The dramatic rise in obesity and metabolic syndrome can be related, at least in part, to environmental chemical factors such as Bisphenol-A (BPA). In this study, we aimed to understand the effects of low-dose Bisphenol-A on the human mature adipocytes and stromal vascular fraction (SVF) cells, obtained from subcutaneous mammary adipose tissue of overweight female patients, undergoing surgical mammary reduction. 24 and/or 48-h exposure to BPA 0.1 nM elicited significant increase of the inflammatory molecules interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemo-attractant protein 1α (MCP1α) and induced G protein-coupled estrogen receptor 30 (GPR30) levels more than two-fold both in mature adipocytes and SVF cells. These effects were similar to that obtained in the presence of GPR30-specific agonist G1 (100 nM) and were reverted by G15 (1 µM), a GPR30-selective antagonist. As a result of BPA-GPR30 signaling activation, fatty acid synthase (FAS) and leptin mRNA levels were significantly higher upon BPA exposure (P < 0.05) in mature adipocytes, with an opposite effect on adiponectin (ADIPOQ). In addition, an increase in SVF cell proliferation and ERK1/2 phosphorylation, was observed, compared to untreated cells. G15 reverted all of these effects. Interestingly, the action of BPA on SVF cell growth was mimicked by IL-8 treatment and was reverted by incubation with anti-IL8 antibodies. All these data suggest that BPA at 0.1 nM, a ten times lower concentration than environmental exposure, increases the expression of pro-inflammatory cytokines via GPR30 both in mature mammary adipocytes and in SVF cells with a possible involvement of IL-8.
Ilaria Cimmino, Francesco Oriente, Vittoria D’Esposito, Domenico Liguoro, Pasquale Liguoro, Maria Rosaria Ambrosio, Serena Cabaro, Francesco D’Andrea, Francesco Beguinot, Pietro Formisano, and Rossella Valentino
Suzuka Onishi and Kohsuke Kataoka
Insulin plays a central role in glucose homeostasis and is produced exclusively by pancreatic islet β-cells. Insulin gene transcription is regulated by a set of β-cell-enriched transcription factors that bind to cis-regulatory elements within the promoter region, and regulation of the insulin gene promoter is closely linked to β-cell functionality. PIASy, a member of the PIAS family of SUMO E3 ligases, is thought to affect insulin gene transcription, but its mechanism of action is not fully understood. Here, we demonstrate that PIASy interacts with MafA and represses insulin gene promoter activity. MafA is a β-cell-restricted basic leucine-zipper transcriptional activator that binds to the C1 element of the insulin gene promoter. In line with previous studies showing the transactivator domain of MafA is SUMOylated, PIASy enhanced the SUMOylation of MafA. However, a SUMOylation-deficient mutant of MafA was still repressed by PIASy, indicating that this modification is dispensable for repression. Using a series of MafA and PIASy mutants, we found that the basic domain of MafA and the amino-terminal region of PIASy containing the SAP domain are necessary for their interaction. In addition, SUMO-interacting motif 1 (SIM1) at the carboxyl-terminal region of PIASy was required to repress the synergistic transactivation of MafA, Pdx1, and Beta2, transcription factors playing central roles in β-cell differentiation and function. The PINIT and SP-RING domains in the middle region of PIASy were dispensable. These findings suggest that PIASy binds to MafA through the SAP domain and negatively regulates the insulin gene promoter through a novel SIM1-dependent mechanism.
David Aguinaga, Mireia Casanovas, Rafael Rivas-Santisteban, Irene Reyes-Resina, Gemma Navarro, and Rafael Franco
Addiction and eating disorders involve brain reward circuits. Binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after drug use is discontinued. Exciting new findings show that receptors for the ‘hunger’ hormone, ghrelin, directly interact with the sigma-1 receptor (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor as a general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders.
