Maternal Choline Supplementation Alters Fetal Growth Patterns in a Mouse Model of Placental Insufficiency

Impairments in placental development can adversely affect pregnancy outcomes. The bioactive nutrient choline may mitigate some of these impairments, as suggested by data in humans, animals, and human trophoblasts. Herein, we investigated the effects of maternal choline supplementation (MCS) on parameters of fetal growth in a Dlx3+/− (distal-less homeobox 3) mouse model of placental insufficiency. Dlx3+/− female mice were assigned to 1X (control), 2X, or 4X choline intake levels during gestation. Dams were sacrificed at embryonic days E10.5, 12.5, 15.5, and 18.5. At E10.5, placental weight, embryo weight, and placental efficiency were higher in 4X versus 1X choline. Higher concentrations of hepatic and placental betaine were detected in 4X versus 1X choline, and placental betaine was positively associated with embryo weight. Placental mRNA expression of Igf1 was downregulated by 4X (versus 1X) choline at E10.5. No differences in fetal growth parameters were detected at E12.5 and 15.5, whereas a small but significant reduction in fetal weight was detected at E18.5 in 4X versus 1X choline. MCS improved fetal growth during early pregnancy in the Dlx3+/− mice with the compensatory downregulation of Igf1 to slow growth as gestation progressed. Placental betaine may be responsible for the growth-promoting effects of choline

Impairment of Vowel Articulation as a Possible Marker of Disease Progression in Parkinson's Disease

Purpose: The aim of the current study was to survey if vowel articulation in speakers with Parkinson’s disease (PD) shows specific changes in the course of the disease. Method: 67 patients with PD (42 male) and 40 healthy speakers (20 male) were tested and retested after an average time interval of 34 months. Participants had to read a given text as source for subsequent calculation of the triangular vowel space area (tVSA) and vowel articulation index (VAI). Measurement of tVSA and VAI were based upon analysis of the first and second formant of the vowels /a/, /i/and /u / extracted from defined words within the text. Results: At first visit, VAI values were reduced in male and female PD patients as compared to the control group, and showed a further decrease at the second visit. Only in female Parkinsonian speakers, VAI was correlated to overall speech impairment based upon perceptual impression. VAI and tVSA were correlated to gait impairment, but no correlations were seen between VAI and global motor impairment or overall disease duration. tVSA showed a similar reduction in the PD as compared to the control group and was also found to further decline between first and second examination in female, but not in male speakers with PD. Conclusions: Measurement of VAI seems to be superior to tVSA in the description of impaired vowel articulation and its further decline in the course of the disease in PD. Since impairment of vowel articulation was found to be independent fro

