Effect of fumaric acid in combination with Asparagopsis taxiformis or nitrate on in vitro gas production, pH, and redox potential.

Reduction in enteric methane (CH4) emissions from cattle can be achieved through use of feed additives, which often results in increased emission of hydrogen (H2). The objective of this study was to investigate in vitro effects of a known hydrogen sink, fumaric acid, in combination with either of 2 methane inhibitors, the macroalga Asparagopsis taxiformis or nitrate, on CH4 and H2 production, feed degradability, pH, and redox potential. A corn silage (0.5 g; control) was incubated in buffered rumen fluid with the addition of 0.025 g of nitrate (Nit), 0.025 g of dried A. taxiformis (Asp), 0.025 g of nitrate + 0.025 g of fumaric acid (Nit+Fum), or 0.025 g of dried A. taxiformis + 0.025 g of fumaric acid (Asp+Fum). Accumulated gas production was determined using the AnkomRF system equipped with airtight gasbags. There were 9 replicates per treatment with 3 replicates per treatment stopped after 24, 36, and 48 h of incubation. The amount of undegraded feed was determined by filtration. Gas composition was determined by gas chromatography. Degradable dry matter, degradable organic matter, pH, redox potential, and gas production data were analyzed using a mixed model. Asp and Asp+Fum reduced CH4 production by 98% or greater at all incubation times, whereas Nit and Nit+Fum reduced CH4 production (mL of CH4/g of dry matter) by 52% to 63% compared with the control. Hydrogen was only detectable in gas from Asp and Asp+Fum treatments, with no difference in H2 production between the 2 treatments. The treatments had only minor effects on redox potential in the fermented rumen fluid, and pH was lowest for treatments including A. taxiformis. In conclusion, both A. taxiformis and nitrate reduced CH4 production. Fumaric acid in combination with A. taxiformis did not reduce H2 production, and treatments including nitrate did not result in any detectable levels of H2. Future dose-response in vitro studies will contribute to investigating the potential of fumaric acid as a hydrogen sink during CH4 mitigation.

Effects of dietary inclusion of 3 Nordic brown macroalgae on enteric methane emission and productivity of dairy cows.

Macroalgae are receiving increased attention as antimethanogenic feed additives for cattle, but most in vivo studies are limited to investigating effects of the red macroalgae Asparagopsis spp. Hence, this study aimed to investigate the CH4 mitigating potential of 3 brown macroalgae from the Northern Hemisphere when fed to dairy cows, and to study the effects on feed intake, milk production, feed digestibility, and animal health indicators. The experiment was conducted as a 4 × 4 Latin square design using 4 lactating rumen, duodenal, and ileal cannulated Danish Holstein dairy cows. The cows were fed a total mixed ration (TMR) without any macroalgae or the same TMR diluted with, on a dry matter basis, either 4% ensiled Saccharina latissima, 4% Ascophyllum nodosum (NOD), or 2% Sargassum muticum (MUT). Each period consisted of 14 d of adaptation, 3 d of digesta and blood sampling, and 4 d of gas exchange measurements using respiration chambers. Milk yield and dry matter intake (DMI) were recorded daily. Blood was sampled on d 13 and 16 and analyzed for health status indicators. None of the 3 species affected the CH4 emission. Moreover, milk yield and DMI were also unaffected. Total-tract digestibility of crude protein was significantly lower for NOD compared with other diets, and additionally, the NOD diet also tended to reduce total-tract digestibility of neutral detergent fiber compared with MUT. Blood biomarkers did not indicate negative effects of the dietary inclusion of macroalgae on cow health. In conclusion, none of the 3 brown macroalgae reduced CH4 emission and did not affect DMI and milk production of dairy cows, whereas negative effects on the digestibility of nutrients were observed when A. nodosum was added. None of the diets would be allowed to be fed in commercial dairy herds due to high contents of iodine, cadmium, and arsenic.

EPA guidance on treatment of negative symptoms in schizophrenia.

Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms.However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms.

EPA guidance on assessment of negative symptoms in schizophrenia.

