Although polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age, its etiology remains poorly understood. From the perspective of developmental origins of health and disease, some studies have investigated the relationship between low birth weight and the prevalence of PCOS and/or PCOS phenotypes in humans; however, the results of these studies were inconclusive. Here, we evaluated the effects of prenatal undernutrition on the metabolic and reproductive phenotypes of dihydrotestosterone-induced PCOS model rats. The PCOS model rats showed increased body weight, food intake, fat weight, adipocyte size and upregulation of inflammatory cytokines in adipose tissue; prenatal undernutrition exacerbated these metabolic changes. Prenatal undernutrition also increased the gene expression of hypothalamic orexigenic factor and decreased the gene expression of anorexigenic factor in the PCOS model rats. In addition, the PCOS model rats exhibited irregular cyclicity, polycystic ovaries and disrupted gene expression of ovarian steroidogenic enzymes. Interestingly, prenatal undernutrition attenuated these reproductive changes in the PCOS model rats. Our results suggest that in dihydrotestosterone-induced PCOS model rats, prenatal undernutrition exacerbates the metabolic phenotypes, whereas it improves the reproductive phenotypes and that such phenotypic changes may be induced by the alteration of some peripheral and central factors.
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Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Yiliyasi Mayila, Rie Yanagihara, Yuri Yamamoto, Akira Kuwahara and Minoru Irahara
Dan Li, Yan Ji, Chunlan Zhao, Yapeng Yao, Anlan Yang, Honghong Jin, Yang Chen, Mingjun San, Jing Zhang, Mingjiao Zhang, Luqing Zhang, Xuechao Feng and Yaowu Zheng
Oxytocin receptor (OXTR) is a G-protein-coupled receptor and known for regulation of maternal and social behaviors. Null mutation (Oxtr−/−) leads to defects in lactation due to impaired milk ejection and maternal nurturing. Overexpression of OXTR has never been studied. To define the functions of OXTR overexpression, a transgenic mouse model that overexpresses mouse Oxtr under β-actin promoter was developed (++ Oxtr). ++ Oxtr mice displayed advanced development and maturation of mammary gland, including ductal distention, enhanced secretory differentiation and early milk production at non-pregnancy and early pregnancy. However, ++ Oxtr dams failed to produce adequate amount of milk and led to lethality of newborns due to early involution of mammary gland in lactation. Mammary gland transplantation results indicated the abnormal mammary gland development was mainly from hormonal changes in ++ Oxtr mice but not from OXTR overexpression in mammary gland. Elevated OXTR expression increased prolactin-induced phosphorylation and nuclear localization of STAT5 (p-STAT5), and decreased progesterone level, leading to early milk production in non-pregnant and early pregnant females, whereas low prolactin and STAT5 activation in lactation led to insufficient milk production. Progesterone treatment reversed the OXTR-induced accelerated mammary gland development by inhibition of prolactin/p-STAT5 pathway. Prolactin administration rescued lactation deficiency through STAT5 activation. Progesterone plays a negative role in OXTR-regulated prolactin/p-STAT5 pathways. The study provides evidence that OXTR overexpression induces abnormal mammary gland development through progesterone and prolactin-regulated p-STAT5 pathway.
Laura Marroqui, Eva Tudurí, Paloma Alonso-Magdalena, Iván Quesada, Ángel Nadal and Reinaldo Sousa dos Santos
Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin resistance and pancreatic β-cell dysfunction or death. Among several environmental factors contributing to type 2 diabetes development, endocrine-disrupting chemicals (EDCs) have been receiving special attention. These chemicals include a wide variety of pollutants, from components of plastic to pesticides, with the ability to modulate endocrine system function. EDCs can affect multiple cellular processes, including some related to energy production and utilization, leading to alterations in energy homeostasis. Mitochondria are primarily implicated in cellular energy conversion, although they also participate in other processes, such as hormone secretion and apoptosis. In fact, mitochondrial dysfunction due to reduced oxidative capacity, impaired lipid oxidation and increased oxidative stress has been linked to insulin resistance and type 2 diabetes. Herein, we review the main mechanisms whereby metabolism-disrupting chemical (MDC), a subclass of EDCs that disturbs energy homeostasis, cause mitochondrial dysfunction, thus contributing to the establishment of insulin resistance and type 2 diabetes. We conclude that MDC-induced mitochondrial dysfunction, which is mainly characterized by perturbations in mitochondrial bioenergetics, biogenesis and dynamics, excessive reactive oxygen species production and activation of the mitochondrial pathway of apoptosis, seems to be a relevant mechanism linking MDCs to type 2 diabetes development.
