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Level of dietary energy and 2,4-thiazolidinedione alter molecular and systemic biomarkers of inflammation and liver function in Holstein cows.

ABSTRACT: The objective of the study was to evaluate the effect of overfeeding a moderate energy diet and a 2,4-thiazolidinedione (TZD) injection on blood and hepatic tissue biomarkers of lipid metabolism, oxidative stress, and inflammation as it relates to insulin sensitivity.Fourteen dry non-pregnant cows were fed a control (CON) diet to meet 100% of NRC requirements for 3 wk, after which half of the cows were assigned to a moderate-energy diet (OVE) and half of the cows continued on CON for 6 wk. All cows received an intravenous injection of 4 mg TZD/kg of body weight (BW) daily from 2 wk after initiation of dietary treatments and for 2 additional week. Compared with CON cows and before TZD treatment, the OVE cows had lower concentration of total protein, urea and albumin over time. The concentration of cholesterol and tocopherol was greater after 2 wk of TZD regardless of diet. Before and after TZD, the OVE cows had greater concentrations of AST/GOT, while concentrations of paraoxonase, total protein, globulin, myeloperoxidase, and haptoglobin were lower compared with CON cows. Regardless of diet, TZD administration increased the concentration of ceruloplasmin, ROMt, cholesterol, tocopherol, total protein, globulin, myeloperoxidase and beta-carotene. In contrast, the concentration of haptoglobin decreased at the end of TZD injection regardless of diet. Prior to TZD injection, the mRNA expression of PC, ANGPTL4, FGF21, INSR, ACOX1, and PPARD in liver of OVE cows was lower compared with CON cows. In contrast, the expression of HMGCS2 was greater in OVE compared with CON cows. After 1 wk of TZD administration the expression of IRS1 decreased regardless of diet; whereas, expression of INSR increased after 2 wk of TZD injection. Cows fed OVE had lower overall expression of TNF, INSR, PC, ACOX1, FGF21, and PPARD but greater HMGCS2 expression. These differences were most evident before and after 1 wk of TZD injection, and by 2 wk of TZD differences in expression for most genes disappeared.Based on molecular and blood data, administration of TZD enhanced some aspects of insulin sensitivity while causing contradictory results in terms of inflammation and oxidative stress. The bovine liver is TZD-responsive and level of dietary energy can modify the effects of TZD. Because insulin sensitizers have been proposed as useful tools to manage dairy cows during the transition period, further studies are required to investigate the potential hepatotoxicity effect of TZD (or similar compounds) in dairy cattle.

SUBMITTER: Hosseini A

PROVIDER: S-EPMC5537929 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:The effects of dietary energy level and 2,4-thiazolidinedione (TZD) injection on feed intake, body fatness, blood biomarkers and TZD concentrations, genes related to insulin sensitivity in adipose tissue (AT) and skeletal muscle, and peroxisome proliferator-activated receptor gamma (PPARG) protein in subcutaneous AT (SAT) were evaluated in Holstein cows. Fourteen nonpregnant nonlactating cows were fed a control low-energy (CON, 1.30 Mcal/kg) diet to meet 100% of estimated nutrient requirements for 3 weeks, after which half of the cows were assigned to a higher-energy diet (OVE, 1.60 Mcal/kg) and half of the cows continued on CON for 6 weeks. All cows received an intravenous injection of TZD starting 2 weeks after initiation of dietary treatments and for an additional 2 weeks, which served as the washout period. Cows fed OVE had greater energy intake and body mass than CON, and TZD had no effect during the administration period. The OVE cows had greater TZD clearance rate than CON cows. The lower concentration of nonesterified fatty acids (NEFA) and greater concentration of insulin in blood of OVE cows before TZD injection indicated positive energy balance and higher insulin sensitivity. Administration of TZD increased blood concentrations of glucose, insulin, and beta-hydroxybutyrate (BHBA) at 2 to 4 weeks after diet initiation, while the concentration of NEFA and adiponectin (ADIPOQ) remained unchanged during TZD. The TZD upregulated the mRNA expression of PPARG and its targets FASN and SREBF1 in SAT, but also SUMO1 and UBC9 which encode sumoylation proteins known to down-regulate PPARG expression and curtail adipogenesis. Therefore, a post-translational response to control PPARG gene expression in SAT could be a counteregulatory mechanism to restrain adipogenesis. The OVE cows had greater expression of the insulin sensitivity-related genes IRS1, SLC2A4, INSR, SCD, INSIG1, DGAT2, and ADIPOQ in SAT. In skeletal muscle, where PPARA and its targets orchestrate carbohydrate metabolism and fatty acid oxidation, the OVE cows had greater glyceroneogenesis (higher mRNA expression of PC and PCK1), whereas CON cows had greater glucose transport (SLC2A4). Administration of TZD increased triacylglycerol concentration and altered expression of carbohydrate- and fatty acid oxidation-related genes in skeletal muscle. Results indicate that overfeeding did not affect insulin sensitivity in nonpregnant, nonlactating dairy cows. The bovine PPARG receptor appears TZD-responsive, with its activation potentially leading to greater adipogenesis and lipogenesis in SAT, while differentially regulating glucose homeostasis and fatty acid oxidation in skeletal muscle. Targeting PPARG via dietary nutraceuticals while avoiding excessive fat deposition might improve insulin sensitivity in dairy cows during times such as the peripartal period when the onset of lactation naturally decreases systemic insulin release and sensitivity in tissues such as AT.

