Fat from Hermetia illucens Alters the Cecal Gut Microbiome and Lowers Hepatic Triglyceride Concentration in Comparison to Palm Oil in Obese Zucker Rats.

BACKGROUND: Palm oil (PO) is the most widely utilized plant oil for food production. Owing to the great ecologic problems associated with PO production, sustainably produced fats, such as insect fat, might be a suitable alternative. OBJECTIVES: The hypothesis was tested that fat from Hermetia illucens larvae (HF) compared with PO and soybean oil (SO) has no adverse effects on hepatic lipid metabolism, plasma metabolome, and cecal microbiome in obese Zucker rats. METHODS: Thirty male obese Zucker rats were randomly assigned to 3 groups (SO, PO, HF; n = 10 rats/group) and fed 3 different semisynthetic diets containing either SO, PO, or HF as the main fat source for 4 wk. The effects were evaluated by measurement of liver and plasma lipid concentrations, liver transcriptomics, targeted plasma metabolomics, and cecal microbiomics. RESULTS: Supplementation of HF reduced hepatic triglyceride concentration and messenger ribonucleic acid concentrations of selected genes involved in fatty acid and triglyceride synthesis in comparison to PO (P < 0.05). Pairwise comparison of the Simpson index and Jaccard index showed a higher cecal microbial α- and ß-diversity in rats fed the HF diet than in rats fed the PO diet (P = 0.015 and P = 0.027), but no difference between rats fed the diets with SO or PO. Taxonomic analysis of the cecal microbial community revealed a lower abundance of Clostridium_sensu_stricto_1 and a higher abundance of Blautia, Mucispirillum, Anaerotruncus, Harryflintia, and Peptococcus in rats supplemented with HF than in rats supplemented with PO (P < 0.05). CONCLUSIONS: HF, compared with PO, has liver lipid-lowering effects in obese Zucker rats, which may be caused by a shift in the gut microbial community. Thus, HF might serve as a sustainably produced fat alternative to PO for food production.

Effect of dietary phosphorus deprivation during the dry period on the liver transcriptome of high-yielding periparturient dairy cows.

Although dietary phosphorus (P) deprivation extending from the dry period into early lactation impairs health and productivity of cows, restricting dietary P supply during the dry period not only appears to be innocuous but rather effectively mitigates hypocalcemia during the first wk of lactation. To investigate possible negative metabolic effects of P deprivation during the dry period, the present study tested the hypothesis that restricted dietary P supply during the dry period alters the liver transcriptome of dairy cows during the periparturient period. Thirty late-pregnant multiparous Holstein-Friesian dairy cows entering their second, third, or fourth lactation were assigned to either a dry cow ration with low (LP, 0.16% P in DM) or adequate P content (AP, 0.35% in DM) during the last 4 wk of the dry period (n = 15/group). Liver transcriptomics, which was carried out in a subset of 5 second-parity cows of each group (n = 5), and determination of selected hormones and metabolites in blood of all cows, was performed ∼1 wk before calving and on d 3 postpartum. Liver tissue specimens and blood samples were obtained by a micro-invasive biopsy technique from the right tenth intercostal space and puncture of a jugular vein, respectively. One hundred seventy-five hepatic transcripts were expressed differentially between LP versus AP cows in late pregnancy, and 165 transcripts differed between LP versus AP cows in early lactation (fold change >1.3 and <-1.3, P < 0.05). In late pregnancy, the enriched biological processes of the upregulated and the downregulated transcripts were mainly related to immune processes and signal transduction (P < 0.05), respectively. In early lactation, the enriched biological processes of the upregulated and the downregulated transcripts were involved in mineral transport and biotransformation (P < 0.05), respectively. The plasma concentrations of the hormones and acute-phase proteins (progesterone, insulin-like growth factor 1, serum amyloid α, haptoglobin, and 17ß-estradiol) determined were not affected by P supply. These results suggest that P deprivation during the dry period moderately affects the liver transcriptome of cows in late pregnancy and early lactation, and causes no effects on important plasma hormones and acute-phase proteins indicating no obvious impairment of health or metabolism of the cows.

