Effects of leptin and melanocortin signaling interactions on pubertal development and reproduction.
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ABSTRACT:
SUBMITTER: Israel DD
PROVIDER: S-EPMC3381095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Di-n-butyl phthalate (DBP) is an endocrine-disrupting chemical that has the potential to affect male reproduction. However, the reproductive effects of low-dose DBP are still not well known, especially at the molecular level. In the present study, pubertal male Sprague-Dawley rats were orally administered DBP at a wide range of doses (0.1, 1.0, 10, 100 and 500 mg kg⁻¹ day⁻¹) for 30 days. The selected end points included reproductive organ weights, testicular histopathology and serum hormonal levels. Additionally, proteomic analysis was performed to identify proteins that are differentially expressed as a result of exposure to DBP at low doses (0.1, 1.0 and 10 mg kg⁻¹ day⁻¹). Toxic effects were observed in the high-dose groups, including anomalous development of testes and epididymides, severe atrophy of seminiferous tubules, loss of spermatogenesis and abnormal levels of serum hormones. Treatment with low doses of DBP seemed to exert a 'stimulative effect' on the serum hormones. Proteomics analysis of rat testes showed 20 differentially expressed proteins. Among these proteins, alterations in the expression of HnRNPA2/B1, vimentin and superoxide dismutase 1 (SOD1) were further confirmed by Western blot and immunohistochemistry. Taken together, we conclude that high doses of DBP led to testicular toxicity, and low doses of DBP led to changes in the expression of proteins involved in spermatogenesis as well as changes in the number and function of Sertoli and Leydig cells, although no obvious morphological changes appeared. The identification of these differentially expressed proteins provides important information about the mechanisms underlying the effects of DBP on male rat reproduction.
| S-EPMC3739579 | biostudies-other
Project description:The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.
| S-EPMC4089460 | biostudies-other
Project description:GM3, a precursor for synthesis of a- and b-series gangliosides, is elevated in adipocytes of obese model animals and in sera of obese human patients with type 2 diabetes and/or dyslipidemia. GM3 synthase (GM3S)-KO C57BL/6 mice display enhanced insulin sensitivity and reduced development of high-fat diet-induced insulin resistance. However, the pathophysiological roles of GM3 and related gangliosides in the central control of feeding and metabolism remain unclear. We found that a mouse model (KKAy GM3S KO) generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance. The hypothalamic response to intraperitoneal administration of leptin was greatly reduced in KKAy mice, but was retained in KKAy GM3S KO mice. In studies of a cultured mouse hypothalamic neuronal cell line, enhanced leptin-dependent phosphorylation of ERK was observed in GM3S-deficient cells. Furthermore, KKAy GM3S KO mice did show altered coat color, suggesting that GM3S is also involved in melanocortin signaling. Our findings, taken together, indicate that GM3-related gangliosides play key roles in leptin and melanocortin signaling.
