Metabolic Imprinting Research Articles

Interplay between γδT-Cell Metabolism and Tumour Microenvironment Offers Opportunities for Therapeutic Intervention

Solid tumour targeting using adoptive cell therapy has failed to reproduce the spectacular clinical successes seen with chimeric antigen receptor T cell therapies and B cell malignancies. Low in glucose, oxygen, pH and populated with suppressive cells, the solid tumour microenvironment (TME) remains a formidable obstacle to successful immune targeting. The use of atypical, tissue-tropic lymphocytes, such as γδT cells, may offer enhanced tumour trafficking over canonical αβT cells. Nonetheless, γδT cells too interact with the TME. The consequences of this interaction are poorly understood and of high translational relevance. Lopes and colleagues show that, in a murine context, low glucose environments preferentially retained pro-tumorigenic IL-17-producing γδT cells. Anti-tumorigenic IFN-γ-producing γδT cells, meanwhile, required high ambient glucose to survive and exert effector function. Unexpectedly, this metabolic imprinting was evident in the murine thymus, suggesting that the ontological separation of these functional subsets occurs early in their development. Elucidation of this relationship between TME glucose levels and γδT cell functionality in a human context is likely to carry significant implications for the development of γδT cell-based oncoimmunotherapeutics.

Dinâmica da composição lipídica das fórmulas infantis e suas implicações clínicas

In human milk, the role of lipids as a source for the adequate growth and development of the infant is highlighted. The lipidic system of breast milk, responsible for approximately 50% of calories, is structured for the newborn and the infant. Digestion and absorption of lipids are facilitated by the organization of fat, the type of fatty acid (palmitic, oleic, linoleic, linolenic acids, etc.), the composition of triglycerides and the lipase stimulated by bile salts. In addition, milk contains docosahexaenoic acid, which allows optimal neurological and immunological development. Although the lipid structure of breast milk is extremely complex, it should serve as a model for the dynamics of the lipid composition of infant formulas. The addition of long-chain fatty acids (arachidonic and docosahexaenoic acids) linked to phospholipids in infant formulas can contribute to a better development of infants, as well as acting on the immune system and metabolic imprinting, reducing the risk of chronic non-communicable diseases. Infants receiving formulas with palmitic acid in theß-2 position have a higher lactobacillus count in the feces, when compared to those receiving formulas with palmitic acid in the ß-1 and ß-3 positions, promoting the maintenance of intestinal eubiosis. Infants receiving formulas with ß-2 palmitic acid present bone health similar to infants breastfeeding, as fecal calcium loss does not occur.

Newborn Screening Samples for Diabetes Research: An Underused Resource.

Inborn errors of metabolism and diabetes share common derangements in analytes of metabolic networks that are tested for in newborn screening, usually performed 48–72 h after birth. There is limited research examining the metabolic imprint of diabetes on newborn screening results. This paper aims to demonstrate the links between diabetes, biochemical genetics and newborn screening in investigating disease pathophysiology in diabetes, provide possible reasons for the lack of research in diabetes in newborn screening and offer recommendations on potential research areas. We performed a systematic search of the available literature from 1 April 1998 to 31 December 2018 involving newborn screening and diabetes using OVID, MEDLINE, Cochrane and the PROSPERO register, utilizing a modified extraction tool adapted from Cochrane. Eight studies were included after screening 1312 records. Five studies reanalyzed dried blood spots (DBS) on filter paper cards, and three studies utilized pre-existing results. The results of these studies and how they relate to cord blood studies, the use of cord blood versus newborn screening dried blood spots as a sample and considerations on newborn screening and diabetes research is further discussed. The timing of sampling of newborn screening allows insight into neonatal physiology in a catabolic state with minimal maternal and placental influence. This, combined with the wide coverage of newborn screening worldwide, may aid in our understanding of the origins of diabetes.

