Background Global consumption of protein per capita is rising, while rates of infertility are increasing. However, a clear relationship between protein intake and reproductive health has not been demonstrated. The activation of the quiescent primordial follicles is the first step of folliculogenesis, and their activation must be tightly controlled to prevent premature exhaustion of the ovarian follicular reserve. Methods The primordial follicle reserve of wild-type or liver-specific ablation of fibroblast growth factor 21 (FGF21) in mice, subjected to limited or excessive protein diets or oral gavage test, were detected in vivo. Mouse ovary organ cultures were used to examine the direct role of metabolites or metabolic hormones on primordial follicle activation. Findings Mouse primordial follicle activation, was reduced by restricted protein intake and was accelerated by excessive protein intake, in an ovarian mTORC1 signaling-dependent manner. Furthermore, restricted or excessive protein intake resulted in an augmentation or decline of oocyte number and fertility at older age, respectively. Liver-specific ablation of FGF21, which resulted in a reduction of 87% in circulating FGF21, abrogated the preserving effect of low-protein intake on primordial follicle pool. Interestingly, FGF21 had no direct effect on the activation of primordial follicles, but instead required an adipokine adiponectin. Moreover, AdipoRon, an oral adiponectin receptor agonist, prevented the over-activation effect of excessive protein intake on primordial follicle activation. Interpretation Dietary protein consumption controlled ovarian primordial follicle reserve and fertility, which required coordination between FGF21 and adiponectin. Fund (Grant 31772616).

Infection with transmissible gastroenteritis virus (TGEV) has been associated with villous atrophy within 48 h, which seriously disrupts intestinal homeostasis. However, the underlying mechanisms remain elusive. In this study, we found that TGEV infection severely disrupted intestinal homeostasis via inhibition of self-renewal and differentiation in Lgr5 intestinal stem cells (ISCs). Profoundly, TGEV-encoded NSP10/NSP16 protein complex-mediated the inactivation of Notch signaling provided a mechanistic explanation for this phenomenon. Initial invasions by TGEV-targeted Paneth cells through aminopeptidase N (APN) receptor, then inducing mitochondrial damage and ROS generation in them, ultimately causing Paneth cell decrease and loss of Notch factors (DII4 and Hes5), which are essential for Lgr5 ISCs selfrenewal and differentiation. Interestingly, loss of Notch signaling induced goblet cells differentiation at the cost of absorptive enterocytes and promoted mucins secretion, which accelerated TGEV replication. Therefore, the more differentiation of goblet cells, the greater TGEV infection in jejunum. These results provide a detailed mechanistic pathway by which villous atrophy sharply occurs in TGEV-infected jejunum within 48 h. Thus, the pathogenesis of TGEV can be described as a "bottom up scenario", which is contrary to the traditional "top down" hypothesis. Together, our findings provide a potential link between diarrheal virus infection and crypt cells response that regulates Paneth cells function and Lgr5 ISCs fate and could be exploited for therapeutic application.

Both ovarian E2 and hepatic fibroblast growth factor 21 (FGF21) are critical for energy homeostasis and white adipose tissue browning. Estrogen receptor α (ERα) is abundantly expressed in liver. However, whether FGF21 has a role in E2-induced white adipose tissue browning remains uncertain. In this study, we showed that hepatic Fgf21 expression and secretion during estrus cycle changed with the tetradian oscillatory secretion of circulation E2 in adult, female mice, with their peak expressions and secretions at the proestrus. In addition, exogenous E2 robustly stimulated liver Fgf21 expression and elevated serum FGF21 concentrations, which induced browning gene expression and reduced the tissue weight in subcutaneous white adipose in mice with ovariectomies. The inhibitor of mammalian target of rapamycin (mTOR) and of ERα blocked the induction effect of E2 on the expression of Fgf21 in primary hepatocytes, which revealed that E2 might stimulate FGF21 expression via the ERα-mTOR pathway. Furthermore, FGF21 liver-specific deficiency abolished E2-induced white adipose browning in mice with ovariectomies. This study indicates that ovarian E2 increased liver FGF21 expression directly, which in turn, functioned as an endocrine signal to influence inguinal white adipose tissue browning.-Hua, L., Zhuo, Y., Jiang, D., Li, J., Huang, X., Zhu, Y., Li, Z., Yan, L., Jin, C., Jiang, X., Che, L., Fang, Z., Lin, Y., Xu, S., Li, J., Feng, B., Wu, D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

This study aims to investigate the effects of exogenous catalase (CAT), an antioxidative enzyme from microbial cultures, on intestinal development and microbiota in weaned piglets. Seventy-two weaned piglets were allotted to two groups and fed a basal diet or a basal diet containing 2.0 g/kg exogenous CAT. Results showed that exogenous CAT increased (p < 0.05) jejunal villus height/crypt depth ratio and intestinal factors (diamine oxidase and transforming growth factor-α) concentration. Moreover, dietary CAT supplementation enhanced the antioxidative capacity, and decreased the concentration of pro-inflammatory cytokine in the jejunum mucosa. Exogenous CAT did not affect the concentration of short-chain fatty acids, but decreased the pH value in colonic digesta (p < 0.05). Interestingly, the relative abundance of Bifidobacterium and Dialister were increased (p < 0.05), while Streptococcus and Escherichia-Shigella were decreased (p < 0.05) in colonic digesta by exogenous CAT. Accordingly, decreased (p < 0.05) predicted functions related to aerobic respiration were observed in the piglets fed the CAT diet. Our study suggests a synergic response of intestinal development and microbiota to the exogenous CAT, and provides support for the application of CAT purified from microbial cultures in the feed industry.