A Feraco, A Armani, R Urbanet, A Nguyen Dinh Cat, V Marzolla, F Jaisser and M Caprio
Obesity is a major risk factor that contributes to the development of cardiovascular disease and type 2 diabetes. Mineralocorticoid receptor (MR) expression is increased in the adipose tissue of obese patients and several studies provide evidence that MR pharmacological antagonism improves glucose metabolism in genetic and diet-induced mouse models of obesity. In order to investigate whether the lack of adipocyte MR is sufficient to explain these beneficial metabolic effects, we generated a mouse model with inducible adipocyte-specific deletion of Nr3c2 gene encoding MR (adipo-MRKO). We observed a significant, yet not complete, reduction of Nr3c2 transcript and MR protein expression in subcutaneous and visceral adipose depots of adipo-MRKO mice. Notably, only mature adipocyte fraction lacks MR, whereas the stromal vascular fraction maintains normal MR expression in our mouse model. Adipo-MRKO mice fed a 45% high-fat diet for 14 weeks did not show any significant difference in body weight and fat mass compared to control littermates. Glucose and insulin tolerance tests revealed that mature adipocyte MR deficiency did not improve insulin sensitivity in response to a metabolic homeostatic challenge. Accordingly, no significant changes were observed in gene expression profile of adipogenic and inflammatory markers in adipose tissue of adipo-MRKO mice. Moreover, pharmacological MR antagonism in mature primary murine adipocytes, which differentiated ex vivo from WT mice, did not display any effect on adipokine expression. Taken together, these data demonstrate that the depletion of MR in mature adipocytes displays a minor role in diet-induced obesity and metabolic dysfunctions.
Sonnet S Jonker, Daniel Kamna, Dan LoTurco, Jenai Kailey and Laura D Brown
Placental insufficiency causes intrauterine growth restriction (IUGR), a common complication of pregnancy. In skeletal muscle, IUGR reduces fetal myofibril size, reduces myoblast proliferation and reduces expression of genes in cell cycle regulation clusters. The myocardium is striated like skeletal muscle, and IUGR also reduces cell cycle activity and maturation in cardiomyocytes, despite cardiac output preferentially directed to the coronary circulation. We hypothesized that cardiomyocyte growth restriction would be accompanied by similar changes in cell cycle regulation genes and would reduce cardiomyocyte cell cycle activity, number, maturity and size. Pregnant ewes were housed in elevated ambient temperatures from ~40 to ~115 days of gestation (dGA) to produce placental insufficiency and IUGR; fetal hearts were studied at ~134 dGA. Hearts were biopsied for mRNA analysis and then dissociated into individual myocytes (Control n = 8; IUGR n = 15) or dissected (Control n = 9; IUGR n = 13). IUGR fetuses had low circulating insulin and insulin-like growth factor 1 (IGF1) and high circulating cortisol. Bodies and hearts of IUGR fetuses were lighter than those of Controls. Cardiomyocytes of IUGR fetuses were smaller, less mature, less active in the cell cycle and less numerous than in Controls. Further, there was a pattern of downregulation of cell cycle genes in IUGR ventricles. IUGR growth profiles in heart and skeletal muscle suggest similar regulation despite differences in blood and nutrient delivery prioritization. IGF1 signaling is suggested as a mechanism regulating altered growth in IUGR striated muscle and a potential therapeutic candidate.
Qinghua Wang, Jing Tang, Shujun Jiang, Zan Huang, Anying Song, Siyuan Hou, Xiang Gao and Hai-Bin Ruan
Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE family member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and loss of MAGED1 promoted preadipocyte proliferation and differentiation in vitro. MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to WT littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors and hyperplasia of white adipose tissues (WATs). Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity, normal levels of serum lipids and enhanced secretion of adipokines such as leptin and adiponectin. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.
Stephanie L Clookey, Rebecca J Welly, Terese M Zidon, Michelle L Gastecki, Makenzie L Woodford, Zachary I Grunewald, Nathan C Winn, Dusti Eaton, Natalia G Karasseva, Harold S Sacks, Jaume Padilla and Victoria J Vieira-Potter
Premenopausal females are protected against adipose tissue inflammation and insulin resistance, until loss of ovarian hormone production (e.g., menopause). There is some evidence that females have greater brown adipose tissue (BAT) thermogenic capacity. Because BAT mass correlates inversely with insulin resistance, we hypothesized that increased uncoupling protein 1 (UCP1) expression contributes to the superior metabolic health of females. Given that UCP1 transiently increases in BAT following ovariectomy (OVX), we hypothesized that UCP1 may ‘buffer’ OVX-mediated metabolic dysfunction. Accordingly, female UCP1-knockout (KO) and WT mice received OVX or sham (SHM) surgeries at 12 weeks of age creating four groups (n = 10/group), which were followed for 14 weeks and compared for body weight and adiposity, food intake, energy expenditure and spontaneous physical activity (metabolic chambers), insulin resistance (HOMA-IR, ADIPO-IR and glucose tolerance testing) and adipose tissue phenotype (histology, gene and protein expression). Two-way ANOVA was used to assess the main effects of genotype (G), OVX treatment (O) and genotype by treatment (GxO) interactions, which were considered significant when P ≤ 0.05. UCP1KO mice experienced a more adverse metabolic response to OVX than WT. Whereas OVX-induced weight gain was not synergistically greater for KO compared to WT (GxO, NS), OVX-induced insulin resistance was significantly exacerbated in KO compared to WT (GxO for HOMA-IR, P < 0.05). These results suggest UCP1 is protective against metabolic dysfunction associated with loss of ovarian hormones and support the need for more research into therapeutics to selectively target UCP1 for prevention and treatment of metabolic dysfunction following ovarian hormone loss.