| S-EPMC6071761 | biostudies-literature
Project description:Study questionDoes parental fertility, measured by time to pregnancy (TTP), or use of medically assisted reproduction (MAR) affect pubertal development in the offspring?Summary answerNeither TTP nor type of MAR treatment had clinically relevant implications for mean age at achieving individual pubertal milestones or overall timing of puberty in boys and girls.What is known alreadyParental TTP and MAR have been associated with impaired semen quality in adult sons. Timing of puberty reflects earlier signals of reproductive health, but it remains unclear whether parental fertility or MAR affects pubertal development, especially in the growing generation of children conceived by IVF or ICSI.Study design, size, durationIn this study, 15 819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate = 70%). Parental TTP and use of MAR were reported by mothers in early pregnancy and children's pubertal development data was self-recorded in web-based questionnaires from 11 years of age and 6 monthly throughout puberty (2012-2018).Participants/materials, setting, methodsPubertal development in children (of planned pregnancies, n = 13 285) born by untreated subfecund (TTP: 6-12 months) (n =2038), untreated severely subfeund (TTP: >12 months) (n = 1242), treated subfecund (n = 230) and treated severely subfecund (n = 1234) parents were compared to children born to more fertile parents (TTP: ≤5 months). We estimated mean monthly differences in mean age at achieving individual pubertal milestones (i.e. age at menarche, voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for breast or genital development and pubic hair growth) and a combined indicator of timing of puberty. Further, we compared mean age at achieving the individual pubertal milestones in children born by use of IVF or ICSI (n = 480) with children born by controlled ovarian stimulation or ovulation induction with or without intrauterine insemination (n = 902).Main results and the role of chanceWe found tendencies towards slightly later mean age at male pubertal timing and slightly earlier mean age at female pubertal timing among children born by untreated subfecund, treated subfecund, untreated severely subfecund and treated severely subfecund parents. There were no specific patterns with increasing TTP, use of MAR nor type of MAR treatment, and the magnitude of the mean differences for individual milestones and overall timing of puberty were small, i.e. 0.9 months (95% CI: -1.0; 2.8) for first ejaculation and -0.5 months (95% CI: -2.0; 1.0) months for age at menarche in boys and girls, respectively, born by treated severely subfecund parents when compared with children born by more fertile parents.Limitations, reasons for cautionNon-differential misclassification of the self-reported information on parental TTP and pubertal development in the offspring may serve as an alternative explanation of the findings, possibly biasing the estimates towards the null. The information on pubertal development was collected from around 11 years of age and onwards.Wider implications of the findingsThis study adds to the growing body of literature suggesting only limited harmful effects of parental subfecundity and MAR on offspring's long-term growth and development.Study funding/competing interest(s)This work was supported by the Danish Council for Independent Research [DFF 4183-00152]; and the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.
| S-EPMC6443115 | biostudies-literature
Project description:IntroductionEpidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD.MethodsPubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis.ResultsHFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-?B activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages.ConclusionsTaken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.
| S-EPMC3978633 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty.
| S-EPMC6768472 | biostudies-literature
Project description:The leptin-melanocortin signaling pathway has a central role in body weight regulation, energy homeostasis, and fat modulation. This pathway regulates the hypothalamic food intake and energy expenditure, with the help of the major genes such as melanocortin 4 receptor (MC4R), signal transducer and activator of transcription 3 (STAT3), and Leptin (LEP), alongside with other genes and enzymes in the pathway. This project aimed to evaluate the role of leptin-melanocortin signaling pathway gene variants in body weight gain and fatness modulation in sheep. In this project, a total of 524 individuals from 5 different native sheep breeds were collected from their native habitats. Including Ujmuqin (n=96) from Xilinguole Meng, Inner Mongolia Province, Sunits sheep (n=96) from Wulanchabu city of Inner Mongolia, Guangling big-tailed sheep (n=145) from Datong, Shanxi Province, Small- Tailed Han sheep (n=90) at Heze, Shandong, and Hu sheep (n=97) from Yichang, Hubei. PCR products from DNA of 524 sheep were used to identify polymorphisms within the CDS region of the MC4R and STAT3 genes using available reference sequences of sheep MC4R ENSOARG00000004034, and STAT3 ENSOARG00000001511. DNA sequencing was performed by Quintarabio Company (Wuhan, China). Reference sequences and sequenced fragments were analyzed using version 12 DNASTAR? Lasergene Genomics Suite Software, Madison, WI, USA. Our data indicated that the genetic polymorphisms of the major genes involved in the leptin-melanocortin signaling pathway are significantly associated with the growth, development and fatness of the sheep.
2019-10-02 | PRJEB34293 | EVA
Project description:The role of PI3K in leptin physiology has been difficult to determine due to its actions downstream of several metabolic cues, including insulin. Here, we used a series of mouse models to dissociate the roles of specific PI3K catalytic subunits and of insulin receptor (InsR) downstream of leptin signaling. We show that disruption of p110? and p110? subunits in leptin receptor cells (LR??+?) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LR??+? mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110? in LR??) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LR?? mice have normal locomotor activity and thermogenesis. Blunted PI3K in leptin receptor (LR) cells enhanced leptin sensitivity in metabolic regulation due to increased basal hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN levels. However, these mice are unresponsive to leptin's effects on growth and puberty. We further assessed if these phenotypes were associated with disruption of insulin signaling. LR?InsR mice have no metabolic or growth deficit and show only mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in energy expenditure, growth, and reproduction. These actions are independent from insulin signaling.
