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Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose-Derived Stem Cells

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ABSTRACT

Increased visceral fat, rather than subcutaneous fat, during the onset of obesity is associated with a higher risk of developing metabolic diseases. The inherent adipogenic properties of human adipose-derived stem cells (ASCs) from visceral depots are compromised compared with those of ASCs from subcutaneous depots, but little is known about the underlying mechanisms. Using ontological analysis of global gene expression studies, we demonstrate that many genes involved in retinoic acid (RA) synthesis or regulated by RA are differentially expressed in human tissues and ASCs from subcutaneous and visceral fat. The endogenous level of RA is higher in visceral ASCs; this is associated with upregulation of the RA synthesis gene through the visceral-specific developmental factor WT1. Excessive RA-mediated activity impedes the adipogenic capability of ASCs at early but not late stages of adipogenesis, which can be reversed by antagonism of RA receptors or knockdown of WT1. Our results reveal the developmental origin of adipocytic properties and the pathophysiological contributions of visceral fat depots.

No MeSH data available.


Endogenous levels of RA are higher in VS ASCs. A: A representative graph showing increased levels of normalized RARE luciferase reporter activity in VS ASCs of S11 when compared with SC ASCs. B: A representative graph showing increased levels of RA in VS ASCs as measured by LC-MS. The data are averaged from cells of two subjects (S11 and S13). See also Supplementary Fig. 2. C: A representative graph showing increased levels of retinol (ROL) in VS ASCs of S11, measured by LC-MS. *P < 0.05 denotes significant change (n = 2).
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Figure 4: Endogenous levels of RA are higher in VS ASCs. A: A representative graph showing increased levels of normalized RARE luciferase reporter activity in VS ASCs of S11 when compared with SC ASCs. B: A representative graph showing increased levels of RA in VS ASCs as measured by LC-MS. The data are averaged from cells of two subjects (S11 and S13). See also Supplementary Fig. 2. C: A representative graph showing increased levels of retinol (ROL) in VS ASCs of S11, measured by LC-MS. *P < 0.05 denotes significant change (n = 2).

Mentions: Since higher RA-mediated activity was observed in VS ASCs than in SC ASCs, we assessed endogenous RA levels using three different methods. First, a Luciferase reporter assay using the RARE indicated that VS ASCs rendered a significantly higher RA-responsive activity than SC ASCs (Fig. 4A). Second, endogenous levels of RA were assessed by ultrasensitive surface-enhanced Raman spectroscopy using the scheme and spectra shown in Supplementary Fig. 2A–C. The surface-enhanced Raman spectroscopy measurement indicated significant upregulation of RA in VS ASCs compared with SC ASCs (Supplementary Fig. 2D). A similar increase of endogenous RA in VS ASCs was observed when the conventional method using LC-MS was used (Fig. 4B). The level of the RA precursor retinol, as measured by LC-MS, also indicated a significant increase in VS ASCs compared with SC ASCs (Fig. 4C).


Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose-Derived Stem Cells
Endogenous levels of RA are higher in VS ASCs. A: A representative graph showing increased levels of normalized RARE luciferase reporter activity in VS ASCs of S11 when compared with SC ASCs. B: A representative graph showing increased levels of RA in VS ASCs as measured by LC-MS. The data are averaged from cells of two subjects (S11 and S13). See also Supplementary Fig. 2. C: A representative graph showing increased levels of retinol (ROL) in VS ASCs of S11, measured by LC-MS. *P < 0.05 denotes significant change (n = 2).
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Related In: Results  -  Collection

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Figure 4: Endogenous levels of RA are higher in VS ASCs. A: A representative graph showing increased levels of normalized RARE luciferase reporter activity in VS ASCs of S11 when compared with SC ASCs. B: A representative graph showing increased levels of RA in VS ASCs as measured by LC-MS. The data are averaged from cells of two subjects (S11 and S13). See also Supplementary Fig. 2. C: A representative graph showing increased levels of retinol (ROL) in VS ASCs of S11, measured by LC-MS. *P < 0.05 denotes significant change (n = 2).
Mentions: Since higher RA-mediated activity was observed in VS ASCs than in SC ASCs, we assessed endogenous RA levels using three different methods. First, a Luciferase reporter assay using the RARE indicated that VS ASCs rendered a significantly higher RA-responsive activity than SC ASCs (Fig. 4A). Second, endogenous levels of RA were assessed by ultrasensitive surface-enhanced Raman spectroscopy using the scheme and spectra shown in Supplementary Fig. 2A–C. The surface-enhanced Raman spectroscopy measurement indicated significant upregulation of RA in VS ASCs compared with SC ASCs (Supplementary Fig. 2D). A similar increase of endogenous RA in VS ASCs was observed when the conventional method using LC-MS was used (Fig. 4B). The level of the RA precursor retinol, as measured by LC-MS, also indicated a significant increase in VS ASCs compared with SC ASCs (Fig. 4C).

View Article: PubMed Central - PubMed

ABSTRACT

Increased visceral fat, rather than subcutaneous fat, during the onset of obesity is associated with a higher risk of developing metabolic diseases. The inherent adipogenic properties of human adipose-derived stem cells (ASCs) from visceral depots are compromised compared with those of ASCs from subcutaneous depots, but little is known about the underlying mechanisms. Using ontological analysis of global gene expression studies, we demonstrate that many genes involved in retinoic acid (RA) synthesis or regulated by RA are differentially expressed in human tissues and ASCs from subcutaneous and visceral fat. The endogenous level of RA is higher in visceral ASCs; this is associated with upregulation of the RA synthesis gene through the visceral-specific developmental factor WT1. Excessive RA-mediated activity impedes the adipogenic capability of ASCs at early but not late stages of adipogenesis, which can be reversed by antagonism of RA receptors or knockdown of WT1. Our results reveal the developmental origin of adipocytic properties and the pathophysiological contributions of visceral fat depots.

No MeSH data available.