Nutrivolatilomics of Urinary and Plasma Samples to Identify Candidate Biomarkers after Cheese, Milk, and Soy-Based Drink Intake in Healthy Humans

The characterization of volatile compounds in biological fluids offers a distinct approach to study the metabolic imprint of foods on the human metabolome, particularly to identify novel biomarkers of food intake (BFIs) that are not captured by classic metabolomics. Using a combination of dynamic headspace vacuum transfer In Trap extraction and gas chromatography coupled with mass spectrometry, we measured volatile compounds (the "volatilome") in plasma and urine samples from a randomized controlled crossover intervention study in which 11 healthy subjects ingested milk, cheese, or a soy-based drink. More than 2000 volatile compounds were detected in plasma, while 1260 compounds were detected in urine samples. A postprandial response in plasma was confirmed for 697 features. Univariate and multivariate analyses identified four molecules in plasma and 31 molecules in urine samples differentiating the ingestion of the foods, of which three metabolites in plasma and nine in urine were specific to the dairy products. Among these molecules, heptan-2-one, 3,5-dimethyloctan-2-one, and undecan-2-one in plasma and 3-ethylphenol, heptan-2-one, 1-methoxy-2-propyl acetate, and 9-decenoic acid were highly discriminative for dairy or cheese intake. In urine, 22 volatile compounds were highly discriminative for soy-based drink intake. The majority of these molecules have not been reported in humans. Our findings highlight the potential of plasma and urinary volatilomics for detection of novel dietary biomarkers.

0346 Metabolic Aging and Sleep Loss: Metabolite Signatures Link Sleep Deprivation and Aging Across Tissues

Abstract Introduction Insufficient sleep is a hallmark of modern society, and sleep deprivation (SD) is a risk factor for neurodegenerative and cardiometabolic disorders. The interactions of aging with systemic and local metabolic alterations induced by sleep deprivation are essentially unexplored. In this study, we demonstrate a shared metabolic imprint of SD and aging in plasma, liver, and hippocampus. Methods Young (2 - 4 months) and aged (22 - 24 months) mice were sleep deprived (N = 10/group) for 5 hours followed by collection of blood plasma, liver and hippocampus. The samples were extracted and subjected to UPLC-MS/MS based targeted metabolomics analysis. Results Young animals displayed greater sensitivity to SD induced metabolic changes with >40% more metabolites perturbed in each sample type measured compared to aged animals. Enrichment analysis based on known disease-associated metabolites suggests that plasma change in young animals are of pathological relevance, but not in aged animals. A common hepatic signature of sleep-loss across the two age groups consisted of ketosis and urea cycle perturbation. Approximately 20-30% of measured metabolites exhibit similar changes when the sleep deprivation induced signature is compared with the aging metabolic imprint in a tissue-dependent manner. Central energetics, urea cycle and aromatic amino acid metabolism highlight the common pathways altered by sleep and aging in the periphery. In the hippocampus, choline and acetylcholine pools were depleted, potentially providing insight into the changes in metabolism that accompany analogous defects in memory consolidation. Conclusion These results support the notion that SD makes the ‘young seem old’. The results further connect neurobehavioral observations tying together aging and sleep loss, by implicating molecular mechanisms at the level of metabolism. Support This work was supported by NIH grant R21AG052905 (AMW, AS), P50AG017628 (TA; A.I. Pack, PI) and R01AG062398 (TA, JT). TA was supported by the Brush Family Chair in Biology at Penn and is currently supported by the Roy J. Carver Chair of Neuroscience at Iowa.

Cattle adapted to tropical and subtropical environments: social, nutritional, and carcass quality considerations.