Replacement of soybean oil by Hermetia illucens larvae fat in broiler diets alters the breast muscle lipidome and reduces lipid oxidation of the breast muscle during heat-processing.

Replacement of soybean oil by insect fat from Hermetia illucens (HI) has been reported to increase the proportions of saturated fatty acids (SFA) and decrease those of polyunsaturated fatty acids (PUFA) in total lipids of breast and thigh meat in broilers. Since the susceptibility of meat to oxidation is strongly dependent on its PUFA content, the present study hypothesised that replacement of soybean oil by HI larvae fat in broiler diets reduces the formation of lipid oxidation products, including oxidation products of cholesterol and phytosterols, in heat-processed breast muscle of broilers. To test this hypothesis, 100 male, 1-day-old Cobb 500 broilers were assigned to three groups and fed three different nutrient adequate diets, which varied only in the fat source (group HI-0: 0% HI larvae fat and 5% soybean oil; group HI-2.5: 2.5% HI larvae fat and 2.5% soybean oil; group HI-5.0: 5.0% HI larvae fat and 0% soybean oil), in a three-phase feeding system for 35 days. While the growth performance of the broilers was not different, the absolute and relative breast muscle weights were higher in group HI-5.0 than in group HI-0 (p < 0.05). The proportions of C12:0, C14:0, C14:1, C16:0, C16:1 and total SFA were higher and those of C18:1, C18:2 n-6, C18:3 n-3 and total PUFA were lower in breast muscle total lipids of group HI-5.0 than in groups HI-2.5 and HI-0 (p < 0.05). Lipidomic analysis of breast muscle revealed that the concentration of triacylglycerols was 46% and 53% lower in groups HI-2.5 and HI-5.0, respectively, than in group HI-0 (p < 0.05), whereas all other lipid classes detected did not differ among groups. Concentrations of thiobarbituric acid-reactive substances, 7α-hydroxycholesterol, 7ß-hydroxycholesterol and total cholesterol oxidation products in heat-processed breast muscle were lower in group HI-5.0 than in group HI-0 (p < 0.05). Concentrations of oxidation products of phytosterols in heat-processed breast muscle were generally much lower than those of cholesterol oxidation products and did not differ between the three groups of broilers. In conclusion, complete replacement of soybean oil with HI larvae fat in broiler diets strongly alters the fatty acid composition of breast muscle total lipids and reduce lipid oxidation of the breast muscle during heat-processing.

Inflammation and necrosis syndrome is associated with alterations in blood and metabolism in pigs.

BACKGROUND: Swine inflammation and necrosis syndrome (SINS) can lead to significant clinical alterations at tail, ears, claws and other parts of the body in suckling piglets, weaners and fatteners. Clinical findings are associated with vasculitis, intima proliferation and thrombosis. The syndrome can be found in newborns, indicating a primarily endogenous aetiology. It has been hypothesized that SINS is triggered by gut-derived microbial-associated molecular patterns, causing derangements in liver metabolism and activity of peripheral white blood cells involving inflammation and blood haemostasis. In order to characterize these metabolic derangements of SINS for the first time, red and white blood counts, parameters of blood haemostasis, serum metabolites and acute phase proteins in the serum were analysed in 360 piglets, weaners and fatteners, each with significantly different SINS scores. RESULTS: SINS scores and haematological/clinical chemical parameters were significantly associated (P < 0.05), especially in weaners and fatteners. Higher degrees of clinical SINS were associated with increased numbers of monocytes and neutrophils. Blood coagulation was altered in weaners and a thrombocytopenia was found in fatteners. Additionally, acute phase proteins, especially C-reactive protein and fibrinogen were increased in serum. Serum metabolites and serum liver enzymes were slightly altered. Aspartate transaminase levels overall exceeded physiological limit and increased in parallel with SINS scores in fatteners. CONCLUSION: Clinical inflammation and necrosis at tail, ears, claws and other parts of the body were significantly associated with haematology and serum clinical chemistry, especially in weaners and fatteners. The involvement of inflammatory cells, blood coagulation, acute phase proteins and certain serum metabolites support the inflammatory-necrotising character of the syndrome and provide starting points for further studies to decipher its exact pathogenesis. The low to moderate variations seem less suitable for diagnostic use.