BACKGROUND: During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent. METHODS: In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice. RESULTS: Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings.This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use second-generation scales, at least to complement first-generation ones.The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment.Several recommendations are provided for the identification of secondary negative symptoms in clinical settings. CONCLUSIONS: The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia.

Effects of alternative feed additives to medicinal zinc oxide on productivity, diarrhoea incidence and gut development in weaned piglets.

The use of medicinal zinc oxide (ZnO) must be phased out by 2022, thus prompting an urgent need for alternative strategies to prevent diarrhoea in weaner piglets. The objectives of this study were to assess the impact on weaner piglet performance, diarrhoea incidence and gut development, when (1) dietary ZnO supplementation was substituted by alternative commercial products based on macroalgae, specific probiotics or synbiotics, or (2) dietary ZnO inclusion was reduced from 2500 to 1500 ppm. A total of 4680 DLY piglets (DanBred, Herlev, Denmark), weaned around 35 days of age, were randomly assigned according to sex and BW to six different dietary treatment groups. A basal diet was supplemented with no ZnO (NC = negative control), 2500 ppm ZnO (PC = positive control), 1500 ppm ZnO (RDZ = reduced dose of ZnO) or commercial macroalgae (OceanFeed™ Swine = OFS), probiotic Miya-Gold or synbiotic GærPlus products. The piglets entered and exited the weaner unit at ~7.0 and 30 kg BW, respectively. In-feed ZnO was provided the first 10 days post-weaning, while the alternative supplements were fed throughout the weaner period. As expected, the average daily feed intake, average daily weight gain (ADG), feed conversion ratio (FCR) and diarrhoea incidence were improved in the PC compared to NC group (P < 0.05) during phase 1 consistent with improved indices of villi development observed in subgroups of piglets sacrificed 11 days post-weaning. Reduction of ZnO to 1500 ppm lowered ADG (P < 0.05) and slightly increased incidence of diarrhoea during the first 10 days after weaning (but not later) without affecting FCR. None of the three alternative dietary additives, including a 10-fold increased dose of GærPlus than recommended, improved piglet performance, gut health and gut development above that of NC piglets. The OFS piglets sacrificed 11 days after weaning had significantly lower weights of hindgut tissue and contents compared to the PC group, consistent with antimicrobial activity of the product, which was detected from anaerobic in vitro fermentation. In conclusion, dietary ZnO supplementation during the first 10 days post-weaning may be reduced from 2500 to 1500 ppm without major negative implications for weaner piglet performance and health in herds under a high management level. However, none of the alternative dietary supplements were able to improve piglet performance or gut health, when ZnO was omitted from the diet.

Short-term safety of preoperative administration of botulinum toxin A for the treatment of large ventral hernia with loss of domain.

PURPOSE: Preoperative intramuscular-administered botulinum toxin A (BTA) in the lateral abdominal muscles prior to abdominal wall reconstruction has been reported to produce a flaccid paralysis and improve the primary closure rate of large ventral hernias with loss of domain. Complications to this treatment remain sparsely described. The aim of the current study was to report safety and short-term outcome of abdominal wall reconstruction aided by BTA administration. METHODS: This was a retrospective two-center study including all patients undergoing abdominal wall reconstruction for ventral hernia aided by preoperative BTA administration to the lateral abdominal muscles. Data were retrieved from patient charts and included preoperative demographic and perioperative information as well as postoperative 30-day complications and readmissions. RESULTS: A total of 37 patients underwent BTA administration prior to hernia repair. The mean age and body mass index were 59.5 (SD 10.1) years and 31.1 (SD 5.2) kg/m2. The BTA injections were administered mean 31.6 days (SD 10.0) prior to the hernia repair. One (2.7%) patient reported pain as a complication immediately after the BTA administration. Subsequent to the hernia repair, six (16.2%) patients were readmitted within 30 days. Nine patients (24.3%) had wound complications and medical complications occurred in seven (18.9%) patients. CONCLUSIONS: We found early preoperative administration of BTA a safe adjunct to large ventral hernia repair, without adverse events related to the administration preoperative. Future studies should further highlight the efficacy of preoperative BTA for reconstruction of otherwise untreatable hernias.