Project description:BackgroundThe aim of the study was to investigate the effect of energy overfeeding during the dry period on adipose tissue transcriptome profiles during the periparturient period in dairy cows.MethodsFourteen primiparous Holstein cows from a larger cohort receiving a higher-energy diet (1.62 Mcal of net energy for lactation/kg of dry matter; 15% crude protein) for ad libitum intake to supply 150% (OVR) or 100% (CTR) of energy requirements from dry off until parturition were used. After calving, all cows received the same lactation diet. Subcutaneous adipose tissue (SAT) biopsies were collected at - 14, 1, and 14 d from parturition (d) and used for transcriptome profiling using a bovine oligonucleotide microarray. Data mining of differentially expressed genes (DEG) between treatments and due to sampling time was performed using the Dynamic Impact Approach (DIA) and Ingenuity Pathway Analysis (IPA).ResultsThere was a strong effect of over-feeding energy on DEG with 2434 (False discovery rate-corrected P < 0.05) between OVR and CTR at - 14 d, and only 340 and 538 at 1 and 14 d. The most-impacted and activated pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database that were highlighted by DIA analysis at - 14 d in OVR vs. CTR included 9 associated with carbohydrate metabolism, with 'Pyruvate metabolism', 'Glycolysis/gluconeogenesis', and 'Pentose phosphate pathway' among the most-activated. Not surprisingly, OVR led to marked activation of lipid metabolism (e.g. 'Fatty acid biosynthesis' and 'Glycerolipid metabolism'). Unexpected metabolic pathways that were activated at - 14 d in OVR included several related to metabolism of amino acids (e.g. branched chain) and of cofactors and vitamins (thiamin). Among endocrine and immune system pathways, at - 14 d OVR led to marked activation of 'PPAR signalling' and 'Antigen processing and presentation'. Among key pathways affected over time in OVR, a number were related to translation (e.g. mTOR signaling), endocrine/immune signaling (CXCR4 and IGF1), and lipid metabolism (oxidative phosphorylation) with greater activation in OVR vs. CTR specifically at - 14 d. Although statistical differences for several pathways in OVR vs. CTR nearly disappeared at 1 and 14 vs. - 14 d, despite the well-known catabolic state of adipose depots after calving, the bioinformatics analyses suggested important roles for a number of signaling mechanisms at - 14 vs. 14 than 1 vs. -14 d. This was particularly evident in cows fed to meet predicted energy requirements during the dry period (CTR).ConclusionsData underscored a strong activation by overfeeding energy of anabolic processes in the SAT exclusively prepartum. The study confirmed that higher-energy diets prepartum drive a transcriptional cascade of events orchestrated in part by the activation of PPARγ that regulate preadipocyte differentiation and lipid storage in SAT. Novel aspects of SAT biology to energy overfeeding or change in physiologic state also were uncovered, including the role of amino acid metabolism, mTOR signaling, and the immune system.

Project description:Background:Dairy cows can readily overconsume dietary energy during most of the prepartum period, often leading to higher prepartal concentrations of insulin and glucose and excessive body fat deposition. The end result of these physiologic changes is greater adipose tissue lipolysis post-partum coupled with excessive hepatic lipid accumulation and compromised health. Although transcriptional regulation of the adipose response to energy availability is well established in non-ruminants, such regulation in cow adipose tissue depots remains poorly characterized. Results:Effects of ad-libitum access to high [HIGH; 1.62 Mcal/kg of dry matter (DM)] or adequate (CON; 1.35 Mcal/kg of DM) dietary energy for 8 wk on mesenteric (MAT) and subcutaneous (SAT) adipose tissue transcript profiles were assessed in non-pregnant non-lactating Holstein dairy cows using a 13,000-sequence annotated bovine oligonucleotide microarray. Statistical analysis revealed 409 and 310 differentially expressed genes (DEG) due to tissue and diet. Bioinformatics analysis was conducted using the Dynamic Impact Approach (DIA) with the KEGG pathway database. Compared with SAT, MAT had more active biological processes related to adipose tissue accumulation (adiponectin secretion) and signs of pro-inflammatory processes due to adipose tissue expansion and macrophage infiltration (generation of ceramides). Feeding the HIGH diet led to changes in mRNA expression of genes associated with cell hypertrophy (regucalcin), activation of adipogenesis (phospholipid phosphatase 1), insulin signaling activation (neuraminidase 1) and angiogenesis (semaphorin 4G, plexin B1). Further, inflammation due to HIGH was underscored by mRNA expression changes associated with oxidative stress response (coenzyme Q3, methyltransferase), ceramide synthesis (N-acylsphingosine amidohydrolase 1), and insulin signaling (interferon regulatory factor 1, phosphoinositide-3-kinase regulatory subunit 1, retinoic acid receptor alpha). Activation of ribosome in cows fed HIGH indicated the existence of greater adipocyte growth rate (M-phase phosphoprotein 10, NMD3 ribosome export adaptor). Conclusions:The data indicate that long-term ad-libitum access to a higher-energy diet led to transcriptional changes in adipose tissue that stimulated hypertrophy and the activity of pathways associated with a slight but chronic inflammatory response. Further studies would be helpful in determining the extent to which mRNA results also occur at the protein level.

