BackgroundThe incidence of obesity has risen dramatically over the last few decades. This epidemic may be affected by exposure to xenobiotic chemicals. Bisphenol A (BPA), an endocrine disruptor, is detectable at nanomolar levels in human serum worldwide. Adiponectin is an adipocyte-specific hormone that increases insulin sensitivity and reduces tissue inflammation. Thus, any factor that suppresses adiponectin release could lead to insulin resistance and increased susceptibility to obesity-associated diseases.ObjectivesIn this study we aimed to compare a) the effects of low doses of BPA and estradiol (E2) on adiponectin secretion from human breast, subcutaneous, and visceral adipose explants and mature adipocytes, and b) expression of putative estrogen and estrogen-related receptors (ERRs) in these tissues.MethodsWe determined adiponectin levels in conditioned media from adipose explants or adipocytes by enzyme-linked immunosorbant assay. We determined expression of estrogen receptors (ERs) α and β, G-protein–coupled receptor 30 (GPR30), and ERRs α, β, and γ by quantitative real-time polymerase chain reaction.ResultsBPA at 0.1 and 1 nM doses suppressed adiponectin release from all adipose depots examined. Despite substantial variability among patients, BPA was as effective, and often more effective, than equimolar concentrations of E2. Adipose tissue expresses similar mRNA levels of ERα, ERβ, and ERRγ, and 20- to 30-fold lower levels of GPR30, ERRα, and ERRβ.ConclusionsBPA at environmentally relevant doses inhibits the release of a key adipokine that protects humans from metabolic syndrome. The mechanism by which BPA suppresses adiponectin and the receptors involved remains to be determined.

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SummaryBisphenol A (BPA) is one of the most prevalent and best studied endocrine disruptors. After years of exposure to consumer products containing BPA, most individuals tested have circulating BPA at the low nanomolar levels. In addition to its well documented actions on the reproductive system, BPA exerts a wide variety of metabolic effects. This review summarizes recent findings on the ability of BPA, at environmentally relevant doses, to inhibit adiponectin and stimulate the release of inflammatory adipokines such as interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) from human adipose tissue. Expression of several classical and non-classical estrogen receptors in human adipose tissue raises the possibility of their involvement as mediators of BPA actions. The implications of these observations to the obesity-related metabolic syndrome and its sequalae are discussed.Keywords bisphenol A; adiponectin; inflammatory cytokines; human adipose tissue; metabolic syndrome BPA: Overview and Controversial IssuesBPA is a small (228 Da) molecule which is used as a monomer in polymerization reaction to produce polycarbonate plastics (Fig 1). Polycarbonates are used in numerous consumer products, including food and water containers, baby bottles, lining of food and beverage metal cans, medical tubing, epoxy resins and dental fillings Welshons et al., 2006). Small amounts of BPA can migrate from the polymers to food or water especially upon heating (Le et al., 2008). Studies conducted in the USA, Europe and Japan, have documented widespread human exposure to BPA, with detected levels ranging from 0.3 to 5 ng/ml (approximately 1-20 nM) in serum and breast milk (Welshons et al., 2006)). Being lipophilic, BPA also accumulates in human fat (Fernandez et al., 2007). Bisphenol A diglycidyl ether (BADGE), is a component of epoxy resins (Fig 1). Workers who spray epoxy resins had higher urinary and plasma levels of both BADGE and BPA than controls, indicating that BPA can be endogenously generated from BADGE (Hanaoka et al., 2002).In 1993, Krishnan et al discovered a substance that leached from polycarbonate flasks during autoclaving and acted like an estrogen by increasing the proliferation of breast cancer cells (Krishnan et al., 1993). Using sequential chromatography they identified this compound as BPA. Soon thereafter, BPA was detected in food cans and dental cement (Brotons et al., 1995;Olea et al., 1996). At about the same time, we were studying interactions between prolactin (PRL) and estradiol (E2). Upon noticing a striking structural similarity between BPA and the potent estrogen diethylstilbestrol (DES) (Fig 1), we set out to examine if BPA altered PRL production. Our study (Steinmetz et al., 1997) was the first to show estrogen-like properties of BPA within the neuroendocrine axis in vitro and in vivo. This was followed by reporting on the effects of BPA on the reproductive tract in female rats , and the induction of prolonged hyperprolactinemia following treatment of neonatal rats with BPA (Khurana et al., 2000)...

Pituitary-derived prolactin (PRL) is a well-known regulator of the lactating mammary gland. However, the recent discovery that human adipose tissue produces PRL as well as expresses the PRL receptor (PRLR) highlights a previously unappreciated action of PRL as a cytokine involved in adipose tissue function. Biologically active PRL is secreted by all adipose tissue depots examined: breast, visceral and subcutaneous. The expression of adipose PRL is regulated by a non-pituitary, alternative superdistal promoter. PRL expression and release increases during early pre-adipocyte differentiation and is stimulated by cyclic AMP activators, including beta adrenergic receptor agonists. PRL release from subcutaneous adipose explants is attenuated during obesity, suggesting that adipose PRL production is altered by the metabolic state. Several lines of evidence indicate that PRL suppresses lipid storage as well as the release of adipokines such as adiponectin, interleukin-6 and possibly leptin. PRL has also been implicated in the regulation of adipogenesis. A newly developed PRL-secreting human adipocyte cell line, LS14, should allow comprehensive examination of the regulation and function of adipocyte-derived PRL. Collectively, these studies raise the prospect that PRL affects energy homeostasis through its action as an adipokine and is involved in the manifestation of insulin resistance.

Prolactin (PRL), best recognized for its lactogenic activity, is also involved in the regulation of metabolic homeostasis in both mammalian and nonmammalian species. Although several mouse models have been used to study the metabolic functions of PRL, a clear-cut consensus has not emerged given the limited and often conflicting data. To clarify the role of PRL in metabolic homeostasis in males and nonlactating females, we used the PRL-deficient mouse. Our objectives were to compare: 1) weight gain, 2) body composition, 3) serum lipid profile, 4) circulating leptin and adiponectin levels, and 5) glucose tolerance in PRL knockout, heterozygous, and wild-type mice maintained on standard chow, high-fat, or low-fat diets. In addition, we compared the lipolytic actions of PRL using adipose tissue explants from mice, rats, and humans. We are reporting that PRL deficiency does not affect the rate of weight gain, body composition, serum lipids, or adiponectin levels in either sex on any diet. Glucose tolerance was slightly impaired in very young PRL knockout male pups but not in adults or in females at any age. Leptin was elevated in male, but not female, PRL knockout mice maintained on a low-fat diet. PRL did not affect lipolysis in adipose tissue explants from mice but significantly inhibited glycerol release from both rat and human adipose explants in a dose-dependent manner. We conclude that PRL deficiency has negligible gross metabolic effects in mice.