Resveratrol Alleviates the Inhibitory Effect of Tunicamycin-Induced Endoplasmic Reticulum Stress on Expression of Genes Involved in Thyroid Hormone Synthesis in FRTL-5 Thyrocytes.

Recently, ER stress induced by tunicamycin (TM) was reported to inhibit the expression of key genes involved in thyroid hormone synthesis, such as sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), and their regulators such as thyrotropin receptor (TSHR), thyroid transcription factor-1 (TTF-1), thyroid transcription factor-2 (TTF-2) and paired box gene 8 (PAX-8), in FRTL-5 thyrocytes. The present study tested the hypothesis that resveratrol (RSV) alleviates this effect of TM in FRTL-5 cells. While treatment of FRTL-5 cells with TM alone (0.1 µg/mL) for 48 h strongly induced the ER stress-sensitive genes heat shock protein family A member 5 (HSPA5) and DNA damage inducible transcript 3 (DDIT3) and repressed NIS, TPO, TG, TSHR, TTF-1, TTF-2 and PAX-8, combined treatment with TM (0.1 µg/mL) and RSV (10 µM) for 48 h attenuated this effect of TM. In conclusion, RSV alleviates TM-induced ER stress and attenuates the strong impairment of expression of genes involved in thyroid hormone synthesis and their regulators in FRTL-5 thyrocytes exposed to TM-induced ER stress. Thus, RSV may be useful for the treatment of specific thyroid disorders, provided that strategies with improved oral bioavailability of RSV are applied.

Effect of Ecdysterone on the Hepatic Transcriptome and Lipid Metabolism in Lean and Obese Zucker Rats.

Conflicting reports exist with regard to the effect of ecdysterone, the predominating representative of steroid hormones in insects and plants, on hepatic and plasma lipid concentrations in different rodent models of obesity, fatty liver, and diabetes, indicating that the effect is dependent on the rodent model used. Here, the hypothesis was tested for the first time that ecdysterone causes lipid-lowering effects in genetically obese Zucker rats. To test this hypothesis, two groups of male obese Zucker rats (n = 8) were fed a nutrient-adequate diet supplemented without or with 0.5 g ecdysterone per kg diet. To study further if ecdysterone is capable of alleviating the strong lipid-synthetic activity in the liver of obese Zucker rats, the study included also two groups of male lean Zucker rats (n = 8) which also received either the ecdysterone-supplemented or the non-supplemented diet. While hepatic and plasma concentrations of triglycerides and cholesterol were markedly higher in the obese compared to the lean rats (p < 0.05), hepatic and plasma triglyceride and cholesterol concentrations did not differ between rats of the same genotype fed the diets without or with ecdysterone. In conclusion, the present study clearly shows that ecdysterone supplementation does not exhibit lipid-lowering actions in the liver and plasma of lean and obese Zucker rats.

Effect of Tenebrio molitor larvae meal on the antioxidant status and stress response pathways in tissues of growing pigs.

Insect meal (IM) produced from edible insects, such as Tenebrio molitor, has been recognised as a potentially suitable protein component in feeding rations for monogastric livestock. While several studies with broilers have shown that animal´s health is not negatively affected by IM, less is known with regard to the influence of IM on metabolism of pigs. The present study investigates whether IM from Tenebrio molitor larvae causes oxidative stress and activates oxidative stress-sensitive signalling pathways in key metabolic tissues of pigs. To address this question, male 5-week-old crossbred pigs were randomly assigned to three groups of 10 pigs each and fed nutrient-adequate, isonitrogenous diets either without (CON) or with 5% IM or 10% IM from Tenebrio molitor larvae for 4 weeks. Concentrations of thiobarbituric acid reactive substances, tocopherols and glutathione in liver, gastrocnemius muscle and/or plasma did not differ between groups. Activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD) in the liver and of GPX and SOD in gastrocnemius muscle were not different between groups, whereas the activity of CAT in skeletal muscle was increased in the two IM-fed groups compared to group CON (p < 0.05). The mRNA levels of most of the target genes of oxidative stress-sensitive signalling pathways, such as nuclear factor-κB, nuclear factor erythroid 2-related factor 2 and endoplasmic reticulum stress-induced unfolded protein response, in liver and gastrocnemius muscle did not differ between the three groups. The present study shows that feeding a diet containing adequate levels of antioxidants, such as vitamin E and selenium, and Tenebrio molitor larvae meal as a protein component neither causes oxidative stress nor activates oxidative stress-sensitive signalling pathways in key metabolic tissues of growing pigs. Based on these observations, IM from Tenebrio molitor larvae can be regarded as a safe source of protein in growing pigs.

