284Cardiometabolic risk of visceral fat: Regulation of stem cells multipotency in visceral and subcutaneous adipose tissue

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Purpose: The precise mechanisms underlying the differential function and cardiometabolic risk of white adipose tissue (WAT) remain unclear. Visceral (VWAT) and subcutaneous (SCWAT) adipose tissue have different metabolic functions that seem related to their different intrinsic expansion capacities. Here we have hypothesized that WAT characteristics are determined by their resident adipose stem cells (ASCs) and understanding the differential regulation of adipocyte biogenesis may be critical to prevent the metabolic co-morbidities of visceral obesity.

Methods: ASCs from 3 different VWAT depots (epididymal, mesenteric and retroperitoneal) and SCWAT were characterized by flow cytometry and real time PCR, in both healthy lean (ZLC) and diabetic obese (ZDF) rats, to identify their stemness and their adipogenic differentiation commitment. Notch signalling pathway, that plays a critical role in adipocyte differentiation, was analyzed in depth.

Results: ASCs from different WAT showed significant differences in expression of main molecules governing the stemness and the earlier adipogenic differentiation steps in both ZLC and ZDF. The SCWAT and VWAT transcriptome differed greatly, showing a greater maintenance of the pluripotency and undifferentiated state in ASCs derived from VWAT compared with ASCs derived from SCWAT. The analysis performed on Notch system revealed that Notch target genes (Hes and Hey families) were up-regulated in ASCs derived from visceral depots. Upon adipogenic differentiation, adipocyte cell markers were down-regulated in ASCs from VWAT in comparison to ASCs from SCWAT, revealing a lower adipogenic capacity in ASCs of visceral origin than in those of SCWAT in accordance with the differential activation of Notch signalling. Notch up-regulation by its activator phenethylisothiocyanate (PEITC) attenuated the adipogenic differentiation of ASCs from SCWAT whereas Notch inhibition by N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-Butyl Ester (DAPT) increased the adipogenic differentiation of ASCs from visceral origin. We observed the same behaviour in healthy as well as diabetic conditions. In an adipogenic environment, ZDF rats, the inability of VWAT to form new adipocytes would lead to the adipocyte hypertrophy and limited storage capacity, leading to ectopic fat deposition and, ultimately, to the cardiometabolic alterations.

Conclusions: The differential activation of Notch in ASCs is at the origin of the different intrinsic WAT expansion capacities that contribute to the regional variations in WAT-homeostasis and to its associated cardiometabolic risk.

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