Project description:Mitigation of greenhouse gas emissions is relevant for reducing the environmental impact of ruminant production. In this study, the rumen microbiome from Holstein cows was characterized through a combination of 16S rRNA gene and shotgun metagenomic sequencing. Methane production (CH4 ) and dry matter intake (DMI) were individually measured over 4-6 weeks to calculate the CH4 yield (CH4 y = CH4 /DMI) per cow. We implemented a combination of clustering, multivariate and mixed model analyses to identify a set of operational taxonomic unit (OTU) jointly associated with CH4 y and the structure of ruminal microbial communities. Three ruminotype clusters (R1, R2 and R3) were identified, and R2 was associated with higher CH4 y. The taxonomic composition on R2 had lower abundance of Succinivibrionaceae and Methanosphaera, and higher abundance of Ruminococcaceae, Christensenellaceae and Lachnospiraceae. Metagenomic data confirmed the lower abundance of Succinivibrionaceae and Methanosphaera in R2 and identified genera (Fibrobacter and unclassified Bacteroidales) not highlighted by metataxonomic analysis. In addition, the functional metagenomic analysis revealed that samples classified in cluster R2 were overrepresented by genes coding for KEGG modules associated with methanogenesis, including a significant relative abundance of the methyl-coenzyme M reductase enzyme. Based on the cluster assignment, we applied a sparse partial least-squares discriminant analysis at the taxonomic and functional levels. In addition, we implemented a sPLS regression model using the phenotypic variation of CH4 y. By combining these two approaches, we identified 86 discriminant bacterial OTUs, notably including families linked to CH4 emission such as Succinivibrionaceae, Ruminococcaceae, Christensenellaceae, Lachnospiraceae and Rikenellaceae. These selected OTUs explained 24% of the CH4 y phenotypic variance, whereas the host genome contribution was ~14%. In summary, we identified rumen microbial biomarkers associated with the methane production of dairy cows; these biomarkers could be used for targeted methane-reduction selection programmes in the dairy cattle industry provided they are heritable.

Project description:We investigated the temporal dynamics of ruminal pH and the composition and predicted functions of the rumen bacterial community in Holstein cows during the periparturient period. Eight multiparous Holstein cows (body weight; 707.4 ± 29.9 kg, parity; 3.6 ± 0.6) were used for continuous reticulo-ruminal pH measurement, among which five were also used for bacterial community analysis. Rumen fluid samples were collected at 3 weeks before and 2 and 6 weeks after parturition, and blood samples were collected 3 weeks before and 0, 2, 4, and 6 weeks after parturition. After the parturition, reduction in the 1-h mean reticulo-ruminal pH was associated with a significant (P < 0.05) increase in total volatile fatty acid concentration. However, with the exception of a significant change in an unclassified genus of Prevotellaceae (P < 0.05), we detected no significant changes in the compositions of major bacterial phyla or genera or diversity indices during the periparturient period. On the basis of predicted functional analysis, we identified a total of 53 MetaCyc pathways (45 upregulated), 200 enzyme commissions (184 upregulated), and 714 Kyoto Encyclopedia of Genes and Genomes orthologs (667 upregulated) at 6 weeks postpartum that were significantly (P < 0.05) different to those at 3 weeks prepartum. Among the 14 MetaCyc pathways (P < 0.05) in which pyruvate is an end product, PWY-3661 [log2-fold change (FC) = 5.49, false discovery rate (FDR) corrected P < 0.001] was the most highly upregulated pyruvate-producing pathway. In addition, P381-PWY [adenosylcobalamin biosynthesis II (aerobic); FC = 5.48, FDR corrected P < 0.001] was the second most upregulated adenosylcobalamin (Vitamin B12)-producing pathway. In contrast, PWY-2221 (FC = -4.54, FDR corrected P = 0.003), predominantly found in pectinolytic bacteria, was the most downregulated pathway. Our findings indicate that changes in rumen bacterial community structure are not strictly associated with transitions in parturition or diet; however, we did observe changes in reticulo-ruminal pH and the metabolic adaptation of predicted functional pathways. Consequently, predictive analysis of postpartum functional pathways may enable us to gain insights into the underlying functional adaptations of bacterial communities in Holstein cows during the periparturient period.

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Level of dietary energy and 2,4-thiazolidinedione alter molecular and systemic biomarkers of inflammation and liver function in Holstein cows.

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