Leandro Nieto, Mariana Fuertes, Josefina Rosmino, Sergio Senin, and Eduardo Arzt
Retinoic acid (RA), an active metabolite of Vitamin A, and bone morphogenetic protein 4 (BMP-4) pathways control the transcription of pro-opiomelanocortin (Pomc), the precursor of ACTH. We describe a novel mechanism by which RA and BMP-4 act together in the context of pituitary corticotroph tumoral cells to regulate Pomc transcription. BMP-4 and RA exert a potentiated inhibition on Pomc gene expression. This potentiation of the inhibitory action on Pomc transcription was blocked by the inhibitory SMADs of the BMP-4 pathway (SMAD6 and SMAD7), a negative regulator of BMP-4 signaling (TOB1) and a blocker of RA pathway (COUP-TFI). AtT-20 corticotrophinoma cells express RA receptors (RARB, RXRA and RXRG) which associate with factors of BMP-4 (SMAD4 and SMAD1) signaling cascade in transcriptional complexes that block Pomc transcription. COUP-TFI and TOB1 disrupt these complexes. Deletions and mutations of the Pomc promoter and a specific DNA-binding assay show that the complexes bind to the RARE site in the Pomc promoter. The enhanced inhibitory interaction between RA and BMP-4 pathways occurs also in another relevant corticotroph gene promoter, the corticotropin-releasing hormone receptor 1 (Crh-r1). The understanding of the molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.
Charit Taneja, Sakshi Gera, Se-Min Kim, Jameel Iqbal, Tony Yuen, and Mone Zaidi
FSH has a primary function in procreation, wherein it induces estrogen production in females and regulates spermatogenesis in males. However, in line with our discoveries over the past decade of non-unitary functions of pituitary hormones, we and others have described hitherto uncharacterized functions of FSH. Through high-affinity receptors, some of which are variants of the ovarian FSH receptor (FSHR), FSH regulates bone mass, adipose tissue function, energy metabolism, and cholesterol production in both sexes. These newly described actions of FSH may indeed be relevant to the pathogenesis of bone loss, dysregulated energy homeostasis, and disordered lipid metabolism that accompany the menopause in females and aging in both genders. We are therefore excited about the possibility of modulating circulating FSH levels toward a therapeutic benefit for a host of age-associated diseases, including osteoporosis, obesity and dyslipidemia, among other future possibilities.
Sasha R Howard
Delayed puberty represents the clinical presentation of a final common pathway for many different pathological mechanisms. In the majority of patients presenting with significantly delayed puberty, there is a clear family history of delayed or disturbed puberty, and pubertal timing is known to be a trait with strong heritability. Thus, genetic factors clearly play a key role in determining the timing of puberty, and mutations in certain genes are recognised as responsible for delayed or absent puberty in a minority of patients. Through the identification of causal genetic defects such as these we have been able to learn a great deal about the pathogenesis of disrupted puberty and its genetic regulation. Firstly, deficiency in key genes that govern the development of the gonadotropin-releasing hormone system during fetal development may result in a spectrum of conditions ranging from isolated delayed puberty to absent puberty with anosmia. Secondly, a balance of inhibitory and excitatory signals, acting upstream of GnRH secretion, are vital for the correct timing of puberty. These act to repress the hypothalamic–pituitary–gonadal axis during mid-childhood and allow it to reactivate at puberty, and alterations in this equilibrium can cause delayed (or precocious) puberty. Thirdly, disturbances of energy metabolism inputs to the kisspeptin–GnRH system may also lead to late onset of puberty associated with changes in body mass.
Trinidad Raices, María Luisa Varela, Casandra Margarita Monzón, María Florencia Correa Torrado, Romina María Pagotto, Marcos Besio Moreno, Carolina Mondillo, Omar Pedro Pignataro, and Elba Nora Pereyra
Testicular Leydig cells (LC) are modulated by several pathways, one of them being the histaminergic system. Heme oxygenase-1 (HO-1), whose upregulation comprises the primary response to oxidative noxae, has a central homeostatic role and might dysregulate LC functions when induced. In this report, we aimed to determine how hemin, an HO-1 inducer, affects LC proliferative capacity and whether HO-1 effects on LC functions are reversible. It was also evaluated if HO-1 interacts in any way with histamine, affecting its regulatory action over LC. MA-10 and R2C cell lines and immature rat LC were used as models. Firstly, we show that after a 24-h incubation with 25 µmol/L hemin, LC proliferation is reversibly impaired by cell cycle arrest in G2/M phase, with no evidence of apoptosis induction. Even though steroid production is abrogated after a 48-h exposure to 25 µmol/L hemin, steroidogenesis can be restored to control levels in a time-dependent manner if the inducer is removed from the medium. Regarding HO-1 and histamine interaction, it is shown that hemin abrogates histamine biphasic effect on steroidogenesis and proliferation. Working with histamine receptors agonists, we elucidated that HO-1 induction affects the regulation mediated by receptor types 1, 2 and 4. In summary, HO-1 induction arrests LC functions, inhibiting steroid production and cell cycle progression. Despite their reversibility, HO-1 actions might negatively influence critical phases of LC development and differentiation affecting their function as well as other androgen-dependent organs. What’s more, we have described a hitherto unknown interaction between HO-1 induction and histamine effects.
