A recent health article in Time magazine (1) reported that rising obesity may reduce life expectancy in the United States by nearly a year and slow the modest improvements in mortality rates over the past 20 years tied to the reduction of cardiovascular disease and cancer-related deaths. This is further compounded by the impact of obesity on pregnancy losses, including miscarriage, preterm birth, stillbirth, and neonatal death. As the obesity epidemic in the United States (and elsewhere around the world) continues to worsen, researchers are looking to these earliest days of life for answers. Specifically, investigators are looking at the interface of mother and fetus: measuring and manipulating hormonal, inflammatory, and genetic factors. Reproductive processes are energetically expensive, and physiological mechanisms limit them if nutritional resources are perceived to be scarce or unavailable (2–4). One of these permissive mechanisms is the adipocyte hormone leptin, which is low in starvation conditions (2–4). However, obesity introduces a different set of challenges, as serum leptin levels are high; but this overabundance of circulating leptin can lead to leptin resistance (5). Many obese women can conceive, but what happens between conception and birth concerning metabolic influences of obesity is largely unknown. In 2011, pioneering research by Donato et al. (6) revealed that the ventral premammillary nucleus (PMV) was a critical target site for leptin’s permissive effect on reproduction. Donato et al. (6) used a mouse model (Leprneo/neo) that had a flippase recognition target–flanked neomycin codon that targeted the Lepr locus and rendered the mice leptin receptor null, exhibiting the phenotype of the morbidly obese Lepr-deficient db/db mice. These researchers then selectively reactivated the leptin receptor in the PMV of the hypothalamus by delivering flippase-recombinase via an adenovirus. The PMV-Lepr–reactivated mice responded by entering puberty and becoming pregnant. They remained morbidly obese and exhibited a high rate of embryo resorption and fetal death. In this issue, Mahany et al. (7) report in-depth studies of PMV-Lepr–restored mice to determine mechanisms underlying embryo resorption. In addition, they compared the impact of maternal obesity with that of maternal high-fat diet (HFD) on gene expression in the developing placenta. Similar to the Leprneo/neo PMV-Lepr–restored line, PMV LeprloxTB-reactivated females showed vaginal opening, had corpora lutea, and displayed comparable uterine size to wild-type females (7). However, the selective LEPR restoration only mildly improved pregnancy outcomes. Only about half of the females showed signs of pregnancy. Of these, implantation numbers appeared to be comparable to wild-type mice, but the number of resorbed fetuses was significantly increased (7). Because the fetuses in these PMV Lepr-reactivated females carried one wild-type allele of Lepr, they reasoned that the loss of one allele of Lepr might have caused the increased resorptions. Therefore, they appropriately studied mice bearing only one allele of Lepr (Lepr db/+) (7). These females were mildly overweight but fertile, with no differences in pregnancy outcomes and resorptions. Furthermore, tests comparing their offspring showed that wild-type embryos or Lepr db/+ embryos were resorbed in nearly equal numbers. This clever approach proved that the absence of one allele of Lepr could not explain the increased resorptions seen in the PMV-Lepr–reactivated mice. This comprehensive study then focused on histopathological and molecular analyses of placental implants from these PMV-Lepr–reactivated mice, comparing them with those from wild-type mice. During implantation, the syncytiotrophoblast invades the uterine wall in finger-like projections called villi, creating a labyrinth of lacunae into which maternal blood spills. The villi house the fetal vessels that grow to optimize the transfer of nutrition and gases. Thus, angiogenesis is an important developmental step to insure adequate nutrition and gas exchange. Thorough histopathological analyses of the resorbed fetuses showed large areas of necrosis within the vessels of the placental villi and the syncytiotrophoblast. This was accompanied by an influx of inflammatory cells and low to moderate mineralization. At the molecular level, a mouse angiogenesis quantitative polymerase chain reaction array done with resorbed placentas revealed changes in genes involved with angiogenesis, inflammation, cellular growth, and response to stress (7). Normal female placentas showed increased expression of genes associated with angiogenesis, cellular growth, and stress, whereas normal male placentas showed only an increase in Insl3 expression. These interesting sex differences show that maternal obesity has a considerable sex-specific impact on gene expression, even on unabsorbed fetuses. The authors next studied the impact of an HFD on pregnancy (7). Wild-type mice fed an HFD (60%) for 16 weeks gained weight, although they could hardly be considered obese (average weight 28.7 g). Nevertheless, the HFD did interfere with pregnancy in two of the seven females. The remaining females had implantation numbers comparable to those of control-fed females. Quantitative polymerase chain reaction arrays detected striking differences in placental gene expression when compared with the PMV-Lepr–reactivated mice. In the mice exposed to HFD, there were 40-fold increases in some stress and cellular response genes in the placentas over those of the control placentas. The apparent lack of gross fat gain compared with physiological changes associated with obesity makes these results even more interesting. This comprehensive study showed a direct correlation between the degree of obesity and a negative pregnancy outcome (7). The study clearly advances the field by elegantly distinguishing the impact of an HFD from that following morbid obesity. Based on differences seen in the gene expression of resorbed vs nonresorbed placentas from obese reactivated PMV-LEPRloxTB females, the authors conclude that physiological compensatory changes can occur in some cases in an attempt to override the negative effects of obesity on pregnancy. The study appropriately notes that the mouse is a good model for studies of implantation and metabolic regulation of reproduction. However, we researchers also need to recognize that ubiquitous knockouts of any gene may alter development of multiple organs and neuronal pathways. That being said, the study by Mahany et al. (7) probes new corners of the reproductive field and opens the door for future studies of obesity and HFD-induced placental dysfunction. Abbreviations: Abbreviations: HFD high-fat diet PMV ventral premammillary nucleus Acknowledgments Financial Support: This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK113776, Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant R01-HD087057, and National Institute of General Medical Sciences Grants P30-GM11070 and P20-GM103425. Disclosure Summary: The authors have nothing to disclose. References 1. Ducharme J. Obesity shaved almost a year off U.S. life expectancy, study says. Time, January 15, 2018. Available at http://time.com/5100737/obesity-lowering-life-expectancy-united-states/. Accessed 15 January 2018. 2. Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK, Steiner RA. Leptin is a metabolic signal to the reproductive system. Endocrinology . 1996; 137( 7): 3144– 3147. Google Scholar CrossRef Search ADS PubMed 3. Elias CF. Leptin action in pubertal development: recent advances and unanswered questions. Trends Endocrinol Metab . 2012; 23( 1): 9– 15. Google Scholar CrossRef Search ADS PubMed 4. Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertility. Cell Mol Life Sci . 2013; 70( 5): 841– 862. Google Scholar CrossRef Search ADS PubMed 5. Scarpace PJ, Zhang Y. Leptin resistance: a prediposing factor for diet-induced obesity. Am J Physiol Regul Integr Comp Physiol . 2009; 296( 3): R493– R500. Google Scholar CrossRef Search ADS PubMed 6. Donato J Jr Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S Jr Coppari R, Zigman JM, Elmquist JK, Elias CF. Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest . 2011; 121( 1): 355– 368. Google Scholar CrossRef Search ADS PubMed 7. Mahany EB, Han X, Borges BC, da Silveira Cruz-Machado S, Allen SJ, Garcia-Galiano D, Hoenerhoff MJ, Bellefontaine NH, Elias CF. Obesity and high fat diet induce distinct changes in placental gene expression and pregnancy outcome [published online ahead of print February 9, 2018]. Endocrinology . Copyright © 2018 Endocrine Society
Endocrinology – Oxford University Press
Published: Apr 1, 2018
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