Marlise Guerrero Schimpf, María M Milesi, Enrique H Luque and Jorgelina Varayoud
In a previous work, we detected that postnatal exposure to a glyphosate-based herbicide (GBH) alters uterine development in prepubertal rats causing endometrial hyperplasia and increasing cell proliferation. Our goal was to determine whether exposure to low dose of a GBH during postnatal development might enhance the sensitivity of the uterus to an estrogenic treatment. Female Wistar pups were subcutaneously injected with saline solution (control) or GBH using the reference dose (2 mg/kg/day, EPA) on postnatal days (PND) 1, 3, 5 and 7. At weaning (PND21), female rats were bilaterally ovariectomized and treated with silastic capsules containing 17β-estradiol (E2, 1 mg/mL) until they were 2 months of age. On PND60, uterine samples were removed and processed for histology, immunohistochemistry and mRNA extraction to evaluate: (i) uterine morphology, (ii) uterine cell proliferation by the detection of Ki67, (iii) the expression of the estrogen receptors alpha (ESR1) and beta (ESR2) and (iv) the expression of WNT7A and CTNNB1. GBH-exposed animals showed increased luminal epithelial height and stromal nuclei density. The luminal and glandular epithelium were markedly hyperplastic in 43% of GBH-exposed animals. GBH exposure caused an increase in E2-induced cell proliferation in association with an induction of both ESR1 and ESR2. GBH treatment decreased membranous and cytoplasmic expression of CTNNB1 in luminal and glandular epithelial cells and increased WNT7A expression in the luminal epithelium. These results suggest that early postnatal exposure to a GBH enhances the sensitivity of the rat uterus to estradiol and induces histomorphological and molecular changes associated with uterine hyperplasia.
Guillaume Mabilleau, Benoit Gobron, Aleksandra Mieczkowska, Rodolphe Perrot and Daniel Chappard
Glucose-dependent insulinotropic polypeptide (GIP) has been recognized in the last decade as an important contributor of bone remodelling and is necessary for optimal bone quality. However, GIP receptors are expressed in several tissues in the body and little is known about the direct vs indirect effects of GIP on bone remodelling and quality. The aims of the present study were to validate two new GIP analogues, called [d-Ala2]-GIP-Tag and [d-Ala2]-GIP1–30, which specifically target either bone or whole-body GIP receptors, respectively; and to ascertain the beneficial effects of GIP therapy on bone in a mouse model of ovariectomy-induced bone loss. Both GIP analogues exhibited similar binding capacities at the GIP receptor and intracellular responses as full-length GIP1–42. Furthermore, only [d-Ala2]-GIP-Tag, but not [d-Ala2]-GIP1–30, was undoubtedly found exclusively in the bone matrix and released at acidic pH. In ovariectomized animals, [d-Ala2]-GIP1–30 but not [d-Ala2]-GIP-Tag ameliorated bone stiffness at the same magnitude than alendronate treatment. Only [d-Ala2]-GIP1–30 treatment led to significant ameliorations in cortical microarchitecture. Although alendronate treatment increased the hardness of the bone matrix and the type B carbonate substitution in the hydroxyapatite crystals, none of the GIP analogues modified bone matrix composition. Interestingly, in ovariectomy-induced bone loss, [d-Ala2]-GIP-Tag failed to alter bone strength, microarchitecture and bone matrix composition. Overall, this study shows that the use of a GIP analogue that target whole-body GIP receptors might be useful to improve bone strength in ovariectomized animals.
Jennifer A Crookshank, Daniel Serrano, Gen-Sheng Wang, Christopher Patrick, Baylie S Morgan, Marie-France Paré and Fraser W Scott
It is unknown whether there is a gene signature in pancreas which is associated with type 1 diabetes (T1D). We performed partial pancreatectomies on 30-day preinsulitic, diabetes-prone BioBreeding (BBdp) rats to prospectively identify factors involved in early prediabetes. Microarrays of the biopsies revealed downregulation of endoplasmic reticulum (ER) stress, metabolism and apoptosis. Based on these results, additional investigations compared gene expression in control (BBc) and BBdp rats age ~8, 30 and 60 days using RT-qPCR. Neonates had increased ER stress gene expression in pancreas. This was associated with decreased insulin, cleaved caspase-3 and Ins1 whereas Gcg and Pcsk2 were increased. The increase in ER stress was not sustained at 30 days and decreased by 60 days. In parallel, the liver gene profile showed a similar signature in neonates but with an early decrease of the unfolded protein response (UPR) at 30 days. This suggested that changes in the liver precede those in the pancreas. Tnf and Il1b expression was increased in BBdp pancreas in association with increased caspase-1, cleaved caspase-3 and decreased proinsulin area. Glucagon area was increased in both 30-day and 60-day BBdp rats. Increased colocalization of BIP and proinsulin was observed at 60 days in the pancreas, suggesting insulin-related ER dysfunction. We propose that dysregulated metabolism leads to ER stress in neonatal rats long before insulitis, creating a microenvironment in both pancreas and liver that promotes autoimmunity.