Combined effects of moderate exercise and short-term fasting on markers of immune function in healthy human subjects.

This study aimed to investigate the effects of a short-term (36 h) fasting period combined with an acute bout of exercise on markers of immune function and inflammation in healthy human subjects. Fourteen moderately trained male subjects (aged 19-39 yr) participated in a 36-h fasting trial (FA-T), followed by an acute bout of moderate exercise (60% V̇o2max). After 1 wk, the same subjects, as their own control, participated in a nonfasting trial (NFA-T) in which they performed an exercise trial of the same duration and intensity. Blood samples were taken before, immediately after, and 1 h after each exercise bout and analyzed for several immunological and metabolic markers. At baseline, fasting subjects showed lower levels of T cell apoptosis, lymphocyte-proliferative responses, IL-6, monocyte chemoattractant protein-1 (MCP-1), insulin, and leptin (P < 0.05) as well as higher levels of neutrophil oxidative burst and thiobarbituric acid reactive substances (TBARS) than those in the NFA-T (P < 0.05). After the exercise protocol, fasted subjects revealed higher T cell apoptosis, neutrophil oxidative burst, TBARS, TNFα, and MCP-1 levels as well as lower levels of lymphocyte-proliferative response, IL-6, insulin, and leptin than those in the NFA-T (P < 0.05). Short-term fasting aggravates perturbations in markers of immune function, and inflammation was induced by an acute moderate-intensity exercise protocol.

Insect Meal as Alternative Protein Source Exerts Pronounced Lipid-Lowering Effects in Hyperlipidemic Obese Zucker Rats.

BACKGROUND: Specific dietary proteins exert strong health-related effects compared with casein. OBJECTIVE: Herein, the hypothesis was tested using screening and conventional biochemical and molecular biological techniques that protein-rich insect meal compared with casein influences metabolic health in hyperlipidemic rats. METHODS: A 4-wk feeding trial with male, 8-wk-old homozygous obese Zucker rats (n = 36) and male, 8-wk-old heterozygous lean Zucker rats (n = 12) was performed. Obese rats were randomly divided into 3 obese groups (OC, OI50, and OI100) of 12 rats each and lean rats served as a lean control group (LC). LC and OC were fed a control diet with 20% casein as protein source, whereas in OI50 and OI100 50% and 100% of the casein, respectively, was replaced isonitrogenously by insect meal from Tenebrio molitor L. All data were analyzed by 1-factor ANOVA, except transcriptomic data which were analyzed by groupwise comparisons with the OC group. RESULTS: Transcript profiling revealed a coordinated inhibition by -17% to -521% and -37% to -859% of genes involved in fatty acid, triacylglycerol (TG), and cholesterol biosynthesis in the livers of OI100 and OI50, respectively, compared with OC (P < 0.05). Enzyme activities of fatty acid synthase, glucose-6 phosphate dehydrogenase, and 3-hydroxy-3-methylglutaryl-coenzyme-A reductase in the liver were 100-150% greater in OC compared with LC, but reduced by 50-60% in OI100 compared with OC (P < 0.05), to the same level as in LC. Liver and plasma concentrations of TG and cholesterol were 250-1000%, 30-800%, and 40-600% higher in OC, OI50, and OI100, respectively, than in LC (P < 0.05), but 40-60% and 20-60% lower in OI100 and OI50, respectively, than in group OC (P < 0.05). Plasma and liver concentrations of homocysteine were 20-30% lower in group OI100 than in group OC (P < 0.05). CONCLUSION: Insect meal exerts pronounced lipid-lowering effects in hyperlipidemic rats and, thus, might be useful for hyperlipidemic individuals.

