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. 2013 Sep;62(9):2997-3004.
doi: 10.2337/db13-0473.

Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4

Birgit Gustafson  1 , Ann Hammarstedt, Shahram Hedjazifar, Ulf Smith
Affiliations

Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4

Birgit Gustafson et al. Diabetes. 2013 Sep.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Differentiation of human preadipocytes from the abdominal subcutaneous adipose tissue is related to the adipose cell size of the donors. Purified stromal-vascular cells were differentiated for 21 days in vitro and then stained with Oil Red O to show the lipid droplets (top). The negative correlation between the amount of lipids accumulated during differentiation and the adipose cell size of the donors is shown (bottom). Data is from ref. .
FIG. 2.
FIG. 2.
Schematic figure of the overarching regulation of adipogenesis from mesenchymal stem cells and other uncommitted precursor cells. WNT/WISP2 silencing is a prerequisite for adipogenic commitment and subsequent differentiation of preadipocytes into mature adipose cells by activation of transcription factors of the C/EBP family and the key regulator of adipogenesis, PPARγ.
FIG. 3.
FIG. 3.
Temporal increase of PPARγ2, DKK1, and secreted sFRP1 mRNA levels following addition of differentiation cocktail to abdominal preadipocytes. Note that DKK1 is more rapidly induced than PPARγ2 and sFRP1. Data are means of 3 experiments.
FIG. 4.
FIG. 4.
Differentiation of human preadipocytes from different donors with high to low (top, left to right) accumulation of lipid droplets. High differentiation is associated with inhibited WNT activation seen as reduced β-catenin levels and induction of DKK1 protein. Intermediate or low differentiation has low inhibition of β-catenin and induction of DKK1. Adding exogenous DKK1 (+DKK) induced DKK1 protein in the cells, reduced β-catenin, and improved differentiation (not shown). For additional data, see ref. . Ad, adipocytes; Pre Ad, preadipocytes.
FIG. 5.
FIG. 5.
Regulation of precursor cell commitment by BMP4 (left) and subsequent differentiation of the preadipocytes (right). Precursor cells are kept undifferentiated by WNT activation and the intracellular and secreted mediator WISP2. Cytosolic WISP2 binds the PPARγ transcriptional activator ZNF423/Zfp423 and retains it in the cytosol. BMP4 dissociates this complex whereby ZNF423/Zfp423 enters the nucleus and activates PPARγ. However, full activation of PPARγ also requires inhibition of extracellular WNT/WISP2, probably involving the rapid induction of the secreted WNT antagonist DKK1 (see Fig. 3). Committed preadipocytes undergo differentiation following PPARγ/c/EBP activation leading to increased BMP4 induction which, as a secreted protein, can activate commitment of other precursor cells through a paracrine action and also promote differentiation. The inability of this putative feedback regulation to prevent hypertrophic obesity may be due to increased expression of BMP inhibitors antagonizing the effect of the secreted BMP4. See the text for details. Adapted from Hammarstedt et al. (53). pSMAD1/5/8, phosphorylation of SMAD family members 1,5, and 8.
See this image and copyright information in PMC

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