BackgroundMaternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment.Methodology/Principal FindingsWe examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage.Conclusions/SignificanceOur results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes.

The ruminant conceptus synthesizes and secretes interferon (IFN)-tau, which presumably acts via an intrauterine paracrine mechanism to signal maternal recognition of pregnancy. The aims of this study were to determine whether IFN-stimulated genes (ISG) such as ISG15 and OAS-1 are differentially expressed in blood cells circulating in the uterus of ewes; whether extrauterine components of the reproductive tract such as the corpus luteum (CL) also express mRNA for these ISG, and whether antiviral activity is greater in uterine vein than in uterine artery during early pregnancy. The concentrations of mRNA for both ISG were significantly greater (P < 0.0001) in endometrium and jugular blood of 15-d pregnant ewes than in nonpregnant ewes. ISG15 and OAS-1 mRNA concentrations were also greater (P < 0.05) in CL from 15-d pregnant ewes than in nonpregnant ewes. Immunohistochemistry revealed intense staining for ISG15 in large luteal cells on d 15 of pregnancy. Blood cells from uterine artery and vein of 15-d pregnant ewes had similar ISG15 and OAS-1 mRNA concentrations, suggesting that these cells were not conditioned by IFN-tau within the uterus. By using an antiviral assay, uterine venous blood was found to contain 500- to 1000-fold higher concentrations of bioactive IFN-tau than in uterine arterial blood on d 15 of pregnancy. It is concluded that uterine vein releases IFN-tau, which induces ISG in extrauterine tissues such as the CL during the time of maternal recognition of pregnancy.

Obesity in women is a concern in many countries. This causes numerous health issues; however, this review focuses on the impact of obesity on women's reproduction, and in particular the oocyte. Data from infertility clinics and experimental animal models that address the effects of obesity are presented. Bidirectional communication and metabolic support from the surrounding cumulus cells are critical for oocyte development, and the impact of obesity on these cells is also addressed. Both oocyte maturation and metabolism are impaired due to obesity, negatively impacting further development. In addition to reproductive hormones, obesity induced elevations in insulin, glucose, or free fatty acids, and changes in adipokines appear to impact the developmental competence of the oocyte. The data indicate that any one of these hormones or metabolites can impair oocyte developmental competence in vivo, and the combination of all of these factors and their interactions are the subject of ongoing investigations.

Impaired oocyte quality has been demonstrated in diabetic mice; however, the potential pathways by which maternal diabetes exerts its effects on the oocyte are poorly understood. Cumulus cells are in direct contact with the oocyte via gap junctions and provide essential nutrients to support oocyte development. In this study, we investigated the effects of maternal diabetes on the mitochondrial status in cumulus cells. We found an increased frequency of fragmented mitochondria, a decreased transmembrane potential and an aggregated distribution of mitochondria in cumulus cells from diabetic mice. Furthermore, while mitochondrial biogenesis in cumulus cells was induced by maternal diabetes, their metabolic function was disrupted as evidenced by lower ATP and citrate levels. Moreover, we present evidence suggesting that the mitochondrial impairments induced by maternal diabetes, at least in part, lead to cumulus cell apoptosis through the release of cytochrome c. Together the deleterious effects on cumulus cells may disrupt trophic and signaling interactions with the oocyte, contributing to oocyte incompetence and thus poor pregnancy outcomes in diabetic females.

The oocyte, sperm, and preimplantation embryo have unique metabolic needs that must be met to ensure successful pregnancy. The family of facilitative glucose transporters (GLUTs) plays a major role in providing metabolic substrates to these tissues. The variety of GLUTs expressed in these tissues allows the flexibility to adapt to a changing environment. Alterations in glucose transport and metabolism at the earliest stages of development can impact fetal development. Research into the mechanisms of normal glucose transport into cells is critical to improving outcomes in the increasingly common diabetic maternal environment. Here we review the current understanding in the distribution and role of glucose transporters in gametes and preimplantation embryos under normal and diabetic conditions.

