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

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.

Hoxa5 Promotes Adipose Differentiation via Increasing DNA Methylation Level and Inhibiting PKA/HSL Signal Pathway in Mice

“…Hoxa5 expression can be up-regulated by retinoic acid [25, 26]. Retinoic acid may reduce body fat and improve insulin sensitivity in lean and obese rodents.…”

Retinoic acid is abundantly detected in different depots of adipose tissue by SERS

“…As expected from the gene expression changes, endogenous RA levels were found higher in VS-ASCs than SC-ASCs. 14 Consequently, many genes known to be downstream targets of RA were confirmed to be differentially expressed. These include VS-enriched genes (NR2F1, MGP, RARRES1, RARRES2, PLAT, PTGS1, CDKN2B, HOXA4, HOXA5, BAPX1, F3, MEIS1, and CDH6) and SC-enriched genes (MME, PITX2, TNC, ENPP2, CTSK, and CRYAB).…”

“…We previously employed 3 methods to measure endogenous RA levels, namely indirect Luciferase-based reporter assay under the control of RA response element, LC/MS-based measurement, and SERS-based quantification. 14 We further took advantage of the SERS method we developed in assessing endogenous RA levels for adipose tissue in comparison to other tissues from mice. The principle of our protocol is similar to ELISA using HRP.…”

“…The product SERS spectra show specific Raman bands at 1191, 1337, and 1605 cm ¡1 that is characteristic of TMB 2C . 14,19 The intensity of the specific Raman band corresponding to 1605 cm ¡1 wavenumber was selected as the peak of interest as its intensity is inversely proportional to the concentration of RA present in the sample (Fig. 2C).…”

“…14,19 Briefly we used 633 nm excitation laser with 10% laser power, 1800 line/mm grating along with cooled CCD. For sample focusing we used 20X objective lens with N.A 0.4.…”