Phosphatidylcholines: Beyond the Membrane

Phosphatidylcholines (PC) are the most abundant phospholipids in mammalian cells, where they serve well-characterized structural roles, maintaining membrane integrity, facilitating lipoprotein assembly and serving as a surfactant in the lung. Over the past decade, seminal papers have been published that describe novel roles for specific PC species derived from both the cytidine diphosphate-choline (CDP-choline) and phosphatidylethanolamine N-methyltransferase (PEMT) pathways of PC synthesis; these roles include both nuclear receptor agonism and generating critical physiological pools of the omega 3 fatty acid, docosahexaenoic acid (DHA). In addition to these novel functions, complex interactions between PC and its substrate, choline, with growth and energetic status have emerged, following the observation that the mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of PC synthesis through the CDP-choline pathway. Presented in this dissertation are the tests of our primary hypotheses informed directly from these emerging areas of phosphatidylcholine biology. Chapter 2 of this dissertation examines the impact of diet on the production of dilauroylphosphatidylcholine (DLPC), a phosphatidylcholine species enriched in lauric acid that was recently identified as a ligand for the nuclear receptor, liver receptor homolog-1 (LRH-1). DLPC binding to LRH-1 results in modulation of LRH-1-dependent hepatic gene expression and improvements in glucose and lipid handling. While DLPC has been convincingly shown to bind and activate LRH-1 when provided exogenously to cultured cells and mice, endogenous production of DLPC has not been observed, questioning its significance in the regulation of mammalian physiology. We hypothesized that the absence of DLPC in mammalian tissues results from substrate insufficiency (i.e. low lauric acid supply) and that provision of lauric acid, either in the culture media or the mammalian diet, will result in endogenous DLPC production, and be associated with functional LRH-1 activation. Cell culture models, animal feeding experiments, and a single-blind, randomized, controlled crossover acute feeding study in human participants were used to test this hypothesis. As hypothesized, provision of lauric acid in the cell culture media, animal diet, and human diet resulted in the acute and chronic production of DLPC. In cultured cells, this was associated with upregulation of LRH-1 dependent transcripts, an effect that was blunted by co-treatment with a LRH-1 antagonist. In animals, feeding of high fat diets containing lauric acid, utilizing purified lauric acid or coconut oil-based diets, resulted in substantial improvements in glucose handling as indicated by an oral glucose tolerance test. Chapter 3 of this dissertation examines the association of dietary choline intake and reproductive stage with plasma lysophosphatidylcholine (LPC)-DHA among women participants of a 10 week controlled feeding study. LPC-DHA has been recently highlighted as a physiological pool of DHA for maintaining the supply of this critical polyunsaturated fatty acid to extrahepatic organs during growth and development. We hypothesized that reproductive life-stage, dietary choline intake (22% provided as deuterium-labeled choline) and genetic variants in one-carbon metabolism would impact plasma unlabeled and labeled LPC-DHA in response to controlled feeding. To address these hypotheses, we measured unlabeled and deuterium-labeled plasma LPC-DHA in samples from a previously conducted controlled feeding study performed in non-pregnant, pregnant, and lactating women randomized to either 480 or 930mg of choline per day. Consistent with our hypotheses, we observed a significant reduction in unlabeled plasma LPC-DHA in pregnant and lactating women relative to non-pregnant women at week 10; only non-pregnant women exhibited significant increases in LPC-DHA from baseline to week 10 while consuming the study diets. Choline intake and one-carbon metabolism variants were not associated with unlabeled plasma LPC-DHA. However, both choline intake and reproductive life-stage altered the enrichment of PEMT- and CDP-choline-derived LPCs. In Chapter 4 of this dissertation, we explore roles for choline and phospholipid metabolism in the context of a novel animal model of adolescent severe acute malnutrition (aSAM). This complex disorder is characterized by negative energy balance, impaired growth, and multiple micronutrient deficiencies; severe forms of aSAM, namely kwashiorkor, are further complicated by an idiopathic fatty liver. The sensitivity of this fatty liver to dietary choline remains unknown. To characterize the potential for choline supplementation to serve as a metabolic therapy in aSAM, we developed a maize vegetable diet (MVD), comprised of foods typically consumed by children who will go on to develop kwashiorkor. The MVD was fed to weanling mice with or without choline supplementation, and compared to typical chow diets, to determine impacts on growth, body composition, and potential to alleviate the hallmark characteristic of kwashiorkor, fatty liver. We further explored the metabolic fate of dietary choline, hypothesizing that choline would be oxidized to betaine to support PC synthesis through the PEMT pathway in this context of lower mTORC1 activity and reduced CDP-choline pathway activity. Mice consuming our novel maize vegetable diet exhibited impaired growth relative to chow fed mice, and developed hepatic steatosis, consistent with human kwashiorkor. The addition of choline to the maize vegetable diet resulted in amelioration of the hepatic steatosis, and a greater hepatic concentration of betaine; choline partitioning to betaine is consistent with a role for the PEMT pathway in supporting PC synthesis in the context of malnutrition

Perspective: Estrogen and the Risk of Cognitive Decline: A Missing Choline(rgic) Link?

Factors that influence the risk of neurocognitive decline and Alzheimer's disease (AD) may provide insight into therapies for both disease treatment and prevention. Although age is the most striking risk factor for AD, it is notable that the prevalence of AD is higher in women, representing two-thirds of cases. To explore potential underlying biological underpinnings of this observation, the intent of this article is to explore the interplay between cognitive aging and sex hormones, the cholinergic system, and novel hypotheses related to the essential nutrient choline. Mechanistic evidence points toward estrogen's neuroprotective effects being strongly dependent on its interactions with the cholinergic system, a modulator of attentional functioning, learning, and memory. Estrogen has been shown to attenuate anticholinergic-induced impairments in verbal memory and normalize patterns of frontal and occipital cortex activation, resulting in a more "young adult" phenotype. However, similar to estrogen replacement's effect in cardiovascular diseases, its putative protective effects may be restricted to early postmenopausal women only, a finding supportive of the "critical window hypothesis." Estrogen's impact on the cholinergic system may act both locally in the brain but also through peripheral tissues. Estrogen is critical for inducing endogenous choline synthesis via the phosphatidylethanolamine N-methyltransferase (PEMT) gene-mediated pathway of phosphatidylcholine (PC) synthesis. PEMT is dramatically induced in response to estrogen, producing not only a PC molecule and source of choline for the brain but also a key source of the long-chain ω-3 fatty acid, DHA. Herein, we highlight novel hypotheses related to hormone replacement therapy and nutrient metabolism aimed at directing future preclinical and clinical investigation