| S-EPMC5752267 | biostudies-other
Project description:ObjectiveEpidemiological studies indicate associations between childhood exposure with phthalates and bisphenol A (BPA) and the pubertal development. We examined associations between the pre-pubertal phthalate and BPA body burden and the longitudinally assessed sexual maturation of eight- to thirteen-year-old children.MethodsWe started with eight- to ten-year-old children in the baseline study and quantified phthalate metabolites and BPA in 472 urine samples (250 boys; 222 girls; mean age: 8.8 years). Associations between the pubertal development, assessed in three annual follow-up studies by Puberty Development scale questionnaires (PD scales), and the chemical exposure from the baseline visit were longitudinally analyzed with generalized estimation equations.ResultsThe number of children with both chemical measures and PD scores (calculated from the PD scales) was 408. In the third follow-up, 49% of the girls and 18% of the boys had reached mid-puberty. For girls, we observed a delayed pubertal development with the di-hexyl-ethyl phthalate (DEHP) metabolites (β: -0.16 to -0.23; p ≤ 0.05 or p ≤ 0.1), mono-n-butyl phthalate (β: -0.15; 95% CI: -0.31; 0.01), mono-benzyl phthalate (β: -0.11; 95% CI: -0,24; -0,01), and mono-ethyl phthalate (MEP) (β: -0.15; 95% CI: -0.28; -0.01). In addition, significant non-linear associations of the DEHP metabolites and BPA with the PD scores were found, when their quadratic effects were included in the GEE models. In boys, no consistent relationships between the PD scores and the chemicals were detected except of an accelerated development with the ∑DEHP metabolites (β: 0.16; 95% CI: -0.02; -0.34).ConclusionWe found indications that pre-pubertal exposures with phthalates and BPA were associated with pubertal timing in children, particularly in girls. For boys, associations were inconsistent, and not necessarily in line with the known anti-androgenicity of some phthalates during prenatal exposure.
| S-EPMC5695814 | biostudies-literature
Project description:RT-PCR analysis of gar pituitary and brain indicated that different combinations of gar melanocortin receptor mRNAs are present in the same tissues with mRNAs for gar mrap1 and gar mrap2. Against this background, an objective of this study was to determine whether the ligand sensitivity for either ACTH or α-MSH was affected when gar (g) melanocortin receptors (Mcrs) were co-expressed with either of the accessory proteins gMrap1 or gMrap2 in Chinese Hamster Ovary cells. The results indicated that gMc2r has an obligatory requirement for co-expression with gMrap1 in order for the receptor to be activated by hACTH(1-24). In addition, activation of gMc2r did not occur when the receptor was expressed alone or co-expressed with gMrap2. Furthermore, co-expression of gMc2r with gMrap1 followed by stimulation with NDP-MSH resulted in a low level of activation (only at 10-7 M and 10-6 M). However, gMc1r, gMc3r, gMc4r, and gMc5r responded to stimulation by NDP-MSH in a more robust manner. Co-expression of gMc1r, gMc3r, gMc4r, and gMc5r with gMRAP1 had no effect on sensitivity to stimulation by NDP-MSH or hACTH(1-24). Co-expression with gMRAP2 had no negative or positive effect on ligand sensitivity for gMc1r, gMc3r, and gMc5r, however this treatment did increase the activation of CHO cells transfected with gMc4r following stimulation with both hACTH(1-24) (p < 0.001), and NDP-MSH (p < 0.001). Co-expression of gMC5R with either gMRAP1 or gMRAP2 increased trafficking of gMC5R to the plasma membrane. These pharmacological observations are compared to the response of melanocortin receptors from other neopterygian fishes, cartilaginous fishes, and tetrapods to stimulation by ACTH(1-24) and forms of α-MSH.
| S-EPMC7263024 | biostudies-literature