Short communication: Relationship between body condition score and plasma adipokines in early-lactating Holstein dairy cows.

We hypothesized that plasma adipokine concentrations of early-lactation dairy cows are related to body condition score (BCS) at calving and to markers of metabolic status of the cow. As part of a larger study with 117 multiparous Holstein dairy cows, which had high BCS (BCS >4.0) or normal BCS (3.25-3.5) at calving, 22 cows were randomly selected (n = 11 per group) to be enrolled in this study. Cows were divided into 2 groups based on their BCS at calving: (1) normal BCS with BCS of 3.35 ± 0.13 (mean ± SD) and (2) high BCS cows with BCS of 4.14 ± 0.17. The 22 selected animals did not have a clinically diagnosed health problem after calving. Blood samples were taken right after calving (d 1) and before morning feeding on d 8, 15, and 21 postpartum concurrently with body condition scoring for all cows. Blood samples were analyzed for plasma adiponectin, leptin, tumor necrosis factor-α, and IL-6. The mean BCS remained highest in high-BCS cows during the first 21 d in milk. Leptin concentrations decreased progressively for all cows after calving. However, differences in BCS at calving were not related to leptin concentrations. Adiponectin, IL-6, and tumor necrosis factor-α concentrations were neither influenced by days in milk nor BCS after calving. Leptin and the leptin-to-adiponectin ratio did not show any correlation at any time point during the first 21 d in milk with plasma concentrations of nonesterified fatty acids or ß-hydroxybutyrate, which are considered as markers of metabolic status. Only for IL-6 at d 8 did we find a strong correlation with metabolic status indicators. In conclusion, plasma adipokine concentrations during the first 3 wk postpartum were not related to BCS in lactating Holstein cows that were clinically healthy at calving.

Fetal over- and undernutrition differentially program thyroid axis adaptability in adult sheep.

OBJECTIVE: We aimed to test, whether fetal under- or overnutrition differentially program the thyroid axis with lasting effects on energy metabolism, and if early-life postnatal overnutrition modulates implications of prenatal programming. DESIGN: Twin-pregnant sheep (n = 36) were either adequately (NORM), under- (LOW; 50% of NORM) or overnourished (HIGH; 150% of energy and 110% of protein requirements) in the last-trimester of gestation. From 3 days-of-age to 6 months-of-age, twin lambs received a conventional (CONV) or an obesogenic, high-carbohydrate high-fat (HCHF) diet. Subgroups were slaughtered at 6-months-of-age. Remaining lambs were fed a low-fat diet until 2½ years-of-age (adulthood). METHODS: Serum hormone levels were determined at 6 months- and 2½ years-of-age. At 2½ years-of-age, feed intake capacity (intake over 4-h following 72-h fasting) was determined, and an intravenous thyroxine tolerance test (iTTT) was performed, including measurements of heart rate, rectal temperature and energy expenditure (EE). RESULTS: In the iTTT, the LOW and nutritionally mismatched NORM:HCHF and HIGH:CONV sheep increased serum T3, T3:T4 and T3:TSH less than NORM:CONV, whereas TSH was decreased less in HIGH, NORM:HCHF and LOW:HCHF. Early postnatal exposure to the HCHF diet decreased basal adult EE in NORM and HIGH, but not LOW, and increased adult feed intake capacity in NORM and LOW, but not HIGH.Conclusions: The iTTT revealed a differential programming of central and peripheral HPT axis function in response to late fetal malnutrition and an early postnatal obesogenic diet, with long-term implications for adult HPT axis adaptability and associated consequences for adiposity risk.

Evaluation of the feeding value of Dichrostachys cinerea pods for fattening pigs in Cuba.