Common Genetic Variants Alter Metabolism and Influence Dietary Choline Requirements

Nutrient needs, including those of the essential nutrient choline, are a population wide distribution. Adequate Intake (AI) recommendations for dietary choline (put forth by the National Academies of Medicine to aid individuals and groups in dietary assessment and planning) are grouped to account for the recognized unique needs associated with age, biological sex, and reproductive status (i.e., pregnancy or lactation). Established and emerging evidence supports the notion that common genetic variants are additional factors that substantially influence nutrient requirements. This review summarizes the genetic factors that influence choline requirements and metabolism in conditions of nutrient deprivation, as well as conditions of nutrient adequacy, across biological sexes and reproductive states. Overall, consistent and strong associative evidence demonstrates that common genetic variants in choline and folate pathway enzymes impact the metabolic handling of choline and the risk of nutrient inadequacy across varied dietary contexts. The studies characterized in this review also highlight the substantial promise of incorporating common genetic variants into choline intake recommendations to more precisely target the unique nutrient needs of these subgroups within the broader population. Additional studies are warranted to facilitate the translation of this evidence to nutrigenetics-based dietary approaches

LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury

Acute hepatic injury is observed in response to various stressors, including trauma, ingestion of hepatic toxins, and hepatitis. Investigations to date have focused on extrinsic and intrinsic signals required for hepatocytes to proliferate and regenerate the liver in response to injury, though there is a more limited understanding of induced stress responses promoting hepatocyte survival upon acute injury. In this issue of the JCI, Sun and colleagues detail a mechanism by which local activation of the nuclear receptor liver receptor homolog-1 (LRH-1; NR5A2) directly induces de novo asparagine synthesis and expression of asparagine synthetase (ASNS) in response to injury and show that this response restrains hepatic damage. This work opens up several avenues for inquiry, including the potential for asparagine supplementation to ameliorate acute hepatic injury

A forgotten resource critical to the future of behavior analysis: Undergraduate psychology majors

The demand for board-certified applied behavior analysts is not being met, and there is a perception that fewer students are exposed to systematic courses in basic and applied behavior analysis than was true a generation ago. This article outlines how we have successfully implemented an undergraduate curriculum in behavior analysis within a traditional department of psychology. Certification credentials offered by the Behavior Analysis Certification Board facilitated the approval of this curriculum, and the cultural practice selection contingencies that supported the creation of our curriculum in behavior analysis may be similar at other comprehensive universities. Advice for developing an undergraduate program in behavior analysis within a psychology department is outlined. We also summarize strategies we have used to attract talented students to the courses and the significant impact these strategies have had on the number of our graduates who pursue graduate training in basic and applied behavior analysis. Attracting the best and brightest students to behavior analysis is critical to the future of the field

Genetic Variants in One-Carbon Metabolism and Their Effects on DHA Biomarkers in Pregnant Women: A Post-Hoc Analysis

The delivery of docosahexanoic acid (DHA) to the fetus is dependent on maternal one-carbon metabolism, as the latter supports the hepatic synthesis and export of a DHA-enriched phosphatidylcholine molecule via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway. The following is a post-hoc analysis of a choline intervention study that sought to investigate whether common variants in one-carbon metabolizing genes associate with maternal and/or fetal blood biomarkers of DHA status. Pregnant women entering their second trimester were randomized to consume, until delivery, either 25 (n = 15) or 550 (n = 15) mg choline/d, and the effects of genetic variants in the PEMT, BHMT, MTHFD1, and MTHFR genes on DHA status were examined. Variant (vs. non-variant) maternal PEMT rs4646343 genotypes tended to have lower maternal RBC DHA (% total fatty acids) throughout gestation (6.9% vs. 7.4%; main effect, p = 0.08) and lower cord RBC DHA at delivery (7.6% vs. 8.4%; main effect, p = 0.09). Conversely, variant (vs. non-variant) maternal MTHFD1 rs2235226 genotypes exhibited higher cord RBC DHA (8.3% vs. 7.3%; main effect, p = 0.0003) and higher cord plasma DHA (55 vs. 41 μg/mL; main effect, p = 0.05). Genotype tended to interact with maternal choline intake (p < 0.1) to influence newborn DHA status for PEMT rs4646343 and PEMT rs7946. These data support the need to consider variants in one-carbon metabolic genes in studies assessing DHA status and requirements during pregnancy