Notch Signaling Pathway Activation in Normal and Hyperglycemic Rats Differs in the Stem Cells of Visceral and Subcutaneous Adipose Tissue

Abstract

The precise mechanisms underlying the differential function and cardiometabolic risk of white adipose tissue (WAT) remain unclear. Visceral adipose tissue (V WAT ) and subcutaneous adipose tissue (SC WAT ) have different metabolic functions that seem to be ascribed to their different intrinsic expansion capacities. Here we have hypothesized that the WAT characteristics are determined by the resident adipose-derived stem cells (ASCs) found in the different WAT depots. Therefore, our objective has been to investigate adipogenesis in anatomically distinct fat depots. ASCs from five different WAT depots were characterized in both healthy lean and diabetic obese rats, showing significant differences in expression of some of genes governing the stemness and the earlier adipogenic differentiation steps. Notch-target genes [Hes (hairy and enhancer of split) and Hey (hairy/enhancer of split related with YRPW motif) families] were upregulated in ASCs derived from visceral depots. Upon adipogenic differentiation, adipocyte cell markers were downregulated in ASCs from V WAT in comparison to ASCs from SC WAT , revealing a lower adipogenic capacity in ASCs of visceral origin than in those of SC WAT in accordance with the differential activation of Notch signaling. Notch upregulation by its activator phenethyl isothiocyanate attenuated the adipogenic differentiation of ASCs from SC WAT 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. In conclusion, the differential activation of Notch in ASCs is the origin of the different intrinsic WAT expansion capacities that contribute to the regional variations in WAT homeostasis and to its associated cardiometabolic risk.

Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity

“…Another identified candidate was claudin 1 ( CLDN1 ) encoding an integral membrane protein and a component of tight junction strands. We further observed the heart and neural crest derivatives expressed 2 ( HAND2 ) which may play a role in adipogenic differentiation via NOTCH signaling [30], [31] and the cluster of differentiation 36 ( CD36 ), which is involved in lipid metabolism [32], [33]. Further, we also confirmed known candidate genes such as the homeobox C6 ( HOXC6 ) and the peroxisome proliferator-activated receptor gamma ( PPARG ).…”

“…Hand2 is involved in Notch signaling in heart development of mice [41]. Considering that NOTCH signaling also plays a major role in adipogenic differentiation [30], [31], mainly through inhibiting ASC (Adipose tissue-Derived-Stem Cells) differentiation to adipocytes and thereby affecting the adipose tissue expansion capacity [30], this might indicate reduced adipocyte differentiation in OVAT. In line with this, increased Notch signaling in mice blocked the expansion of white adipose tissue, ectopic fat accumulation and insulin resistance [42], which further supports the potential dysfunctional role of OVAT [1], [2].…”

Effect of Diabetes Mellitus on Adipocyte-Derived Stem Cells in Rat

“…The reservoir of stem cells in subcutaneous adipose tissue is known to change in diabetes. Adipose‐derived stem cells (ASCs), derived from the stromal vascular fraction, exhibit impaired viability, and differentiation (Ferrer‐Lorente et al, ,), including endothelial cell (EC), and angiogenic differentiation potential (Koci et al, ; Policha et al, ; Rennert et al, ). Diabetes is also known to limit the therapeutic potential of endothelial progenitor cells (EPCs) and bone marrow‐derived progenitor cells (BMPCs) (Tepper et al, ; Fadini et al, ; Li et al, ), and has been proposed to have deleterious effects on stem cells due to oxidative stress (Saki et al, ).…”

“…Multiple signaling pathways, several of which are involved in stem cell maintenance, are affected by diabetes in adipose tissue, including the Notch, Wnt, fibroblast growth factors (FGF) (Ferrer‐Lorente et al, ,), and the bone morphogenetic proteins (BMPs) (Dunn, ; Qian et al, ). The BMPs are important for both adipose tissue development and vascular formation (Schulz and Tseng, ; Tang and Lane, ; Dyer et al, ), and recent studies suggest that BMP expression is altered in response to diabetes in multiple tissues.…”

Adipocyte biology: It is time to upgrade to a new model

“…Similarly, Griesche et al () demonstrated that, while incorporating additional wash steps and immunoselection for several markers into the isolation protocol improved the homogeneity of ASC cultures, these steps also resulted in considerably lower cell yields, and had little impact on the differentiation potential of these cells. Moreover, expression of CD29, CD90, and CD105 may vary between ASCs from different adipose tissue depots (Ferrer‐Lorente, Bejar, & Badimon, ), or with obesity, high‐fat feeding, and exercise (Oñate et al, ; Pincu et al, ), and therefore immunoselection for these markers may differentially affect cell yields in studies where these factors are being examined.…”