Beef production needs to increase from 60 million to 130 million tons by 2050 to feed a growing world population, and 70% of this production increase is expected from beef industries located in subtropical and tropical regions of the world. Bos indicus-influenced cattle predominate in these regions but are often managed using practices developed for Bos taurus breeds reared in temperate climates. Hence, a fundamental step to meet the increasing global demand for beef is to develop specific management for B. indicus-influenced cattle in tropical or subtropical environments. Bos taurus and B. indicus are different subspecies, and diverge in social and biological functions due to selection pressure caused by complex evolutionary and domestication processes. Bos indicus cattle display different social responses compared with B. taurus counterparts, which must be taken into account by management planning as these traits directly impact cattle performance and welfare. In tropical and subtropical regions, warm-season perennial C4 grasses are the dominant forages, and their availability has a significant influence on the productivity of beef cattle systems. The resilience of C4 grasses under adverse conditions is one of their most important characteristics, even though these forages have reduced nutritive value compared with forages from temperate climates. Accordingly, nutritional planning in tropical and subtropical conditions must include management to optimize the quantity and quality of C4 forages. Nutritional requirements of cattle raised within these conditions also require special attention, including inherent metabolic compromises to cope with environmental constraints and altered energy requirements due to body composition and heat tolerance. Nutritional interventions to enhance beef production need to be specifically tailored and validated in B. indicus-influenced cattle. As an example, supplementation programs during gestation or early life to elicit fetal programming or metabolic imprinting effects, respectively, yield discrepant outcomes between subspecies. Bos indicus-influenced cattle produce carcasses with less marbling than B. taurus cattle, despite recent genetic and management advances. This outcome is mostly related to reduced intramuscular adipocyte volume in B. indicus breeds, suggesting a lesser need for energy stored intramuscularly as a mechanism to improve thermotolerance in tropical and subtropical climates.

346 Supplementing Ca salts of soybean oil to enhance carcass quality of beef cattle via metabolic imprinting events

Abstract This experiment evaluated the effects of supplementing Ca salts of soybean oil (CSSO) at 2 mo of age via creep-feeding, upon weaning at 6 months of age, or no CSSO supplementation on growth and carcass development of beef cattle. A total of 64 steers were enrolled in this study over 2 years (32 steers/year), with 4 phases per year: creep-feeding (d 0 to 60), pre-weaning (d 61 to 120), post-weaning (d 121 to 180) and feedlot (181 to slaughter). On d 0 steers were ranked by body weight (BW) and age (114 ± 2 kg; 66 ± 0.5 d) and randomly assigned, in a 2 x 2 factorial, to receive 80 g/steer daily (creep-feeding) or 150 g/steer daily (post-weaning) of CSSO. Non-supplemented steers (CON) were provided with equivalent saturated fat supplement. On d 0, 61, 120, 180, and 330 steers were evaluated for longissimus muscle depth, backfat thickness, and marbling via real time ultrasonography, blood was sampled for determination of plasma fatty acid composition, muscle samples were collected via needle biopsy, and BW was recorded. After the creep-feeding phase, CSSO steers had greater (P < 0.01) plasma concentrations of linoleic, omega-6, and total PUFA compared with CON. Steers that received CSSO during the postweaning phase had greater (P < 0.01) plasma concentrations of linoleic, omega·-6, and total FA compared with CON prior to feedlot entry. No treatment differences were detected for performance or body composition responses (P > 0.25) during any phase. However, mRNA expression of adipogenic/lipogenic genes was greater (P < 0.03) prior to slaughter (d 330) in muscle of steers that had received CSSO during the creep-feeding phase. Results from this experiment suggest that supplementing CSSO to nursing beef steers via creep feeding stimulated metabolic imprinting effects through enhanced adipogenic gene expression, however did not alter phenotypic variables.

