Process of stem cells differentiating into fat cells
Histology features of alipoblast, also known as an adipocyte precursor cell or preadipocyte.
Adipogenesis is the formation ofadipocytes (fat cells) from stem cells.[1] It involves 2 phases, determination, and terminal differentiation. Determination ismesenchymal stem cells committing to the adipocyte precursor cells, also known as lipoblasts or preadipocytes which lose the potential to differentiate to other types of cells such aschondrocytes,myocytes, andosteoblasts.[2] Terminal differentiation is that preadipocytes differentiate into mature adipocytes. Adipocytes can arise either from preadipocytes resident in adipose tissue, or from bone-marrow derived progenitor cells that migrate to adipose tissue.[3]
Adipocytes play a vital role in energy homeostasis and process the largest energy reserve astriglycerol in the body of animals.[4] Adipocytes stay in a dynamic state, they start expanding when the energy intake is higher than the expenditure and undergo mobilization when the energy expenditure exceeds the intake. This process is highly regulated by counter regulatory hormones to which these cells are very sensitive. The hormoneinsulin promotes expansion whereas the counter hormonesepinephrine,glucagon, andACTH promote mobilization. Adipogenesis is a tightly regulated cellular differentiation process, in which mesenchymal stem cells committing to preadipocytes and preadipocytes differentiating into adipocytes. Cellular differentiation is a change of gene expression patterns which multipotent gene expression alters to cell type specific gene expression. Therefore, transcription factors are crucial for adipogenesis. Transcription factors,peroxis proliferator-activated receptor γ (PPARγ) andCCAAT enhancer-binding proteins (C/EBPs) are main regulators of adipogenesis.[5] Comparing with cells from other lineage, the in vitro differentiation of fat cells is authentic and recapitulates most of the characteristic feature of in vivo differentiation. The key features of differentiated adipocytes are growth arrest, morphological change, high expression of lipogenic genes and production ofadipokines likeadiponectin,leptin,resistin (in the mouse, not in humans) andTNF-alpha.
In vitro studies on differentiation have used the pre-committed preadipocyte lineage, such as 3T3-L1 and 3T3-F442A cell line, or preadipocytes isolated from the stromal-vascular fraction of white adipose tissue. In vitro differentiation is a highly ordered process. Firstly, proliferating preadipocytes arrest growth usually by contact inhibition. The growth arrest followed by the earliest events, including a morphological change of preadipocyte from the fibroblast-shape to the round-shape and the induction of transcription factorsC/EBPβ, andC/EBPδ. The second phase of growth arrest is the expression of two key transcription factorsPPARγ andC/EBPα which promote expression of genes that confer the characteristics of mature adipocytes. These genes includeadipocyte protein (aP2), insulin receptor, glycerophosphate dehydrogenase, fatty acid synthase, acetyl CoA carboxylase,glucose transporter type 4 (Glut 4) and so on.[6] Through this process, lipid droplets accumulate in theadipocyte. However, preadipocytes cell lines have difficulty differentiating into adipocytes. Preadipocytes display CD45− CD31− CD34+ CD29+ SCA1+ CD24+ surface markers can proliferate and differentiate to adipocytes in vivo.[7]
PPARγ is a member of the nuclear-receptor superfamily and is the master regulator of adipogenesis.PPARγ heterodimerizes with retinoid X receptor (RXR) and then binds to DNA, which activates the promoters of the downstream genes.PPARγ induces fat-cell specific genes, including aP2, adiponectin andphosphoenolpyruvate carboxykinase (PEPCK). PPARg activation has effects on several aspects of the mature adipocyte characteristics such as morphological changes, lipid accumulation, and the acquisition of insulin sensitivity.[21]PPARγ is necessary and sufficient to promote fat cell differentiation.PPARγ is required for embryonic stem cells (ES cells) differentiation toadipocytes.[22] The expression ofPPARγ itself is sufficient to convert fibroblast intoadipocytes in vitro.[23] Other pro-adipogenic factors likeC/EBPs and Krüppel-like factors (KLFs) have been shown to induce thePPARγ promoter. Moreover,PPARγ is also required to maintain the expression of genes that characterize the mature adipocyte.[24] Thiazolidinediones (TZDs), antidiabetic agents which well used differentiation cocktail in vitro, promoting the activity ofPPARγ.
C/EBPs, transcription factors, are members of the basic-leucine zipper class. cAMP, an inducer of adipogenesis, can promote expression ofC/EBPβ andC/EBPδ.[25] At the early stage of differentiation, the transient increase ofC/EBPβ andC/EBPδ mRNA and protein levels are thought to activate the adipogenic transcription factors,PPARγ andC/EBPα.PPARγ andC/EBPα can feedback to induce the expression of each other as well as their downstream genes.[26]C/EBPα also plays an important role in the insulin sensitivity of adipocytes.[27] However,C/EBPγ suppresses differentiation which might due to inactivation byC/EBPβ.
AlthoughPPARγ andC/EBPα are master regulators of adipogenesis, other transcription factors function in the progression of differentiation. Adipocyte determination and differentiation factor 1 (ADD1) and sterol regulatory element binding protein 1 (SREBP1) can activatePPARγ by the production of an endogenousPPARγ ligand or directly promote the expression ofPPARγ. cAMP-responsive element binding protein promotes differentiation, while the activation ofPPARγ andC/EBPα is also responsive to negative regulation.T-cell factor/lymphoid enhancer-binding factor (TCF/LEF),[28] GATA2/3,[29] retinoic acid receptor α,[30] and SMAD6/7[31] don't affect the expression ofC/EBPβ andC/EBPδ but inhibit the induction ofPPARγ andC/EBPα.
Wnt/β-catenin signaling suppresses adipogenesis, by promoting the differentiation of mesenchymal stem cells intomyocytes andosteocytes but blocking the commitment to the adipocytic lineage.[35] Wnt/β-catenin inhibits the differentiation of preadipocytes by inhibiting the induction ofPPARγ andC/EBPα.
Bone morphogenetic proteins (BMPs) are transforming growth factor β (TGFβ) superfamily members. BMP2 can either stimulates the determination of multipotent cells or induce osteogenesis through different receptor heteromers.[36] BMPs also promotes the differentiation of preadipocytes.
Senescent adipose progenitor cells in subcutaneous adipose tissue has been shown to suppress adipogenic differentiation.[37] Reduced adipogenesis in obese persons is due to increased senescent cells in adipose tissue rather than reduced numbers of stem/progenitor cells.[38]
^Darmon M, Serrero G, Rizzino A, Sato G (April 1981). "Isolation of myoblastic, fibro-adipogenic, and fibroblastic clonal cell lines from a common precursor and study of their requirements for growth and differentiation".Experimental Cell Research.132 (2):313–27.doi:10.1016/0014-4827(81)90107-5.PMID7215448.
^Aaronson SA, Todaro GJ (October 1968). "Development of 3T3-like lines from Balb-c mouse embryo cultures: transformation susceptibility to SV40".Journal of Cellular Physiology.72 (2):141–8.doi:10.1002/jcp.1040720208.PMID4301006.S2CID31332589.
^Reznikoff CA, Brankow DW, Heidelberger C (December 1973). "Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division".Cancer Research.33 (12):3231–8.PMID4357355.
^Tontonoz P, Hu E, Spiegelman BM (December 1994). "Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor".Cell.79 (7):1147–56.doi:10.1016/0092-8674(94)90006-x.PMID8001151.S2CID54387527.