Dichrostachys cinerea (L.) Wight & Arn. is a tropical leguminous shrub widely regarded as an invasive species in Cuba, after having invaded a significant proportion of its arable land during the past decades. Concurrently, smallholder pig producers are highly constrained by the scarcity of protein feeds. This study aimed to assess the feeding value of D. cinerea pod meal (DCPM) as an alternative protein supplement for pigs in Cuban smallholder production systems. An on-farm feeding trial was carried out with three groups (N = 10) of growing-fattening pigs over 60 days, where DCPM replaced 0, 15, and 30% in DM of a dietary commercial concentrate. Then, in an in vivo digestibility trial with eight growing pigs, apparent digestibilities of DCPM were determined for dry matter (DM), organic matter (OM) and crude protein (CP). Finally, in vitro digestibilities for OM (fecal and ileal) and CP (ileal) were determined. In the feeding trial, pig body weight gains were not affected by increased dietary substitution levels of concentrate for DCPM. Blood parameters, with a few exceptions, did not show significant differences among groups. Values for in vivo OM and CP digestibilities were 40.81 and 50.26%, and substantially higher than in vitro values. In conclusion, our results showed that at least 30% of DM in commercial concentrate could be substituted by DCPM without affecting pig growth performances under Cuban smallholder conditions. The low digestibility of DCPM is, however, not acceptable for intensive pig production systems. In vitro enzyme digestibility methods developed for commercial pig feeds are not suitable for DCPM without further calibration.

Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology.

Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.

Differential hypothalamic leptin sensitivity in obese rat offspring exposed to maternal and postnatal intake of chocolate and soft drink.

BACKGROUND/OBJECTIVE: Intake of high-energy foods and maternal nutrient overload increases the risk of metabolic diseases in the progeny such as obesity and diabetes. We hypothesized that maternal and postnatal intake of chocolate and soft drink will affect leptin sensitivity and hypothalamic astrocyte morphology in adult rat offspring. METHODS: Pregnant Sprague-Dawley rats were fed ad libitum chow diet only (C) or with chocolate and high sucrose soft drink supplement (S). At birth, litter size was adjusted into 10 male offspring per mother. After weaning, offspring from both dietary groups were assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age. RESULTS: As expected, adult offspring fed the S diet post weaning became obese (body weight: P<0.01, %body fat per kg: P<0.001) and this was due to the reduced energy expenditure (P<0.05) and hypothalamic astrogliosis (P<0.001) irrespective of maternal diet. Interesting, offspring born to S-diet-fed mothers and fed the S diet throughout postnatal life became obese despite lower energy intake than controls (P<0.05). These SS offspring showed increased feed efficiency (P<0.001) and reduced fasting pSTAT3 activity (P<0.05) in arcuate nucleus (ARC) compared with other groups. The findings indicated that the combination of the maternal and postnatal S-diet exposure induced persistent changes in leptin signalling, hence affecting energy balance. Thus, appetite regulation was more sensitive to the effect of leptin than energy expenditure, suggesting differential programming of leptin sensitivity in ARC in SS offspring. Effects of the maternal S diet were normalized when offspring were fed a chow diet after weaning. CONCLUSIONS: Maternal intake of chocolate and soft drink had long-term consequences for the metabolic phenotype in the offspring if they continued on the S diet in postnatal life. These offspring displayed obesity despite lowered energy intake associated with alterations in hypothalamic leptin signalling.

Differential metabolic and endocrine adaptations in llamas, sheep, and goats fed high- and low-protein grass-based diets.