33 Nutritional programming of puberty in Bos indicus-influenced heifers

Abstract Approximately 5 million beef heifers enter the U.S. cow herd annually and their lifetime productivity is heavily-dependent upon their ability to attain puberty and produce a calf by 24 mo of age. However, a significant proportion of heifers within existing U.S. production systems fail to achieve these goals, particularly in southern regions where Bos indicus-influenced cattle predominate. Therefore, approaches are needed that facilitate nutritional programming of the reproductive neuroendocrine axis, while minimizing feeding costs and optimizing the consistent establishment of puberty by 14–15 mo of age. Increased BW gain between 4 and 9 mo of age facilitates pubertal development by programming hypothalamic centers that regulate GnRH secretion. Among the different metabolic hormones, leptin plays a critical role in conveying nutritional information to the brain and controlling puberty. Two hypothalamic neuronal populations that express the orexigenic peptide neuropeptide Y (NPY) and the anorexigenic peptide alpha melanocyte-stimulating hormone (αMSH) are key components of afferent pathways that convey inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. Our studies have demonstrated that short-term increases in dietary energy intake during juvenile development result in epigenetic, structural, and functional modifications in these hypothalamic pathways to promote high-frequency, episodic release of GnRH/LH. However, integrating the foundational knowledge of metabolic imprinting of the brain for early puberty with issues related to lifetime performance is complex. One approach has been to employ a novel stair-step nutritional regimen involving alternating periods of dietary energy-restriction and re-feeding during juvenile development. This approach is designed to support early onset of puberty by imprinting functional alterations in the hypothalamus during key periods of brain development while optimizing other aspects of growth and performance. Finally, our recent findings suggest that maternal nutrition during gestation can also induce neuroendocrine changes that are likely to persist and influence reproductive performance throughout adulthood in cattle.

205 Neuroendocrine pathways and the nutritional control of puberty in heifers

Abstract Approximately 5 million beef heifers enter the U.S. cow herd annually, and their lifetime productivity is heavily-dependent upon their ability to attain puberty and produce a calf by 24 mo of age. However, a significant proportion of heifers within existing U.S. production systems fail to achieve these objectives. Therefore, approaches are needed that facilitate nutritional programming of the reproductive neuroendocrine axis, while minimizing feeding costs and optimizing the consistent establishment of puberty by 14–15 mo of age. Accelerated rates of BW gain during early calfhood, particularly between 4 and 9 mo of age, facilitate pubertal development by programming hypothalamic centers that regulate GnRH secretion. Among the different metabolic hormones, leptin plays a critical role in conveying nutritional information to the brain and controlling pubertal progression. Two hypothalamic neuronal populations that express the orexigenic peptide neuropeptide Y (NPY) and the anorexigenic peptide alpha melanocyte-stimulating hormone (αMSH) are key components of afferent pathways that convey inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. Our studies have demonstrated that short-term increases in dietary energy intake during juvenile development result in epigenetic, structural, and functional modifications in these hypothalamic pathways to promote high-frequency, episodic release of GnRH/LH. However, integrating the foundational knowledge of metabolic imprinting of the brain for early puberty with issues related to lifetime performance is complex. One approach has been to employ a novel stair-step nutritional regimen involving alternating periods of dietary energy-restriction and re-feeding during juvenile development. This approach is designed to support early onset of puberty by imprinting genomic, biochemical and morphologic alterations in the hypothalamus during key periods of brain development while optimizing other aspects of growth and performance. Finally, our recent findings suggest that maternal nutrition during gestation can also induce neuroendocrine changes that are likely to persist long after puberty and influence reproductive performance throughout adulthood in cattle.

Molecular profiling of an oleaginous trebouxiophycean alga Parachlorella kessleri subjected to nutrient deprivation for enhanced biofuel production

BackgroundDecreasing fossil fuels and its impact on global warming have led to an increasing demand for its replacement by sustainable renewable biofuels. Microalgae may offer a potential feedstock for renewable biofuels capable of converting atmospheric CO2 to substantial biomass and valuable biofuels, which is of great importance for the food and energy industries. Parachlorella kessleri, a marine unicellular green alga belonging to class Trebouxiophyceae, accumulates large amount of lipids under nutrient-deprived conditions. The present study aims to understand the metabolic imprints in order to elucidate the physiological mechanisms of lipid accumulations in this microalga under nutrient deprivation.ResultsMolecular profiles were obtained using gas chromatography–mass spectrometry (GC–MS) of P. kessleri subjected to nutrient deprivation. Relative quantities of more than 60 metabolites were systematically compared in all the three starvation conditions. Our results demonstrate that in lipid metabolism, the quantities of neutral lipids increased significantly followed by the decrease in other metabolites involved in photosynthesis, and nitrogen assimilation. Nitrogen starvation seems to trigger the triacylglycerol (TAG) accumulation rapidly, while the microalga seems to tolerate phosphorous limitation, hence increasing both biomass and lipid content. The metabolomic and lipidomic profiles have identified a few common metabolites such as citric acid and 2-ketoglutaric acid which play significant role in diverting flux towards acetyl-CoA leading to accumulation of neutral lipids, whereas other molecules such as trehalose involve in cell growth regulation, when subjected to nutrient deprivation.ConclusionsUnderstanding the entire system through qualitative (untargeted) metabolome approach in P. kessleri has led to identification of relevant metabolites involved in the biosynthesis and degradation of precursor molecules that may have potential for biofuel production, aiming towards the vision of tomorrow’s bioenergy needs.

Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring.

Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring. Female Wistar rats consumed a Western diet (WD) for 18weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1. The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased β-cell area and mass. RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and β-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.

Postnatal early overfeeding induces cardiovascular dysfunction by oxidative stress in adult male Wistar rats

AimsObesity is associated with innumerous comorbidities, including cardiovascular diseases, that occur by various mechanisms, including hyperactivation of the renin angiotensin system, oxidative stress and cardiovascular overload. Postnatal early overfeeding (PO) leads to metabolic imprinting that induces weight gain throughout life, and in this paper, we aimed to evaluate cardiovascular parameters and cardiac molecular changes due to obesity induced early in life by PO. Main methodsMale Wistar rats (120-days-old), raised in normal (NL) or small litters (SL), were submitted to cardiac assessment by transthoracic echocardiography and blood pressure evaluation. Thereafter, the hearts and aorta rings from these animals were submitted to ex-vivo isolated assays. Still, cardiac morphological and molecular analyses were performed. Key findingsPO induced ventricular hypertrophy, raised blood pressure, increased fibrosis, and ex-vivo cardiac dysfunction in the SL group. Furthermore, SL animals presented impaired vascular relaxation and increased vascular constriction responses. Besides functional alterations, SL animals presented augmented RAB-1b and SOD-1, despite no changes in RAS receptors expression or Akt/eNOS pathway. SignificanceTaken together, our results consolidate the knowledge that the PO during lactation is critical for cardiometabolic programming, leading to oxidative stress and cardiac remodeling in later stages of life.

РЕГИОНАЛЬНЫЕ АСПЕКТЫ МЛАДЕНЧЕСКОЙ И ДЕТСКОЙ СМЕРТНОСТИ НА ДАЛЬНЕМ ВОСТОКЕ

The article presents the results of long-term observations of the authors to assess the health of pregnant women, children and adolescents of the Far-Eastern Federal District. In the dynamics of the observation there is an improvement in indicators characterizing the health status of women and children: the reduction of morbidity, infant and child mortality. However, these data are much higher than in European countries. Thus, the infant mortality rate on average in the Far Eastern Federal District decreased from 11.0‰ in 2013 to 5.7‰ in 2017 (on average in Russia it was 5.5‰). At the same time, in the “new” countries of the European Union (EU) that are the closest in socio-economic condition to Russia (Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, Slovenia), this figure in 2016 amounted to 3.9‰, and in the “old” countries of the EU it was 3.3‰. The child mortality rate (1-17 years old) in some regions of the Far Eastern Federal District ranges from 73.0 in the Khabarovsk territory (per 100 thousand of the corresponding age) to 101.1 in the Jewish Autonomous Region and on average in Russia in 2016 it was 70.9. And in the EU countries, this figure was significantly lower and amounted to 37.6 in the “new” countries and 31.4 in the “old” countries. In the analysis of risk factors affecting health, infant and child mortality, the following biological factors were noted: maternal health, complicated pregnancy, genetic factors, living conditions and, above all, economic and biogeochemical environmental factors. In areas with a tense and critical assessment of the environmental situation, the proportion of spontaneous abortions, stillbirths, premature, congenital malformations is much higher. In the formation of pathology in children, the deficiency or imbalance of essential, i.e. vital trace elements, the nature of nutrition, nutrient deficiency, and the formation of energy deficiency of immunocompetent blood cells can influence a lot. All these environmental factors, in fact, are etiological and determine different variants of pathology, the formation of metabolic imprinting, the manifestation of fetal programming and the birth of immature offspring. Disturbance of embryogenesis under the influence of these factors leads to the development of various pathologies of newborns, long-term consequences in the form of reproductive dysfunction, pathology of immune reactions, mental dysfunction, and reduced adaptability. As a result, we have an increased morbidity, sick offspring, and a decrease in life expectancy. In order to develop specific measures to reduce morbidity, infant and child mortality, it is necessary to solve a number of medical and organizational measures, strengthen the preventive orientation of medical care for pregnant women, and timely correct the deficit conditions. It is necessary to organize the system of active health follow-up (examination based on automated control systems) of pregnant women, a system of data banks for the examination, treatment and rehabilitation of women with a burdened obstetric history and from the risk group for the development of perinatal pathology at the stage of planning pregnancy (the best option) or in the early stages of pregnancy.