Eui Hyun Kim, Geon A Kim, Anukul Taweechaipaisankul, Seok Hee Lee, Muhammad Qasim, Curie Ahn, and Byeong Chun Lee
Oxidative stress (OS) is a major problem during in vitro culture of embryos. Numerous studies have shown that melatonin, which is known to have antioxidant properties, prevents the occurrence of OS in embryos. However, the molecular mechanisms by which melatonin prevents OS in embryos are still unclear. The present study suggests a possible involvement of the nuclear factor erythroid 2-related factor 2/antioxidant-responsive element (Nrf2/ARE) signaling pathway, which is one of the prominent signals for OS prevention through Nrf2 activation, connecting melatonin, OS prevention and porcine embryonic development. The aim of this study was to investigate the effects of melatonin (10−7 M) on porcine embryonic development via the Nrf2/ARE signaling pathway; brusatol (50 nM; Nrf2 specific inhibitor) was used to validate the mechanism. Treatment of porcine embryo with melatonin significantly increased formation rates of blastocysts and their total cell numbers and also upregulated the expression of Nrf2/ARE signaling and apoptosis-related genes (MT2, NRF2, UCHL, HO-1, SOD1 and BCL-2). Furthermore, the expression of proteins (NRF2 and MT2) was also upregulated in the melatonin-treated group. Concomitantly, brusatol significantly inhibited these effects, upregulating the expression of KEAP1 and BAX, including the expression level of KEAP1 protein. These results provide evidences that melatonin prevents OS through Nrf2/ARE signaling pathway in porcine in vitro fertilization -derived embryos.
Ji Chen, Chao Li, Wenjie Liu, Bin Yan, Xiaoling Hu, and Fengrui Yang
Neuropathic pain represents one of the most common complications associated with diabetes mellitus (DM) that impacts quality of life. Accumulating studies have highlighted the involvement of miRNAs in DM. Thus, the current study aimed to investigate the roles of miR-155 in diabetic peripheral neuropathy (DPN). In vitro DPN models were established using rat Schwann cells (SCs) by treatment with 5.5 mM glucose. Gain- or loss-of-function studies were conducted to determine the effect of miR-155 on Nrf2, cellular function, reactive oxygen species and inflammation. Rat DNP models were established by streptozotocin injection and damage of sciatic nerve. Next, miR-155 antagomir or agomir was employed to investigate the effects associated with miR-155 on motor and sciatic nerve conduction velocity (MNCV, SNCV), angiogenesis and inflammatory response in vivo. Nrf2 was identified to be a target of miR-155 by dual-luciferase reporter gene assay. Silencing of miR-155 or restoration of Nrf2 promoted cell proliferation, inhibited apoptosis and alleviated inflammation in vitro. miR-155 antagomir-induced inhibition increased MNCV and SNCV, strengthened angiogenesis and alleviated inflammation in DPN rats. Additionally, the effects exerted by miR-155 were reversed when Nrf2 was restored both in vitro and in vivo. Taken together, the key findings of our study provide evidence indicating that miR-155 targeted and suppressed Nrf2 in DPN. miR-155 silencing was found to alleviate sciatic nerve injury in DPN, highlighting its potential as a therapeutic target for DPN.
Caitlyn Nguyen-Ngo, Nanthini Jayabalan, Carlos Salomon, and Martha Lappas
Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for mother and baby. An effective therapeutic that can reduce the incidence of GDM and improve long-term maternal and fetal outcomes is a major research priority, crucially important for public health. A lack of knowledge about the underlying pathophysiology of GDM has hampered the development of such therapeutics. What we do know, however, is that maternal insulin resistance, low-grade inflammation and endothelial cell dysfunction are three central features of pregnancies complicated by GDM. Indeed, data generated over the past decade have implicated a number of candidate regulators of insulin resistance, inflammation and endothelial cell dysfunction in placenta, maternal adipose tissue and skeletal muscle. These include nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptors (PPARs), sirtuins (SIRTs), 5′ AMP-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK3), PI3K/mTOR, inflammasome and endoplasmic reticulum (ER) stress. In this review, the identification of these as key modulators of GDM will be discussed. The biochemical pathways involved in the formation of these may represent potential sites for intervention that may translate to therapeutic interventions to prevent the development of GDM.