Potentiation of Adipogenesis by Reactive Oxygen Species is a Unifying Mechanism in the Pro-adipogenic Properties of Bisphenol A and its New Structural Analogues

Abstract

Aims: Structural analogues of bisphenol A (BPA), including BPS and BPF, are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved. Methods: Adipose-derived progenitors were isolated from mice and exposed to various concentrations of BPS, BPA or BPF before induction of adipogenesis. RNAseq in BPS-exposed progenitors revealed modulation in redox pathways. The role of reactive oxygen species (ROS) was assessed by measuring the degree of adipogenesis in the presence or absence of antioxidants. ROS production and mitochondria function were determined by fluorescent assays. Fat mass was measured by TD-NMR in adult mice exposed to BPS during in utero establishment of the adipocyte progenitor pool, and in adult mice exposed to BPS after weaning. Results: Exposure of progenitors to BPS, BPF, BPA or ROS generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation. ROS was higher in bisphenol-exposed cells, while co-treatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondria membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher adiposity, while postnatal exposure had no impact on adiposity in either sex. ROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis.

Maternal obesity and programming of metabolic syndrome in the offspring: searching for mechanisms in the adipocyte progenitor pool

“…Therefore, in both obesity and aging, cellular senescence may be either a cause or consequence of chronic inflammation in WAT, a hallmark of adiposopathy. Findings from our laboratory show that the effect of ROS on adipogenesis is non-linear, such that low levels of ROS potentiate adipogenesis, while high levels impair differentiation [51]. Thus, signals emanating from an adipose microenvironment that has progressed to a state of chronic inflammation and redox imbalance may instigate the transition from adaptive WAT remodeling to adiposopathy.…”

“…The above evidence suggests that the ASC pool senses and responds to a local and transient inflammatory environment, contributing to adaptive adipose tissue remodeling that replaces dead or senescent adipocytes. Redox signaling plays a key role in mediating cellular responses to inflammation and recent work from our laboratory reveals a novel role for reactive oxygen species (ROS) in stimulating adipogenesis [51]. Thus, ROS may serve as second messengers in the transduction of signals from the local environment to control behavior of the progenitor pool.…”