Induced, Imprinted, and Primed Responses to Changing Environments: Does Metabolism Store and Process Information?

Metabolism is the system layer that determines growth by the rate of matter uptake and conversion into biomass. The scaffold of enzymatic reaction rates drives the metabolic network in a given physico-chemical environment. In response to the diverse environmental stresses, plants have evolved the capability of integrating macro- and micro-environmental events to be prepared, i.e., to be primed for upcoming environmental challenges. The hierarchical view on stress signaling, where metabolites are seen as final downstream products, has recently been complemented by findings that metabolites themselves function as stress signals. We present a systematic concept of metabolic responses that are induced by environmental stresses and persist in the plant system. Such metabolic imprints may prime metabolic responses of plants for subsequent environmental stresses. We describe response types with examples of biotic and abiotic environmental stresses and suggest that plants use metabolic imprints, the metabolic changes that last beyond recovery from stress events, and priming, the imprints that function to prepare for upcoming stresses, to integrate diverse environmental stress histories. As a consequence, even genetically identical plants should be studied and understood as phenotypically plastic organisms that continuously adjust their metabolic state in response to their individually experienced local environment. To explore the occurrence and to unravel functions of metabolic imprints, we encourage researchers to extend stress studies by including detailed metabolic and stress response monitoring into extended recovery phases.

Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring.

Intrauterine growth restriction (IUGR) leads to the development of metabolic syndrome in adulthood. To explore the potential mechanisms of metabolic imprinting, we investigated the effect of malnutrition in utero on hepatic unfolded protein response (UPR)-related genes in IUGR offspring. An IUGR rat model was developed by feeding a low-protein diet to pregnant rats. The expression levels and activity of hepatic UPR genes were analysed by quantitative PCR (qPCR) arrays and western blotting. The hepatic UPR molecules heat-shock 70-kDa protein 4l (Hspa4l), mitogen-activated protein kinase 10 (Mapk10), and endoplasmic reticulum to nucleus signalling 2 (Ern2) were markedly downregulated in IUGR foetuses, but the expression of Mapk10 and Ern2 returned to normal levels at 3 weeks postnatal. In contrast, cAMP responsive element binding protein 3-like 3 (Creb3l3) was upregulated in hepatic tissues at embryo 20(E20), then restored to normal in adulthood (12 weeks). The protein levels of activating transcription factor 2 (Atf2) and Atf6, two key factors of the UPR pathway, were upregulated in the livers of IUGR foetuses, and the latter remained upregulated until 12 weeks. Combined with our previous findings showing an increase in hepatic gluconeogenesis enzymes in IUGR offspring, we speculated that aberrant intrauterine milieu impaired UPR signalling in hepatic tissues; these alterations early in life might contribute to the predisposition of IUGR foetuses to adult metabolic disorders.