Effect of lifelong carnitine supplementation on plasma and tissue carnitine status, hepatic lipid metabolism and stress signalling pathways and skeletal muscle transcriptome in mice at advanced age.

While strong evidence from clinical studies suggests beneficial effects of carnitine supplementation on metabolic health, serious safety concerns associated with carnitine supplementation have been raised from studies in mice. Considering that the carnitine doses in these mice studies were up to 100 times higher than those used in clinical studies, the present study aimed to address possible safety concerns associated with long-term supplementation of a carnitine dose used in clinical trials. Two groups of NMRI mice were fed either a control or a carnitine-supplemented diet (1 g/kg diet) from weaning to 19 months of age, and parameters of hepatic lipid metabolism and stress signalling and skeletal muscle gene expression were analysed in the mice at 19 months of age. Concentrations of free carnitine and acetylcarnitine in plasma and tissues were higher in the carnitine than in the control group (P<0·05). Plasma concentrations of free carnitine and acetylcarnitine were higher in mice at adult age (10 and 15 months) than at advanced age (19 months) (P<0·05). Hepatic mRNA and protein levels of genes involved in lipid metabolism and stress signalling and hepatic and plasma lipid concentrations did not differ between the carnitine and the control group. Skeletal muscle transcriptome analysis in 19-month-old mice revealed only a moderate regulation between carnitine and control group. Lifelong carnitine supplementation prevents an age-dependent impairment of plasma carnitine status, but safety concerns associated with long-term supplementation of carnitine at doses used in clinical trials can be considered as unfounded.

Exercise training reverses inflammation and muscle wasting after tobacco smoke exposure.

Long-term cigarette smoking induces inflammatory processes in the pulmonary system that are suggested to "spill over" into systemic inflammation. Regular exercise has been shown to have anti-inflammatory properties. The aim of the study was to investigate the effects of therapeutic exercise on inflammation and muscle wasting in smoke-exposed mice. C57BL/6J mice ( n = 30) were separated into three groups to receive either 1) no specific treatment (control group), 2) 8-mo exposure to cigarette smoke [smoke-exposed (SE) group], or 3) 8 mo of cigarette smoke combined with exercise training during the last 2 mo (SEex group). The inflammatory status was analyzed by quantifying levels of various plasma proteins using multiplex ELISA and detection of lymphocyte surface markers by flow cytometry. Muscle tissue was analyzed by histological techniques and measurements of RNA/protein expression. SE led to decreased maximal O2 uptake (V̇o2max) and maximal running speed ( Vmax), which was reversed by exercise ( P < 0.05). Expression of ICAM-1, VCAM-1, and CD62L on T cells increased and was reversed by exercise ( P < 0.05). Similarly, SE induced an increase of various inflammatory cytokines, which were downregulated by exercise. In muscle, exercise improved the structure, oxidative capacity, and metabolism by reducing ubiquitin proteasome system activation, stimulating insulin-like growth factor 1 expression, and the SE-induced inhibition of mammalian target of rapamycin signaling pathway ( P < 0.05). Exercise training reverses smoke-induced decline in exercise capacity, systemic inflammation, and muscle wasting by addressing immune-regulating, anabolic, and metabolic pathways.

Basic mechanisms of the regulation of L-carnitine status in monogastrics and efficacy of L-carnitine as a feed additive in pigs and poultry.

A great number of studies have investigated the potential of L-carnitine as feed additive to improve performance of different monogastric and ruminant livestock species, with, however, discrepant outcomes. In order to understand the reasons for these discrepant outcomes, it is important to consider the determinants of L-carnitine status and how L-carnitine status is regulated in the animal's body. While it is a long-known fact that L-carnitine is endogenously biosynthesized in certain tissues, it was only recently recognized that critical determinants of L-carnitine status, such as intestinal L-carnitine absorption, tissue L-carnitine uptake, endogenous L-carnitine synthesis and renal L-carnitine reabsorption, are regulated by specific nutrient sensing nuclear receptors. This review aims to give a more in-depth understanding of the basic mechanisms of the regulation of L-carnitine status in monogastrics taking into account the most recent evidence on nutrient sensing nuclear receptors and evaluates the efficacy of L-carnitine as feed additive in monogastric livestock by providing an up-to-date overview about studies with L-carnitine supplementation in pigs and poultry.