This study aimed to elucidate whether distinct endocrine and metabolic adaptations provide llamas superior ability to adapt to low protein content grass-based diets as compared with the true ruminants. Eighteen adult, nonpregnant females (6 llamas, 6 goats, and 6 sheep) were fed either green grass hay with (HP) or grass seed straw (LP) in a cross-over design experiment over 2 periods of 21 d. Blood samples were taken on day 21 in each period at -30, 60, 150, and 240 min after feeding the morning meal and analyzed for plasma contents of glucose, triglyceride, nonesterified fatty acids, ß-hydroxy butyrate (BOHB), urea, creatinine, insulin, and leptin. Results showed that llamas vs sheep and goats had higher plasma concentrations of glucose (7.1 vs 3.5 and 3.6 ± 0.18 mmol/L), creatinine (209 vs 110 and 103 ± 10 µmol/L), and urea (6.7 vs 5.6 and 4.9 ± 0.5 mmol/L) but lower leptin (0.33 vs 1.49 and 1.05 ± 0.1 ng/mL) and BOHB (0.05 vs 0.26 and 0.12 ± 0.02 mmol/L), respectively. BOHB in llamas was extremely low for a ruminating animal. Llamas showed that hyperglycemia coexisted with hyperinsulinemia (in general on the HP diet; postprandially on the LP diet). Llamas were clearly hypercreatinemic compared with the true ruminants, which became further exacerbated on the LP diet, where they also sustained plasma urea at markedly higher concentrations. However, llamas had markedly lower leptin concentrations than the true ruminants. In conclusion, llamas appear to have an intrinsic insulin resistant phenotype. Augmentation of creatinine and sustenance of elevated plasma urea concentrations in llamas when fed the LP diet must reflect distinct metabolic adaptations of intermediary protein and/or nitrogen metabolism, not observed in the true ruminants. These features can contribute to explain lower metabolic rates in llamas compared with the true ruminants, which must improve the chances of survival on low protein content diets.

Inhibition of local blood flow control systems in the mammary glands of lactating cows affects uptakes of energy metabolites from blood.

To test the effect of mammary blood flow on net uptakes of milk precursors by the mammary glands, inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX) were infused into the mammary circulation of 4 lactating cows. Inhibitors were infused in a 4×4 Latin square design, where treatments were infusion for 1 h of saline, NOS inhibitor (Nω-nitro-l-arginine methyl ester hydrochloride), COX inhibitor (indomethacin), or both NOS + COX inhibitors into one external iliac artery. Para-aminohippuric acid was also infused to allow for estimation of iliac plasma flow (IPF), of which approximately 80% flows to the mammary glands. Blood samples were collected before, during, and after inhibitor infusion from the contralateral external iliac artery and ipsilateral mammary vein. Inhibition of COX and NOS each produced a decrease in IPF, although the NOS effect was smaller and IPF continued to be depressed throughout the recovery period. The combination of COX and NOS inhibition produced a 50% depression in IPF and there was no carryover into the recovery period. Treatments that depressed IPF also increased arterial concentrations of acetate, ß-hydroxybutyrate (BHBA), and glucose. Similarly, arteriovenous differences of acetate, BHBA, and glucose were all increased during IPF depression. To correct for a potential effect of arterial concentration, arteriovenous differences were normalized to arterial concentration, producing an extraction percentage. Inhibition of COX increased glucose extraction and tended to increase acetate and BHBA extraction. Dual inhibition only increased BHBA extraction and had no effect on mammary extraction of other metabolites. These extractions did not increase because clearances of glucose and TAG decreased as IPF decreased, and clearances of acetate and BHBA tended to decrease. Net uptake of TAG was depressed by dual NOS/COX inhibition, whereas uptakes of acetate, BHBA, and glucose were not affected by any of the treatments. To separate effects of flow from effects of arterial concentration, uptakes were regressed against IPF and arterial concentration simultaneously. According to the slopes of the regressions, a 10% decrease in IPF from the mean observed during saline infusion resulted in 3.8, 7.3, and 10.4% decreases in uptakes of acetate, glucose, and triacylglycerol, respectively. These findings indicate that mammary blood flow affects milk precursor uptake, and that clearance should not be assumed constant to predict mammary uptakes of milk precursors in situations where blood flow is changing.

Late gestation under- and overnutrition have differential impacts when combined with a post-natal obesogenic diet on glucose-lactate-insulin adaptations during metabolic challenges in adolescent sheep.

