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The objective was to evaluate a liver health index (LHI) by evaluating its association with negative health events, milk yield, and risk of pregnancy within 150 d in milk (DIM). In a retrospective cohort study, an LHI was calculated based on plasma albumin, cholesterol, and bilirubin concentrations for 265 primiparous and 611 multiparous cows 3 to 12 DIM enrolled across 72 farms in the northeastern United States. Mixed effects linear regression models were used to evaluate if (1) metritis (MET), (2) displaced abomasum (DA), (3) clinical ketosis (CK), (4) one or more of the 3 disorders (MET, DA, or CK), (5) 2 or more of the 3 disorders (MET, DA, or CK), or (6) culling within 30 DIM was associated with LHI. Mixed effects linear regression models were used to evaluate if LHI was associated with 305-d mature equivalent milk at the fourth test day (ME305; mean ± standard deviation: 114 ± 13 DIM) and a Cox proportional hazards model was used to evaluate if LHI was associated with pregnancy within 150 DIM. Cows that were diagnosed with MET, DA, CK, one or more of the disorders, 2 or more of the disorders, or were culled within 30 DIM had a lower LHI than cows that were not diagnosed with a disorder or culled. A 1-unit increase in LHI was associated with a 154 ± 38 kg increase in ME305 and a 8% increased risk of pregnancy within 150 DIM [hazard ratio (95% confidence interval): 1.08 (1.03 to 1.14)] for multiparous cows; however, we did not identify a relationship between LHI and ME305 or pregnancy within 150 DIM for primiparous cows. These results suggest that the LHI is associated with health, milk yield, and pregnancy within 150 DIM for multiparous cows and health for primiparous cows; therefore, the LHI can be used as a tool to evaluate transition cow success., (© 2022.)

The objectives were as follows: (1) establish cow-level thresholds for prepartum nonesterified fatty acids (NEFA) and postpartum NEFA, β-hydroxybutyrate (BHB), and haptoglobin (Hp) concentrations associated with negative health events; (2) evaluate cow-level associations between biomarkers and 305-d mature equivalent milk at the fourth test day (ME305) and reproductive performance; and (3) identify herd-alarm levels (proportion of cows sampled above the critical threshold) for biomarkers that are associated with herd-level changes in disorder incidence (displaced abomasum and clinical ketosis), reproductive performance, and ME305. In a prospective cohort study, 1,473 cows from 72 farms were enrolled from the northeastern United States. Blood samples were collected from the same 11 to 24 cows per herd during the late-prepartum and early-postpartum periods. Whole blood was analyzed for postpartum BHB concentrations; plasma was analyzed for prepartum and postpartum NEFA and postpartum Hp concentrations. Critical thresholds for the biomarkers associated with health events for all cows were established using a receiver operating characteristic curve analysis. Poisson, linear mixed effects, and Cox proportional hazards models investigated the association of the biomarkers with health and performance. The prepartum NEFA and Hp threshold associated with culling was ≥0.17 mmol/L and 0.45 g/L, respectively. The postpartum NEFA and BHB thresholds associated with diagnosis of metritis, displaced abomasum, or clinical ketosis were ≥0.46 mmol/L and ≥0.9 mmol/L, respectively. Multiparous cows with prepartum NEFA concentration ≥0.17 mmol/L produced 479 kg less ME305. Multiparous and primiparous cows with postpartum NEFA concentration ≥0.46 mmol/L produced 280 kg less and 446 kg more ME305, respectively. Cows with BHB concentration ≥0.9 and ≥1.1 mmol/L produced 552 kg more ME305 and had a 20% decreased risk of pregnancy within 150 d in milk, respectively; however, multiparous cows with BHB concentration ≥1.5 mmol/L produced 376 kg less ME305. Cows with Hp concentration ≥0.45 g/L produced 492 kg less ME305 and had 28% decreased risk of pregnancy within 150 DIM. Cows with Hp concentration ≥0.45 g/L had 19% decreased pregnancy risk to first service (PRFS). Herds above the herd-alarm levels for prepartum NEFA had a 6.0-percentage unit increase in disorder incidence and a 6.0-percentage unit decrease in 21-d pregnancy rate (PR) for multiparous cows, a 3.9-percentage unit increase in PR and a 5.8-percentage unit increase in the probability of pregnancy for primiparous cows. Herds above the herd-alarm levels for postpartum NEFA had a 5.8- and 4.2-percentage unit increase in disorder incidence for multiparous and primiparous cows, respectively, a 789 kg decrease in ME305 for multiparous cows, and a 6.8- and 6.3-percentage unit decrease and increase in PR and