Regulation of carnitine status in ruminants and efficacy of carnitine supplementation on performance and health aspects of ruminant livestock: a review.

Carnitine has long been known to play a critical role for energy metabolism. Due to this, a large number of studies have been carried out to investigate the potential of supplemental carnitine in improving performance of livestock animals including ruminants, with however largely inconsistent results. An important issue that has to be considered when using carnitine as a feed additive is that the efficacy of supplemental carnitine is probably dependent on the animal's carnitine status, which is affected by endogenous carnitine synthesis, carnitine uptake from the gastrointestinal tract and carnitine excretion. The present review aims to summarise the current knowledge of the regulation of carnitine status and carnitine homeostasis in ruminants, and comprehensively evaluate the efficacy of carnitine supplementation on performance and/or health in ruminant livestock by comparing the outcomes of studies with carnitine supplementation in dairy cattle, growing and finishing cattle and sheep. While most of the studies show that supplemental carnitine, even in ruminally unprotected form, is bioavailable in ruminants, its effect on either milk or growth performance is largely disappointing. However, supplemental carnitine appears to be a useful strategy to offer protection against ammonia toxicity caused by consumption of high levels of non-protein N or forages with high levels of soluble N both, in cattle and sheep.

Sterol regulatory element-binding proteins are transcriptional regulators of the thyroglobulin gene in thyroid cells.

The genes encoding sodium/iodide symporter (NIS) and thyroid peroxidase (TPO), both of which are essential for thyroid hormone (TH) synthesis, were shown to be regulated by sterol regulatory element-binding proteins (SREBP)-1c and -2. In the present study we tested the hypothesis that transcription of a further gene essential for TH synthesis, the thyroglobulin (TG) gene, is under the control of SREBP. To test this hypothesis, we studied the influence of inhibition of SREBP maturation and SREBP knockdown on TG expression in FRTL-5 thyrocytes and explored transcriptional regulation of the TG promoter by reporter gene experiments in FRTL-5 and HepG2 cells, gel shift assays and chromatin immunoprecipitation. Inhibition of SREBP maturation by 25-hydroxycholesterol and siRNA-mediated knockdown of either SREBP-1c or SREBP-2 decreased mRNA and protein levels of TG in FRTL-5 thyrocytes. Reporter gene assays with wild-type and mutated TG promoter reporter truncation constructs revealed that the rat TG promoter is transcriptionally activated by nSREBP-1c and nSREBP-2. DNA-binding assays and chromatin immunoprecipitation assays showed that both nSREBP-1c and nSREBP-2 bind to a SREBP binding motif with characteristics of an E-box SRE at position -63 in the rat TG promoter. In connection with recent findings that NIS and TPO are regulated by SREBP in thyrocytes the present findings support the view that SREBP are regulators of essential steps of TH synthesis in the thyroid gland such as iodide uptake, iodide oxidation and iodination of tyrosyl residues of TG. This moreover suggests that SREBP may be molecular targets for pharmacological modulation of TH synthesis.

Analysis of hepatic transcript profile and plasma lipid profile in early lactating dairy cows fed grape seed and grape marc meal extract.