AIM: To determine whether late gestation under- and overnutrition programme metabolic plasticity in a similar way, and whether metabolic responses to an obesogenic diet in early post-natal life depend on the foetal nutrition history. METHODS: In a 3 × 2 factorial design, twin-pregnant ewes were for the last 6 weeks of gestation (term = 147 days) assigned to HIGH (N = 13; 150 and 110% of energy and protein requirements, respectively), NORM (N = 9; 100% of requirements) or LOW (N = 14; 50% of requirements) diets. The twin offspring were raised on high-carbohydrate-high-fat (HCHF; N = 35) or conventional (CONV; N = 35) diets from 3 days to 6 months of age (around puberty). Then intravenous glucose (GTT; overnight fasted), insulin (ITT; fed) and propionate (gluconeogenetic precursor; PTT; both fed and fasted) tolerance tests were conducted to evaluate (hepatic) metabolic plasticity. RESULTS: Prenatal malnutrition differentially impacted adaptations of particularly plasma lactate followed by glucose, cholesterol and insulin. This was most clearly expressed during PTT in fasted lambs and much less during ITT and GTT. In fasted lambs, propionate induced more dramatic increases in lactate than glucose, and HIGH lambs became more hyperglycaemic, hyperlactataemic and secreted less insulin compared to the hypercholesterolaemic LOW lambs. Propionate-induced insulin secretion was virtually abolished in fasted HCHF lambs, but upregulated in fasted compared to fed CONV lambs. HCHF lambs had the greatest glucose-induced insulin secretory responses. CONCLUSION: Prenatal malnutrition differentially programmed glucose-lactate metabolic pathways and cholesterol homeostasis. Prenatal overnutrition predisposed for hyperglycaemia and hyperlactataemia, whereas undernutrition predisposed for hypercholesterolaemia upon exposure to an obesogenic diet. Prenatal overnutrition (not undernutrition) interfered with pancreatic insulin secretion by non-glucose-dependent mechanisms.

Milk production response to varying protein supply is independent of forage digestibility in dairy cows.

The aim of this experiment was to examine whether the positive response in milk production to increased crude protein (CP) supply in dairy cows was dependent on the digestibility of the forage. Forty-eight lactating Danish Holstein cows were used in a 4 × 4 Latin square design experiment with 4 rations: (1) high digestibility and high CP concentration (HdHp), (2) high digestibility and low CP concentration (HdLp), (3) low digestibility and high CP concentration (LdHp), and (4) low digestibility and low CP concentration (LdLp). All rations contained 30% corn silage, 25% grass-clover silage, and 45% concentrate on a dry matter (DM) basis. Different digestibilities were obtained by replacing a high-digestible grass-clover silage combined with a high-digestible corn silage with a low-digestible grass-clover silage combined with a low-digestible corn silage. Organic matter digestibilities were 79.8 and 74.7% in the high- and low-digestibility rations, respectively. Dietary CP concentration in the ration was increased by substituting barley and sugar beet pulp with rapeseed meal and soybean meal, whereby CP increased from 13.9 to 14.0% (Lp) to 15.7 to 16.0% (Hp). All cows were offered 3 kg of the same concentrate per day in the automatic milking system in addition to the mixed ration. Every feeding period lasted 3 wk, and DM intake and milk yield were measured in the last week in each period, and milk samples for determining milk composition, including fatty acid content, and blood samples were taken during the last 3d of each period. Dry matter intake increased by 2.2 kg/d on Hd compared with Ld and by 0.7 kg/d on Hp compared with Lp. The positive effect on DM intake was reflected in the energy-corrected milk (ECM) yield, as a higher ration digestibility increased the ECM yield by 1.7 kg/d and a higher CP concentration increased it by 1.2 kg/d. We detected no interaction between forage digestibility and CP concentration on milk production. Reduced digestibility was accompanied by an increase in the plasma level of glucose, suggesting that other nutrients were limiting to milk production. In conclusion, milk production responses to dietary CP supply appeared independent of forage digestibility.

Pre-natal undernutrition and post-natal overnutrition are associated with permanent changes in hepatic metabolism markers and fatty acid composition in sheep.

