PCB126 inhibits adipogenesis of human preadipocytes

Abstract

Emerging evidence indicates that persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), are involved in the development of diabetes. Dysfunctional adipocytes play a significant role in initiating insulin resistance. Preadipocytes make up a large portion of adipose tissue and are necessary for the generation of functional mature adipocytes through adipogenesis. PCB126 is a dioxin-like PCB and a potent aryl hydrocarbon receptor (AhR) agonist. We hypothesized that PCB126 may be involved in the development of diabetes through disruption of adipogenesis. Using a newly developed human preadipocyte cell line called NPAD (Normal PreADipocytes), we found that exposure of preadipocytes to PCB126 resulted in significant reduction in their subsequent ability to fully differentiate into adipocytes, more so than when the cells were exposed to PCB126 during differentiation. Reduction in differentiation by PCB126 was associated with downregulation of transcript levels of a key adipocyte transcription factor, PPARγ, and late adipocyte differentiation genes. An AhR antagonist, CH223191, blocked this effect. These studies indicate that preadipocytes are particularly sensitive to the effects of PCB126 and suggest that AhR activation inhibits PPARγ transcription and subsequent adipogenesis. Our results validate the NPAD cell line as a useful model for studying the effects of POPs on adipogenesis.

Suppression of Resting Metabolism by the Angiotensin AT 2 Receptor

“…In contrast, the induction of UCP1 mRNA by NE was significantly blunted with CGP treatment in mouse iWA (Figure 4C). In a third adipose cell culture model consisting of immortalized human subcutaneous preadipocytes (Gadupudi et al, 2015; Vu et al, 2013; Vu et al, 2015), we confirmed a suppressive effect of AT 2 activation upon UCP1 mRNA (Figure 4D). These data support an action of AT 2 receptors to modulate β-adrenergic signaling downstream of cAMP production and the bifurcation of second-messenger modulation of UCP1 expression versus lipolysis.…”

Adipose Tissue as a Site of Toxin Accumulation

“…The best characterized AhR agonists capable of eliciting effects in AT or adipocyte cell lines are TCDD and TCDD-like PCBs, which can be abolished by AhR antagonists (34) (121). Moreover, TCDD-induced impairment of adipogenesis in mouse embryonic fibroblasts was abolished when cells were isolated from AhR deficient mice (26).…”

“…Reduced differentiation of 3T3-L1 cells to adipocytes by TCDD (71) (161) (320), PCBs (121), or DDT (278) was associated with decreased PPARγ gene expression. Further, TCDD suppressed PPARγ and adipogenesis via a MEK/ERK mechanism (79).…”

Persistent organic pollutants and obesity: are they potential mechanisms for breast cancer promotion?

“…PCB126 stimulated intrinsic changes in cell function by decreasing transcript levels of a key regulator of adipogenesis, PPARγ (Gadupudi, et al 2014). The ability of preadipocytes to mature is integral to development and homeostasis.…”

“…POP exposure compromising the ability of preadipocytes to differentiate in children and adolescents has the potential to alter their ability to form normal adipose tissue, ultimately leading to dysfunction and disease. In adults, chronic POPs exposure may alter their ability to replace mature adipocytes caused by cell death, again potentially leading to dysfunctional adipose tissue (Gadupudi et al 2014). …”