OBJECTIVEEvidence suggests that insulin-sensitive glucose transporters (GLUTs) other than GLUT4 may exist. To investigate whether GLUT12 may represent another insulin-sensitive GLUT, transgenic (TG) mice that overexpress GLUT12 were characterized.RESEARCH DESIGN AND METHODSTG mice that overexpressed GLUT12 under a β-actin promoter were generated. Glucose metabolism in TG and wild-type control mice was compared using glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. In addition, basal and insulin-stimulated glucose clearance rates into insulin-sensitive peripheral tissues were measured using [3H]-2-deoxy-d-glucose.RESULTSGLUT12 was overexpressed by 40–75% in TG compared with wild-type mice in insulin-sensitive tissues with no change in GLUT4 content. Body weight and fasting blood glucose did not differ between wild-type and TG mice; however, insulin concentrations were reduced in TG mice. Enhanced oral glucose tolerance was noted in TG mice by a reduced blood glucose excursion compared with wild-type mice (P < 0.05). Enhanced insulin sensitivity was noted by a greater decrease in blood glucose in TG mice during insulin tolerance testing. Hyperinsulinemic-euglycemic clamps confirmed enhanced insulin sensitivity in GLUT12-overexpressing mice (P < 0.01). Tissues of TG mice exhibited normal basal glucose clearance rates; however, under insulin-stimulated conditions, glucose clearance was significantly increased (P < 0.01) in tissues of TG mice.CONCLUSIONSIncreased expression of GLUT12 results in improved whole-body insulin sensitivity mediated by an increased glucose clearance rate in insulin-responsive tissues under insulin-stimulated, but not basal, conditions. These findings provide evidence that GLUT12 represents a novel, second insulin-sensitive GLUT.

Fertilization is essential for species survival. Although Izumo1 and Juno are critical for initial interaction between gametes, additional molecules necessary for sperm:egg fusion on both the sperm and the oocyte remain to be defined. Here, we show that phosphatidylserine (PtdSer) is exposed on the head region of viable and motile sperm, with PtdSer exposure progressively increasing during sperm transit through the epididymis. Functionally, masking phosphatidylserine on sperm via three different approaches inhibits fertilization. On the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Further, oocytes lacking the cytoplasmic ELMO1, or functional disruption of RAC1 (both of which signal downstream of BAI1/BAI3), also affect sperm entry into oocytes. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts. Collectively, these data identify phosphatidylserine on viable sperm and PtdSer recognition receptors on oocytes as key players in sperm:egg fusion.

The objectives of this study were to evaluate the effects of flunixin meglumine (FM), an inhibitor of PGF(2alpha) synthesis, and insertion of an intravaginal progesterone-releasing device (CIDR), on pregnancy rates in beef cattle embryo transfer (ET) recipients, and to examine the effect of a CIDR after embryo transfer on the synchrony of the return to estrus in non-pregnant recipients. Cows (n=622) and heifers (n=90) at three locations were assigned randomly to one of four groups in a 2x2 factorial arrangement of treatments with FM administration (500 mg i.m.) 2-12 min prior to ET, and insertion of a CIDR (1.38 g progesterone) immediately following ET as main effects. Fresh or frozen embryos (Stage=4 or 5; Grade=1 or 2) were transferred on Days 6-9 of the estrous cycle and CIDR devices were removed 13 days after ET. Recipients at Location 2 only were observed for signs of return to estrus. Recipients that returned to estrus at Location 2 were either bred by AI or received an embryo 7 days after estrus. Following the initial ET, there was an FMxlocation interaction on pregnancy rate (P<0.01; Location 1, 89% versus 57%; Location 2, 69% versus 64%; Location 3, 64% versus 67% for FM versus no FM, respectively). Pregnancy rates of embryo recipients were not affected by CIDR administration (P>0.05; 65% with CIDR, 70% without CIDR), however, the timing of the return to estrus was more synchronous (P<0.01) for recipients given a CIDR. Pregnancy rate of recipients bred following a return to estrus did not differ between cows receiving or not receiving a CIDR for resynchronization (P>0.13). Effects of FM on pregnancy rate were location dependent and CIDR insertion at ET improved synchrony of the return to estrus.