BACKGROUND: It was recently reported that dairy cows fed a polyphenol-rich grape seed and grape marc meal extract (GSGME) during the transition period had an increased milk yield, but the underlying reasons remained unclear. As polyphenols exert a broad spectrum of metabolic effects, we hypothesized that feeding of GSGME influences metabolic pathways in the liver which could account for the positive effects of GSGME in dairy cows. In order to identify these pathways, we performed genome-wide transcript profiling in the liver and lipid profiling in plasma of dairy cows fed GSGME during the transition period at 1 week postpartum. RESULTS: Transcriptomic analysis of the liver revealed 207 differentially expressed transcripts, from which 156 were up- and 51 were down-regulated, between cows fed GSGME and control cows. Gene set enrichment analysis of the 155 up-regulated mRNAs showed that the most enriched gene ontology (GO) biological process terms were dealing with cell cycle regulation and the most enriched Kyoto Encyclopedia of Genes and Genomes pathways were p53 signaling and cell cycle. Functional analysis of the 43 down-regulated mRNAs revealed that a great part of these genes are involved in endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and inflammatory processes. Accordingly, protein folding, response to unfolded protein, unfolded protein binding, chemokine activity and heat shock protein binding were identified as one of the most enriched GO biological process and molecular function terms assigned to the down-regulated genes. In line with the transcriptomics data the plasma concentrations of the acute phase proteins serum amyloid A (SAA) and haptoglobin were reduced in cows fed GSGME compared to control cows. Lipidomic analysis of plasma revealed no differences in the concentrations of individual species of major and minor lipid classes between cows fed GSGME and control cows. CONCLUSIONS: Analysis of hepatic transcript profile in cows fed GSGME during the transition period at 1 week postpartum indicates that polyphenol-rich feed components are able to inhibit ER stress-induced UPR and inflammatory processes, both of which are considered to contribute to liver-associated diseases and to impair milk performance in dairy cows, in the liver of dairy cows during early lactation.

Metabolic signals and innate immune activation in obesity and exercise.

The combination of a sedentary lifestyle and excess energy intake has led to an increased prevalence of obesity which constitutes a major risk factor for several co-morbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system. Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IκBα kinase/nuclear factor-κB (IKK/NF- κB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD-like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling. Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing obesity- induced chronic inflammation. This review summarizes current knowledge of the cellular recognition mechanisms for FFAs, the inflammatory signaling pathways triggered by excess FFAs in obesity and the counteractive effects of both acute and chronic exercise on obesity-induced activation of inflammatory signaling pathways. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its comorbidities.

Determination of polyphenol and crude nutrient content and nutrient digestibility of dried and ensiled white and red grape pomace cultivars.

The present study aimed to determine the nutrient and energy content of fresh and ensiled grape pomace (GP) from different grape varieties originating from Germany, and to estimate the feed value of dried white, dried red and ensiled white GP by calculating nutrient digestibility and the content of metabolisable energy (ME) and net energy lactation (NEL) measured in sheep as a ruminant model. GP from red cultivars had higher contents of organic matter (OM), crude protein (CP), ether extract (EE), crude fibre (CF), total phenolic contents (TPC) and ME, whereas the concentrations of ash and sugar were lower than from white cultivars. Compared with untreated GP, ensiled GP had increased concentrations of CP (+19%), ether extract (EE; +23%) and CF (+12%) and a higher ME content (+7%) and markedly decreased concentrations of sugar (-99.6%) and TPC (-48%). The concentrations of dry matter, OM and ash were not different between ensiled and fresh GP. Compared with dried GP, ensiled GP had a higher nutrient digestibility (OM, +32%; CP, +43%; CF, +46%; neutral detergent fibre [NDF], +54%; acid detergent fibre [ADF], +69%) and higher energy values (ME, +16%; NEL, +19%). The digestibility of OM, CP, EE and CF and the energy content were higher for dried red than for dried white GP, whereas the digestibility of NDFOM and ADFOM was lower for dried red than dried white GP. In conclusion, the results show that both red and white GP are suitable dietary sources for enrichment with TPC. Furthermore, compared with drying ensiling of GP improves the feeding value of GP and is a good possibility of preserving the seasonally produced by-product of winemaking for ruminant feeding.

Effect of a negative energy balance induced by feed restriction in lactating sows on hepatic lipid metabolism, milk production and development of litters.