People on a diet to lose weight may be at risk of reproductive failure. To investigate the effects of nutrient restriction on reproductive function and the underlying mechanism, changes of reproductive traits, hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis were examined in postpubertal gilts at anestrus induced by nutrient restriction. Gilts having experienced two estrus cycles were fed a normal (CON, 2.86 kg/d) or nutrient restricted (NR, 1 kg/d) food regimens to expect anestrus. NR gilts experienced another three estrus cycles, but did not express estrus symptoms at the anticipated fourth estrus. Blood samples were collected at 5 days' interval for consecutive three times for measurement of hormone concentrations at the 23th day of the fourth estrus cycle. Individual progesterone concentrations of NR gilts from three consecutive blood samples were below 1.0 ng/mL versus 2.0 ng/mL in CON gilts, which was considered anestrus. NR gilts had impaired development of reproductive tract characterized by absence of large follicles (diameter ≥ 6 mm), decreased number of corepus lutea and atrophy of uterus and ovary tissues. Circulating concentrations of IGF-I, kisspeptin, estradiol, progesterone and leptin were significantly lower in NR gilts than that in CON gilts. Nutrient restriction down-regulated gene expressions of kiss-1, G-protein coupled protein 54, gonadotropin-releasing hormone, estrogen receptor α, progesterone receptor, leptin receptor, follicle-stimulating hormone and luteinizing hormone and insulin-like growth factor I in hypothalamus-pituitary-gonadal axis of gilts. Collectively, nutrient restriction resulted in impairment of reproductive function and changes of hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis, which shed light on the underlying mechanism by which nutrient restriction influenced reproductive function.

The objective of this study was to investigate the effects of dietary supplementation with various fat sources (3.8-3.9% of diet) during late pregnancy and lactation on the reproductive performance, fatty acids profile in colostrum, milk and serum of sow progeny. A total of 80 multiparous sows were randomly fed a control (adding no oil), palm oil (PO), fish oil (FO) or soybean oil (SO) supplemented diet from 90 days of pregnancy to weaning. Supplementation of FO increased litter size of weak piglets, compared with the control-fed sows (P < 0.05). Dietary FO and SO supplementation, enhanced the weaning survival rate, litter weaning weight, litter weight gain and fat content in milk (P < 0.05). The highest immunoglobulin (Ig)G and IgM levels in colostrum and milk were observed in the FO group (P < 0.05). Meanwhile, the highest concentration of C22:5 (n-3) and C22:6 (n-3) in colostrum, milk and piglet serum was observed in the FO group (P < 0.05). Taken together, dietary inclusion of FO or SO improved growth performance of nursing piglets by increasing milk fat output, and FO consumption by sows might benefit the piglets via increasing n-3 polyunsaturated fatty acid availability and immunoglobulins (IgG and IgM) secretion.

Background: There has been a significant increase, to epidemic levels, of obese and overweight women of reproductive age, causing impairments to reproductive health. Time-restricted feeding (TRF) including isocaloric intake has shown to be preventive of obesity-related disorders. However, its therapeutic ability to improve the reproductive function of female remains largely unknown. Methods: Here, we investigated the ability of TRF to improve the reproductive function in wild-type and liver-specific FGF21 knockout female mice. To study fertility, a continuous and a short-term fertility test, gonadotropin releasinghormone (GnRH), and Kisspeptin test were performed. Immortalized GnRH neuron was used to examine the direct role of liver fibroblast growth factor 21 (FGF21) on GnRH secretion. Results: We found that TRF rescues female mice from bodyweight gain and glucose intolerance, as well as ovarian follicle loss and dysfunction of estrus cyclicity induced by high-fat diet. Furthermore, the beneficial effects of the TRF regimen on the reproductive performance were also observed in mice fed both chow and high-fat diet. However, those beneficial effects of TRF on metabolism and reproduction were absent in liver-specific FGF21 knockout mice. In vitro, FGF21 directly acted on GnRH neurons to modulate GnRH secretion via extracellular regulated protein kinases (ERK 1/2) pathway. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Excessive fat intake is a global health concern as women of childbearing age increasingly ingest a high fat diet. We therefore determined the association of a maternal high fat diet in pregnancy with offspring ovarian health during the gestation and postnatal female offspring in pig a model. Thirty-two Yorkshire gilts with similar bodyweights mated at the third estrus were randomly assigned to two nutrition levels of either a control (CON, crude fat: 7.27%) or a high fat diet (HFD, crude fat: 11.78%). Ovary samples were collected during the fetal (Day 55 (g55) and Day 90 of gestation (g90)) and offspring (prepuberty Day 160 (d160) and age at puberty) period to detect ovary development, antioxidant status and apoptosis cells. Maternal HFD did not influence notch signaling gene expression, which regulates primordial follicle formation and transformation, and ovarian histological effect at g55 and g90. However, maternal HFD reduced the numbers of large follicles at d160 and small follicle numbers upon puberty compared to CON in offspring. The results also revealed that the antioxidant index of total antioxidative capability (T-AOC), cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPx) activities and mRNA expression were higher in the CON than the HFD at g90 and d160, whereas, malondialdehyde (MDA) concentration was decreased in the CON. Maternal HFD increased the inhibitor of the apoptosis-related gene of B-cell lymphoma-2 (bcl2) mRNA expression at g90 and d160, whereas, pro-apoptotic-related gene bcl-2 assaciated X protein (bax) was reduced. These data show that the maternal high fat diet does not delay fetal ovarian development, but it changes ovarian health by the induction of oxidative stress and accelerating cell apoptosis in offspring.