Dataset Information

Maternal high-fat diet impairs follicular development of offspring through intraovarian kisspeptin/GPR54 system.

ABSTRACT:

Background

Excessive gestational weight gain (GWG), which is associated with adverse long-term effects on the health of the offspring, has become a major clinical problem. Accumulating evidence indicates that the ovary kisspeptin/GPR54 system directly participates in a series of physiological activities. We used a model of high-fat diet (HFD) during gestational to investigate offspring's ovarian function and whether kisspeptin/GPR54 system is involved.

Methods

After introducing the male and confirmation of mating by checking a vaginal sperm plug, female rats were randomized into two groups: control diet called NCD group and high-fat diet called HFD group. After birth, all rats were changed into a control diet and litter size was adjusted to 12 pups per litter. Ovaries were collected for assessment at postnatal day (PND) 4 and PND 30. The timing of vaginal opening was recorded, and the estrous cyclicity was monitored for 2 consecutive weeks immediately. Primary granulosa cells and ovaries which were taken from PND 4 were collected for determination of the direct effect of kisspeptin-10 (kp-10) in vitro.

Results

Neonatal rats exposed to HFD during gestation had a lower number of secondary follicles in the ovary. The expression of follicle-stimulating hormone receptor (FSHR) and kisspeptin was not altered. At prepuberty, the number of antral follicles and preovulatory follicles was elevated with decreased type III follicles in the HFD group. While the expression of ovulation-related genes was decreased, the expression levels of follicular growth-related genes and steroidogenesis synthesis related genes were elevated. A significant increase in kiss1 mRNA and kisspeptin protein was detected without changes in kiss1r mRNA and GPR54. Maternal high-fat diet during gestation resulted in a significant advanced puberty onset and an irregular estrous cycle in offspring rats. In addition, the administration of kp-10 produced an increase in viability of primary granulosa cells and enlarged the size of oocytes.

Conclusions

HFD exposure during maternal gestation had a long-term effect on reproductive function in the offspring and the increased ovarian kisspeptin/GPR54 system might be involved.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC6343291 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Maternal high-fat diet impairs follicular development of offspring through intraovarian kisspeptin/GPR54 system.

Zhou Zhiyang Z Lin Qi Q Xu Xinxin X Illahi Gaby Sukma GS Dong Chenle C Wu Xueqing X

Reproductive biology and endocrinology : RB&E 20190122 1

<h4>Background</h4>Excessive gestational weight gain (GWG), which is associated with adverse long-term effects on the health of the offspring, has become a major clinical problem. Accumulating evidence indicates that the ovary kisspeptin/GPR54 system directly participates in a series of physiological activities. We used a model of high-fat diet (HFD) during gestational to investigate offspring's ovarian function and whether kisspeptin/GPR54 system is involved.<h4>Methods</h4>After introducing th ...[more]

PMID: 30670046

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Project description:GPR54, Kisspeptin-1 receptor (KISS1R), a member of rhodopsin family, plays a critical role in puberty development and has been proposed to be involved in regulation of energy metabolism. This study aims to explore the function of GPR54 in adipogenesis, lipid metabolism, and obesity in addition to its effect through hormones. Results showed that when fed a high-fat diet, the weight growth of castrated or ovariectomized Gpr54-/- mice was significantly slower than that of WT control, together with a lower triglyceride concentration. The ratio of white adipose tissue was lower, and average size of adipocytes was smaller in Gpr54-/- mice. Meanwhile, there were less adipose tissue macrophages (ATMs), especially pro-inflammatory macrophages. Expression of inflammatory related genes also indicated that inflammatory response caused by obesity was not as drastic in Gpr54-/- mice as in WT mice. Liver triglyceride in Gpr54-/- mice was reduced, especially in female mice. On the other hand, oil drop formation was accelerated when hepatocytes were stimulated by kisspeptin-10 (Kp-10). Primary mesenchymal stem cells (MSCs) of Gpr54-/- mice were less likely to differentiate into adipocytes. When stimulated by Kp-10, 3T3-L1 cell differentiation into adipocytes was accelerated and triglyceride synthesis was significantly promoted. These data indicated that GPR54 could affect obesity development by promoting adipocyte differentiation and triglyceride accumulation. To further elucidate the mechanism, genes related to lipid metabolism were analyzed. The expression of genes involved in lipid synthesis including PPARγ, ACC1, ADIPO, and FAS was significantly changed in Gpr54-/- mice. Among them PPARγ which also participate in adipocyte differentiation displayed a marked reduction. Moreover, phosphorylation of ERK, which involved in GPR54 signaling, was significantly decreased in Gpr54-/- mice, suggesting that GPR54 may promote lipid synthesis and obesity development by activating MAP kinase pathway. Therefore, in addition to the involvement in hormone regulation, our study demonstrated that GPR54 directly participates in obesity development by promoting adipocyte differentiation and fat accumulation. This provided evidence of involvement of GPR54 in lipid metabolism, and revealed new potentials for the identification and development of novel drug targets for metabolic diseases.