AIM: Determine the impacts of pre- and early-post-natal nutrition on selected markers of hepatic glucose and fat metabolism. METHODS: Twin-bearing ewes were fed 100% (NORM) or 50% (LOW) of protein and energy requirements during the last 6-weeks of gestation. Twin-lambs received either a high-carbohydrate high-fat (HCHF) or conventional (CONV) diet from 3 days to 6 months of age (around puberty), whereafter lambs from the four subgroups were slaughtered (16 males/3 females). Remaining lambs (19 females) were fed a moderate diet and slaughtered at 2 years of age (young adults). RESULTS: Pre-natal LOW nutrition was associated with increased hepatic triglyceride, ceramide and free fatty acid content in adulthood (not observed in lambs), which was accompanied by up-regulated early-stage insulin signalling as reflected by increased INSRß and PI3K-p110 protein expression. The HCHF diet increased hepatic triglyceride content in lambs, associated with down-regulated expressions of energy-metabolism-related genes (GLUT1, PPARα, SREBP1c, PEPCK). These post-natal effects were not observed in adult HCHF sheep, after they had received a moderate (body-fat correcting) diet for 1.5 years. Interestingly, pre-natal LOW nutrition induced permanent alterations in hepatic phospholipids' fatty acid composition. Thus, the amount of linoleic acid (C18 : 2 ∆(9,12)) was significantly increased and composition of rumen-derived fatty acids were altered, indicating changed composition of rumenal microbiota. CONCLUSION: Hepatic insulin signalling and linoleic and microbial-derived fatty acid content in phospholipids are targets of foetal programming induced by late-gestation undernutrition. Future studies are required to explain their cause-effect associations with increased risks of developing hepatic steatosis and insulin insensitivity in adulthood.

Late gestation over- and undernutrition predispose for visceral adiposity in response to a post-natal obesogenic diet, but with differential impacts on glucose-insulin adaptations during fasting in lambs.

AIM: To investigate if late gestation under- or overnutrition has similar adverse impacts on visceral adiposity, metabolic and endocrine function in sheep, and if subsequent exposure to a high-fat diet in early post-natal life exaggerates the prenatal programming outcomes later in life. METHODS: Thirty-six twin-pregnant ewes were fed a NORM (fulfilling 100% of daily requirements for energy and protein), LOW (50% of NORM) or HIGH diet (150% of energy and 110% of protein requirements) during the last 6 weeks of gestation (term = 147 days). Post-natally, the twin lambs were subjected to a high-fat or a moderate diet until 6 months of age (around puberty), where metabolic and endocrine adaptability to fasting was examined, and subgroups of animals were killed. RESULTS: Animals exposed to either prenatal under- or overnutrition had reduced subcutaneous fat deposition when fed a high-fat diet, resulting in higher ratios of mesenteric and peri-renal fat relative to subcutaneous fat compared to controls. This was not related to prenatal influences on plasma glucose or insulin. Irrespective of the prenatal diet, high-fat-fed lambs underwent changes resembling the metabolic syndrome with higher plasma glucose, cholesterol, non-esterified fatty acids, triglyceride and lactate combined with abdominal obesity. Peri-renal fat appeared to be a particular target of a high-fat diet post-natally. CONCLUSION: Both prenatal under- and overnutrition predisposed for abdominal adiposity, apparently by reducing the expandability of subcutaneous adipose tissue and induced differential physiological adaptations to fasting. This study does not suggest that exposure to gestational overnutrition will provide a protective effect against development of hyperglycaemia later in life.

Maternal chocolate and sucrose soft drink intake induces hepatic steatosis in rat offspring associated with altered lipid gene expression profile.

AIM: According to the World Diabetes Foundation, there is an urgent need to investigate the impact of maternal health and nutrition during pregnancy to understand the background for the accelerating incidence of obesity and type 2 diabetes. In this study, we specifically concentrated on the role of overfeeding during different developmental periods. METHODS: Sprague-Dawley rats were offered chow or high-fat/high-sucrose diet (chow plus chocolate and soft drink) during gestation and lactation. At birth, offspring were randomly cross-fostered within each dietary group into small and normal litter sizes until weaning, giving four dietary groups. RESULTS: At postnatal day 1, offspring from high-fat/high-sucrose-fed dams were heavier and had increased hepatic triglycerides (TG), hepatic glycogen, blood glucose and plasma insulin compared with offspring from chow-fed dams. Hepatic genes involved in lipid oxidation, VLDL transport and insulin receptor were down-regulated, whereas FGF21 expression was up-regulated. Independent of postnatal litter size, offspring from high-fat/high-sucrose-fed dams aged 21 days had still increased hepatic TG and up-regulated FGF21 expression, while plasma insulin started to decrease. Litter size reduction in offspring from high-fat/high-sucrose-fed dams further increased body weight and adiposity, and up-regulated genes involved in hepatic mitochondrial lipid oxidation and VLDL transport compared with all other groups. Litter size reduction did not have any impact on body weight gain and adiposity in offspring born to chow-fed dams. CONCLUSION: Our results suggest that supplementation of chocolate and soft drink during gestation and lactation contributes to early onset of hepatic steatosis associated with changes in hepatic gene expression and lipid handling.