Short- and long-term consequences for offspring exposed to maternal diabetes: a review

The prevalence of gestational diabetes mellitus is increasing, as is the worldwide prevalence of type 2 diabetes and obesity, even in children and adolescents. Exposure in utero to maternal diabetes carries several short-term consequences due mainly to maternal hyperglycemia, and consequent fetal hyperinsulinemia. Current evidence also supports the hypothesis that adult health and disease have developmental origins, and that disorders in early-life environments prompt metabolic imprinting that results in a greater risk of negative metabolic outcomes later in life. In particular, exposure in utero to maternal diabetes seems to influence long-term metabolic outcomes, carrying a higher risk of obesity and type 2 diabetes, and thus creating a vicious cycle for future generations. In this paper, the short- and long-term consequences of exposure in utero to hyperglycemia are reviewed, focusing particularly on the long-term metabolic consequences, and investigating the possible pathogenic mechanisms involved.

Metabotypes Related to Meat and Vegetable Intake Reflect Microbial, Lipid and Amino Acid Metabolism in Healthy People.

The objective of this study is to develop a new methodology to identify the relationship between dietary patterns and metabolites indicative of food intake and metabolism. Plasma and urine samples from healthy Swiss subjects (n = 89) collected over two time points are analyzed for a panel of host-microbial metabolites using GC- and LC-MS. Dietary intake is evaluated using a validated food frequency questionnaire. Dietary pattern clusters and relationships with metabolites are determined using Non-Negative Matrix Factorization (NNMF) and Sparse Generalized Canonical Correlation Analysis (SGCCA). Use of NNMF allows detection of latent diet clusters in this population, which describes a high intake of meat or vegetables. SGCCA associates these clusters to i) diet-host microbial and lipid associated bile acid metabolism, and ii) essential amino acid metabolism. This novel application of NNMF and SGCCA allows detection of distinct metabotypes for meat and vegetable dietary patterns in a heterogeneous population. As many of the metabolites associated with meat or vegetable intake are the result of host-microbiota interactions, the findings support a role for microbiota mediating the metabolic imprinting of different dietary choices.

Abstract 2234: Dietary-AGE ingestion during puberty modifies the breast microenvironment to alter mammary gland development: Linking diet, development and breast cancer risk

Abstract Evidence supports the notion that critical events during mammary development permanently alter developmentally regulated programs which influence the breast microenvironment to increase breast cancer risk. This is analogous to metabolic memory in diabetic patients where early metabolic events have been found to be remembered and affect disease severity later in life. Advanced glycation end products (AGEs) are highly reactive metabolites that irreversibly accumulate in tissues as we age. AGE accumulation can contribute to pro-inflammatory and -oxidant phenotypes when signaling through the receptor for advanced glycation end products (RAGE). The pathogenic effects of AGE-RAGE signaling include tissue degeneration, protein dysfunction, aberrant cell signaling, and reduced genetic fidelity. AGEs form during normal metabolism but critically, lifestyle factors such as poor diet, a sedentary lifestyle and being obese also contribute to the AGE accumulation pool. The permanence of AGE adducts and their ability to mediate chronic and persistent inflammatory and oxidative stresses is particularly compatible to the concept of metabolic memory. Our dietary studies in pubertal FVB/n mice fed a high AGE diet show a significant dysregulation of mammary gland development and hyperplastic lesion formation. We observe delayed mammary ductal extension, increased ductal branching and aberrant terminal end-bud (TEB) morphology. The basal myoepithelial cell layer surrounding mammary ducts and TEBs was irregular and epithelial cell proliferation was increased. Molecular characterization of these hyperplastic lesions were defined using DCIS progression markers by histopathological staining and qRT-PCR. Elevated AGE levels accompanied increased RAGE expression and increased macrophage and fibroblast infiltration around the TEBs. In attempt to reverse the effects caused by a high AGE diet, mice were fed a control diet after a pubertal high AGE diet. Hyperplastic lesions persisted despite diet intervention. Importantly, hyperplastic lesions were not observed in mice fed a control diet during puberty, then switched to a high AGE diet. These data indicate that exposure to AGE induced changes during puberty may leave a long-lasting imprint analogous to metabolic memory. In conclusion, increased AGE consumption during pubertal growth results in significant disruption of normal mammary development and the appearance of hyperplastic lesions by adulthood. Consumption of a high AGE diet despite a control diet intervention, reveals hyperplastic lesions indicative of metabolic memory. We hypothesize that the high AGE diet may leave a metabolic imprint on the mammary gland microenvironment, increasing the risk of future breast cancer development. Citation Format: Jaime F. Randise, Bradley A. Krisanits, Lourdes M. Nogueira, Kristi L. Helke, Taaliah Campbell, Victoria J. Findlay, David P. Turner. Dietary-AGE ingestion during puberty modifies the breast microenvironment to alter mammary gland development: Linking diet, development and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2234.

