FASEB J 2010;24:326C331 [PubMed] [Google Scholar] 32

FASEB J 2010;24:326C331 [PubMed] [Google Scholar] 32. and promoted adipogenesis CZC-25146 hydrochloride in cells with a low degree of differentiation. The positive effect of DKK1, inhibiting cellular WNT activation by binding to the Kremen/LDL receptorCrelated protein receptors, was not seen with inhibitors of secreted WNT ligands. BMP4 increased differentiation, and BMP4 in the presence of DKK1 produced an additive effect. There was an apparent cross-talk between differentiation and commitment because BMP4 expression increased in differentiating adipocytes, and the addition of the BMP4 inhibitor, Noggin, reduced precursor cell differentiation. Thus, differentiated human adipose cells can promote adipogenesis via endogenous BMP4 activation, and the impaired adipogenesis in hypertrophic obesity is mainly due to an failure to suppress canonical WNT and to induce DKK1. Our current understanding of adipose tissue development in human is that the major pool of preadipocytes evolves before puberty, and after this, there is a 10% annual adipose cell turn-over CZC-25146 hydrochloride (1). Interestingly, research has also shown that individuals with inappropriately enlarged adipose cells for a given BMI (hypertrophic obesity) in the abdominal subcutaneous tissue are characterized by a recruitment of new cells, suggesting that this is causally related to the development of hypertrophic obesity (2). More important, we have recently shown that adipose cell size in the abdominal subcutaneous region is usually, for a given BMI, considerably larger in individuals with a genetic predisposition for type 2 diabetes than in subjects lacking a known heredity or in those with a heredity for overweight/obesity (3,4). These findings link heredity for type 2 diabetes to the development of hypertrophic obesity. Furthermore, hypertrophic adipocytes, even in the absence of obesity per se, are associated with several markers of a dysregulated adipose tissue and systemic as well as local insulin resistance (4,5). In agreement with these in vivo findings, we recently showed that the ability of subcutaneous adipose tissue stromal vascular cells (stromal cells) to undergo adipogenic differentiation was markedly reduced in hypertrophic obesity and that the degree of impairment was positively correlated with adipose cell size of the donor (6). Interestingly, this did not appear to be a consequence of a reduced quantity of early precursor cells because the quantity of cluster of differentiation CD133+ cells was actually increased (6). Together, these findings suggest that hypertrophic obesity is due to an apparent genetic impairment in the ability to recruit and differentiate new subcutaneous adipose precursor cells. This, then, promotes improper cell enlargement, inflammation, and a dysregulated adipose tissue that will favor ectopic lipid accumulation and the development of a metabolically obese phenotype (3,4). Recruitment and differentiation of adipose precursor cells are regulated by the wingless-type mouse mammary tumor computer virus (MMTV) integration site family (WNT) signaling. Thus, a possible mechanism for the perturbed adipogenesis in hypertrophic obesity is an failure to properly suppress WNT activation in precursor cells. Secreted WNT ligands transmission through both canonical and noncanonical pathways. The canonical WNT/-catenin pathway is usually highly active in precursor cells and directs multipotent mesenchymal stem cells (MSC) toward adipogenic, osteogenic, or myogenic differentiation (7,8). The detailed molecular mechanisms for the commitment of multipotent cells into the adipose lineage are poorly understood (9). However, once committed, preadipocytes can undergo the adipogenic program leading to activation of the dominant adipose regulator peroxisome proliferator-activated receptor (PPAR)- as well as the CCAAT/enhancer binding protein (C/EBP) proteins (9,10). WNT signaling can be inhibited by different secreted antagonists (11) including soluble Frizzled-related CZC-25146 hydrochloride proteins (sFRP) 1 and 2, WNT inhibitory factor (WIF) 1 and the Dickkopf (DKK) proteins (12C14). DKK1 inhibits WNT signaling by binding as a high-affinity antagonist to the coreceptors LDL receptorCrelated proteins (LRPs) 5/6 and Kremen1 and 2, thereby preventing formation of the active LRP/Frizzled complex. sFRPs and WIF1 proteins bind to the secreted WNT ligands and thereby inhibit activation (15). Consistent with CALCR the importance of canonical WNT activation, transfection of human MSC isolated from adipose tissue with small interfering RNA (siRNA) for DKK1 reduced adipogenesis (16). We, as well as others, have shown that Dkk1 is usually highly expressed in differentiated 3T3-L1 adipocytes and is induced by the PPAR- agonists (17C19). Thus, activation and secretion of DKK1 might be a mechanism whereby PPAR- can help terminate the WNT transmission and promote adipogenesis (16,19). Bone morphogenetic proteins (BMPs) are users of CZC-25146 hydrochloride the transforming growth factor- superfamily and have been shown to play an important role in the commitment of multipotent precursor cells to CZC-25146 hydrochloride the adipocyte lineage (20C22). Most of the effects of the BMPs are mediated through type 1 and type 2 receptors. Interestingly, specific.