In rodents, forced activation of hepatic peroxisome proliferator-activated receptor α (PPARα) by administration of exogenous PPARα activators during lactation leads to a reduction of milk triacylglycerol (TAG) production. Herein, we investigated whether a negative energy balance (NEB) induced by feed restriction (about 18% lower feed and energy intake) during lactation by increasing the release of fatty acids, which act as PPARα agonists, causes a disruption of hepatic lipid metabolism and thereby impairs milk TAG production in sows. Nutrient and energy content of the milk on day 20 of lactation and gains of litters during the first 14 d and the whole 21 d suckling period did not differ between Control and feed-restricted sows. The mRNA concentrations of several sterol regulatory element-binding protein target genes involved in lipid synthesis in the liver and the plasma concentration of TAG were reduced in the feed-restricted sows, whereas the mRNA concentrations of PPARα target genes involved in fatty acid oxidation in liver and skeletal muscle were not different between groups. In conclusion, it was shown that an NEB during lactation does not adversely affect milk composition and gains of litters, despite inhibiting hepatic expression of genes involved in lipid synthesis and reducing plasma TAG concentration. The finding that PPARα target genes involved in fatty acid utilisation in liver and muscle of sows are not induced by the NEB during lactation may explain that fatty acid availability in the mammary gland is sufficient to maintain milk TAG production and to allow normal litter gain.

Effect of a negative energy balance induced by feed restriction on pro-inflammatory and endoplasmic reticulum stress signalling pathways in the liver and skeletal muscle of lactating sows.

High-producing sows develop typical signs of an inflammatory condition and endoplasmic reticulum (ER) stress in the liver during lactation. At present, it is unknown whether a negative energy balance (NEB) is causative for this. Therefore, an experiment with lactating sows, which were either restricted in their feed intake to 82% of their energy requirement (Group FR) or were fed to meet their energy requirement (Control), was performed and the effect on ER stress-induced unfolded protein response (UPR), nuclear factor kappa B (NF-κB), nuclear factor E2-related factor 2 (Nrf2) and NOD-like receptor P3 (NLRP3) inflammasome signalling in the liver was evaluated. Relative mRNA concentrations of several genes involved in ER stress-induced UPR, NF-κB and NLRP3 inflammasome signalling were reduced in the liver of Group FR compared to the Control group. Plasma concentrations of haptoglobin and C-reactive protein were 13% and 37%, respectively, lower in Group FR than in the Control group, but these differences were not significant. In conclusion, feed restriction in lactating sows inhibits pro-inflammatory and ER stress signalling pathways in the liver, which suggests that not the NEB per se is causative for inflammation and ER stress induction in the liver of lactating sows. Rather it is likely that ER stress during lactation is the consequence of the presence of potent pro-inflammatory and ER stress-inducing stimuli, such as cytokines, reactive oxygen species and microbial components, which enter the circulation as a result of infectious diseases that frequently occur in sows after farrowing.

Treatment with pharmacological PPARα agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents.

BACKGROUND: Treatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor α (PPARα), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPARα leads to an up-regulation of the ubiquitin proteasome system (UPS) which plays a major role in protein degradation in muscle. METHODS: Rats, wild-type and PPARα-deficient mice (PPARα(-/-)) were treated with synthetic PPARα agonists (clofibrate, WY-14,643) to study their effect on the UPS and myofibrillar protein breakdown in muscle. RESULTS: In rats and wild-type mice but not PPARα(-/-) mice, clofibrate or WY-14,643 caused increases in mRNA and protein levels of the ubiquitin ligases atrogin-1 and MuRF1 in muscle. Wild-type mice treated with WY-14,643 had a greater 3-methylhistidine release from incubated muscle and lesser muscle weights. In addition, wild-type mice but not PPARα(-/-) mice treated with WY-14,643 had higher amounts of ubiquitin-protein conjugates, a decreased activity of PI3K/Akt1 signalling, and an increased activity of FoxO1 transcription factor in muscle. Reporter gene and gel shift experiments revealed that the atrogin-1 and MuRF1 promoter do not contain functional PPARα DNA-binding sites. CONCLUSIONS: These findings indicate that fibrates stimulate ubiquitination of proteins in skeletal muscle which in turn stimulates protein degradation. Up-regulation of ubiquitin ligases is probably not mediated by PPARα-dependent gene transcription but by PPARα-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1. GENERAL SIGNIFICANCE: PPARα plays a role in the regulation of the ubiquitin proteasome system.