Different milk feeding intensities during the first 4 weeks of rearing dairy calves: Part 3: Plasma metabolomics analysis reveals long-term metabolic imprinting in Holstein heifers

Adequate nutrition of calves is a fundamental requirement for efficient production in later life. Suboptimal nutrition before weaning could have detrimental long-term effects on metabolic health and could thereby decrease production efficiency. In this study, the metabolomic profiles of German Holstein calves reared on whole milk ad libitum (n = 10), milk replacer ad libitum (n = 9), and milk replacer in restricted amounts (n = 9) were compared. Furthermore, this profiling approach was extended to the first lactation in the same animals for characterizing the long-term effect of quantitative and qualitative dietary manipulations affecting calves during development in a period that is sensitive to metabolic imprinting. Blood plasma samples were collected on d 3, 22, and 52 of life as well as during wk 4 before and wk 3 and 8 after the first calving. Samples were subjected to a targeted metabolomics analysis using the AbsoluteIDQ p180 kit of Biocrates Life Science AG (Innsbruck, Austria). Profiling of metabolomics data was performed by principal component analysis and heatmap visualization of the metabolome, as well as by comparing fold changes and t-test statistics of metabolites. A quantitative identification of 180 plasma metabolites was possible, belonging to the metabolite classes of acyl-carnitines, AA, biogenic amines, phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, and hexoses. Comparing metabolite concentrations between ad libitum-reared and restrictively reared animals revealed significant differences both during calfhood as well as during first lactation. Most dominantly, acylcarnitines of both short- and long-chain length were more abundant in ad libitum reared animals in the long-term, suggesting alterations in mitochondrial function, most likely indicating adaptive mechanisms of energy expenditure. Furthermore, plasma sphingomyelin concentrations were affected by ad libitum versus restricted milk replacer feeding, which can imply long-term modulatory mechanisms affecting insulin sensitivity. The functional characterization of the identified metabolic patterns, particularly the alterations of single lipid species, is required for further improving our understanding of the links between early nutrition shaping metabolic development and a healthy productive life of Holstein dairy cows.

Genetic, management, and nutritional factors affecting intramuscular fat deposition in beef cattle - A review.

Intramuscular fat (IMF) content in skeletal muscle including the longissimus dorsi muscle (LM), also known as marbling fat, is one of the most important factors determining beef quality in several countries including Korea, Japan, Australia, and the United States. Genetics and breed, management, and nutrition affect IMF deposition. Japanese Black cattle breed has the highest IMF content in the world, and Korean cattle (also called Hanwoo) the second highest. Here, we review results of research on genetic factors (breed and sex differences and heritability) that affect IMF deposition. Cattle management factors are also important for IMF deposition. Castration of bulls increases IMF deposition in most cattle breeds. The effects of several management factors, including weaning age, castration, slaughter weight and age, and environmental conditions on IMF deposition are also reviewed. Nutritional factors, including fat metabolism, digestion and absorption of feed, glucose/starch availability, and vitamin A, D, and C levels are important for IMF deposition. Manipulating IMF deposition through developmental programming via metabolic imprinting is a recently proposed nutritional method to change potential IMF deposition during the fetal and neonatal periods in rodents and domestic animals. Application of fetal nutritional programming to increase IMF deposition of progeny in later life is reviewed. The coordination of several factors affects IMF deposition. Thus, a combination of several strategies may be needed to manipulate IMF deposition, depending on the consumer’s beef preference. In particular, stage-specific feeding programs with concentrate-based diets developed by Japan and Korea are described in this article.