result from the sustained activation of PGC-1 expression by PRDM16 and C/EBPβ in addition to PGC-1 coactivation by PRDM16. The majority of experiments investigating PRDM16 functions have relied on its stable exogenous expression. In contrast, endogenous PRDM16 levels appear to be highest early in differentiation and subsequently decline. This may be important for preventing constitutive high expression of energy-dissipating genes and unregulated uncoupling in the mature brown adipocyte. Timed transient PRDM16 expression studies will be required to more fully delineate its roles during development and in the fully differentiated cell. Mice lacking the PRDM16 gene die at birth, preventing a comprehensive phenotypic and functional analysis. However, as brown fat depots develop before birth, late stage Prdm16–/– embryos can be studied. Although siRNA-mediated depletion of PRDM16 from cultured brown preadipocytes almost completely blocked their ability to differentiate into brown fat cells, the defects in Prdm16-null embryonic day 17 brown adipose tissue were significant but surprisingly modest, with a 50% reduction in genes such as UCP1 and Cidea. The fact that a brown fat depot can form at all, in the absence of the Prdm16 gene, indicates that it is not essential for the brown fat programme. Interestingly, a similarly defective brown adipose tissue is found in C/EBPβ-deficient embryos. The generation of double knockout mice for Prdm16 and Cebpb would be worthwhile to fully define the importance of the transcription complex in brown adipose tissue development and function.
Development from Myf5-positive muscle precursors is not the only way to generate brown adipocytes. Interspersed within white adipose tissue are brown adipocytes that appear following cold exposure. Unlike the adipocytes in bona fide brown adipose tissue, these cells are derived from non-muscle precursors that have never expressed the Myf5 gene. In addition, the transdifferentiation of white to brown adipocytes may be important for cold responses and energy balance. There is much to learn about the requisite repertoire of transcription factors and co-regulators that govern differentiation of the two different brown adipocyte lineages. Candidate regulatory factors of brown adipocyte determination include RIP140, a corepressor which displays a physical and functional interaction with PGC-1(Hallberg et al., 2008), as well as pRB, p107 and FOXC2 (Hansen and Kristiansen, 2006). There are 15 additional members of the PRDM family raising the possibility that they fulfil redundant functions which may explain the mildly defective brown fat in the Prdm16-null mice.
The characterization of the brown adipose tissue molecular regulators has important implications for human energy metabolism. Until recently, human brown fat deposits were considered to be present only in newborns. However, PET scans, coupled with tissue sampling, have conclusively identified brown adipose depots, notably between the shoulder blades and around kidneys, in adult humans (Cypess et al., 2009). The activity of these depots is rapidly increased by exposure to cold temperatures and blunted in obese individuals (van Marken Lichtenbelt et al., 2009). Defining the cues that promote brown fat induction, transdifferentiation and activation of the energy expenditure programme will provide new applications for combating the obesity epidemic.
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