Project description:ObjectiveAmylin was found to regulate glucose and lipid metabolism by acting on the arcuate nucleus of the hypothalamus (ARC). Maternal high-fat diet (HFD) induces sex-specific metabolic diseases mediated by the ARC in offspring. This study was performed to explore 1) the effect of maternal HFD-induced alterations in amylin on the differentiation of hypothalamic neurons and metabolic disorders in male offspring and 2) the specific molecular mechanism underlying the regulation of amylin and its receptor in response to maternal HFD.MethodsMaternal HFD and gestational hyper-amylin mice models were established to explore the role of hypothalamic amylin and receptor activity-modifying protein 3 (Ramp3) in regulating offspring metabolism. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and RNA decay assays were performed to investigate the mechanism underlying the influence of maternal HFD on Ramp3 deficiency in the fetal hypothalamus.ResultsMale offspring with maternal HFD grew heavier and developed metabolic disorders, whereas female offspring with maternal HFD showed a slight increase in body weight and did not develop metabolic disorders compared to those exposed to maternal normal chow diet (NCD). Male offspring exposed to a maternal HFD had hyperamylinemia from birth until adulthood, which was inconsistent with offspring exposed to maternal NCD. Hyperamylinemia in the maternal HFD-exposed male offspring might be attributed to amylin accumulation following Ramp3 deficiency in the fetal hypothalamus. After Ramp3 knockdown in hypothalamic neural stem cells (htNSCs), amylin was found to fail to promote the differentiation of anorexigenic alpha-melanocyte-stimulating hormone-proopiomelanocortin (?-MSH-POMC) neurons but not orexigenic agouti-related protein-neuropeptide Y (AgRP-Npy) neurons. An investigation of the mechanism involved showed that IGF2BP1 could specifically bind to Ramp3 in htNSCs and maintain its mRNA stability. Downregulation of IGF2BP1 in htNSCs in the HFD group could decrease Ramp3 expression and lead to an impairment of ?-MSH-POMC neuron differentiation.ConclusionsThese findings suggest that gestational exposure to HFD decreases the expression of IGF2BP1 in the hypothalami of male offspring and destabilizes Ramp3 mRNA, which leads to amylin resistance. The subsequent impairment of POMC neuron differentiation induces sex-specific metabolic disorders in adulthood.

Project description:The kisspeptin/Gpr54 signalling pathway plays a critical role in reproduction by stimulating the secretion of gonadotrophin-releasing hormone (GnRH), yet mice carrying mutations in Kiss1 (which encodes kisspeptin) or Gpr54 exhibit partial sexual maturation. For example, a proportion of female Kiss1(-/-) and Gpr54(-/-) mice exhibit vaginal oestrus, and some male Kiss1(-/-) and Gpr54(-/-) mice exhibit spermatogenesis. To characterise this partial sexual maturation, we examined the vaginal cytology of female Kiss1(-/-) and Gpr54(-/-) mice over time. Almost all mutant mice eventually enter oestrus, and then spontaneously transition from oestrus to dioestrus and back to oestrus again. These transitions are not associated with ovulation, and the frequency of these transitions increases with age. The oestrus exhibited by female Kiss1(-/-) and Gpr54(-/-) mice was disrupted by the administration of the competitive GnRH antagonist acyline, which also resulted in lower uterine weights and, in Kiss1(-/-) mice, lower serum follicle-stimulating hormone (FSH) and luteinising hormone (LH) concentrations. Similarly, male Kiss1(-/-) and Gpr54(-/-) mice treated with acyline had smaller testicular sizes and an absence of mature sperm. In addition to examining intact Kiss1(-/-) and Gpr54(-/-) mice, we also assessed the effects of acyline on gonadotrophin concentrations in gonadectomised mice. Gonadectomy resulted in a significant increase in serum FSH concentrations in male Gpr54(-/-) and Kiss1(-/-) mice. Acyline administration to gonadectomised Kiss1(-/-) and Gpr54(-/-) male mice lowered serum FSH and LH concentrations significantly. By contrast to males, gonadectomy did not result in significant gonadotrophin changes in female Kiss1(-/-) and Gpr54(-/-) mice, but acyline administration was followed by a decrease in LH concentrations. These results demonstrate that, although kisspeptin signalling is critical for the high levels of GnRH activity required for normal sexual maturation and for ovulation, Kiss1(-/-) and Gpr54(-/-) mice retain some degree of GnRH activity. This GnRH activity is sufficient to produce significant effects on vaginal cytology and uterine weights in female mice and on spermatogenesis and testicular weights in male mice.

Dataset Information

Maternal high-fat diet impairs follicular development of offspring through intraovarian kisspeptin/GPR54 system.

Background

Methods

Results

Conclusions

Publications

Maternal high-fat diet impairs follicular development of offspring through intraovarian kisspeptin/GPR54 system.

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