Programming of glucose-insulin homoeostasis: long-term consequences of pre-natal versus early post-natal nutrition insults. Evidence from a sheep model.

AIM: Exposure to adverse intra-uterine conditions can predispose for metabolic disorders later in life. By using a sheep model, we studied (i) how programming of glucose-insulin homoeostasis during late gestation is manifested later in life depending on the early post-natal dietary exposure and (ii) whether dietary alteration in obese individuals can prevent adverse outcomes of early life programming. METHODS: During late gestation, twin-pregnant sheep were fed 100% (NORM) or 50% (LOW) of energy and protein requirements. After birth, offspring were exposed to a moderate (CONV) or high-carbohydrate-high-fat (HCHF) diet until around puberty. Offspring remaining thereafter (exclusively females) were fed a moderate diet until young adulthood. RESULTS: LOW lambs had increased insulin secretory responses during intravenous glucose tolerance tests indicative of reduced insulin sensitivity. HCHF lambs were hypertriglyceridaemic, 75% had mild pancreatic collagen infiltration, and their acute insulin secretory response and insulin clearance during intravenous glucose and insulin tolerance tests, respectively, were reduced. However, NORM-HCHF in contrast to LOW-HCHF lambs had normal glucose tolerance, indicating that later health outcomes are highly influenced by pre-natal nutrition. Dietary alteration normalized glucose-insulin homoeostasis in adult HCHF females, whereas late-gestation undernutrition (LOW) permanently depressed insulin sensitivity. CONCLUSION: Maintenance of glucose tolerance in sheep exposed to pre-natal undernutrition relied on pancreatic hypersecretion of insulin to compensate for reduced insulin sensitivity. A mismatching high-fat diet in early post-natal life interfered with this pancreatic hypersecretion resulting in reduced glucose tolerance. Early post-natal, but not late pre-natal, impacts on glucose-insulin homoeostasis could be reversed by dietary correction later in life.

Prenatal undernutrition and postnatal overnutrition alter thyroid hormone axis function in sheep.

Mounting evidence led us to hypothesize that i) function of the thyroid hormone (TH) axis can be programed by late gestation undernutrition (LG-UN) and ii) early-postnatal-life overnutrition (EL-ON) exacerbates the fetal impacts on TH axis function. In a 2 × 2 factorial experiment, 21 twin-bearing sheep were fed one of two diets during late gestation: NORM (fulfilling energy and protein requirements) or LOW (50% of NORM). From day 3 to 6 months after birth (around puberty), the twin lambs were assigned to each their diet: conventional (CONV) or high-carbohydrate, high-fat, where after half the lambs were killed. Remaining sheep (exclusively females) were fed the same moderate diet until 2 years of age (young adults). At 6 months and 2 years of age, fasting challenges were conducted and target tissues were collected at autopsy. LG-UN caused adult hyperthyroidism associated with increased thyroid expression of genes regulating TH synthesis and deiodination. In one or more of the target tissues, liver, cardiac muscle, and longissimus dorsi muscle, gene expressions were increased by LG-UN for TH receptors (THRA and THRB) and deiodinases but were decreased in visceral and subcutaneous adipose tissues. EL-ON increased TH levels in adolescent lambs, but this was reversed after diet correction and not evident in adulthood. We conclude that LG-UN programed TH axis function at the secretory level and differentially in target tissues, which was increasingly manifested with age. Differential TH signaling in adipose vs other tissues may be part of a mechanism whereby fetal malnutrition can predispose for obesity and other metabolic disorders.