PRFS for multiparous cows, respectively. Herds above the herd-alarm levels for BHB had an 8.5-percentage unit increase in disorder incidence, a 332 and 229 kg increase in ME305 for primiparous and multiparous cows, respectively, and a 3.2-, 5.2-, and 7.0-percentage unit decrease in PR, probability of pregnancy, and PRFS, respectively. Herds above the herd-alarm levels for postpartum Hp had a 5.3-percentage unit increase in disorder incidence. At the cow level and herd level, elevated biomarker concentrations were associated with an increased disorder risk and varied performance responses., (© 2022, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Inadequate feed consumption reduces intestinal barrier function in both ruminants and monogastrics. Objectives were to characterize how progressive feed restriction (FR) affects inflammation, metabolism, and intestinal morphology, and to investigate if glucagon-like peptide 2 (GLP2) administration influences the aforementioned responses. Twenty-eight Holstein cows (157 ± 9 d in milk) were enrolled in 2 experimental periods. Period 1 [5 d of ad libitum (AL) feed intake] served as baseline for period 2 (5 d), during which cows received 1 of 6 treatments: (1) 100% of AL feed intake (AL100; n = 3), (2) 80% of AL feed intake (n = 5), (3) 60% of AL feed intake (n = 5), (4) 40% of AL feed intake (AL40; n = 5), (5) 40% of AL feed intake + GLP2 administration (AL40G; 75 µg/kg of BW s.c. 2×/d; n = 5), or (6) 20% of AL feed intake (n = 5). As the magnitude of FR increased, body weight and milk yield decreased linearly. Blood urea nitrogen and insulin decreased, whereas nonesterified fatty acids and liver triglyceride content increased linearly with progressive FR. Circulating endotoxin, lipopolysaccharide binding protein, haptoglobin, serum amyloid A, and lymphocytes increased or tended to increase linearly with advancing FR. Circulating haptoglobin decreased (76%) and serum amyloid A tended to decrease (57%) in AL40G relative to AL40 cows. Cows in AL100, AL40, and AL40G treatments were euthanized to evaluate intestinal histology. Jejunum villus width, crypt depth, and goblet cell area, as well as ileum villus height, crypt depth, and goblet cell area, were reduced (36, 14, 52, 22, 28, and 25%, respectively) in AL40 cows compared with AL100 controls. Ileum cellular proliferation tended to be decreased (14%) in AL40 versus AL100 cows. Relative to AL40, AL40G cows had improved jejunum and ileum morphology, including increased villus height (46 and 51%), villus height to crypt depth ratio (38 and 35%), mucosal surface area (30 and 27%), cellular proliferation (43 and 36%), and goblet cell area (59 and 41%). Colon goblet cell area was also increased (48%) in AL40G relative to AL40 cows. In summary, progressive FR increased circulating markers of inflammation, which we speculate is due to increased intestinal permeability as demonstrated by changes in intestinal architecture. Furthermore, GLP2 improved intestinal morphology and ameliorated circulating markers of inflammation. Consequently, FR is a viable model to study consequences of intestinal barrier dysfunction and administering GLP2 appears to be an effective mitigation strategy to improve gut health., (Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Modern dairy cows meet the energy demand of early lactation by calling on hormonally driven mechanisms to increase the use of lipid reserves. In this context, we recently reported that fibroblast growth factor-21 (FGF21), a hormone required for efficient use of lipid reserves in rodents, is upregulated in periparturient dairy cows. Increased plasma FGF21 in early lactation coincides with elevated circulating concentrations of glucagon (GCG) and nonesterified fatty acids (NEFA). To assess the relative contribution of these factors in regulating FGF21, two experiments were performed in energy-sufficient, nonpregnant, nonlactating dairy cows. In the first study, cows were injected with saline or GCG every 8 h over a 72-h period. GCG increased hepatic FGF21 mRNA by an average of fivefold over matched controls but had no effect on plasma FGF21. In the second study, cows were infused and injected with saline, infused with Intralipid and injected with saline, or infused with Intralipid and injected with GCG. Infusions and injections were administered intravenously over 16 h and subcutaneously every 8 h, respectively. Intralipid infusion increased plasma NEFA from 92 to 550 µM within 3 h and increased plasma FGF21 from 1.3 to >11 ng/ml 6 h later; FGF21 mRNA increased by 34-fold in liver but remained invariant in adipose tissue. GCG injections during the Intralipid infusion had no additional effects on plasma NEFA, liver FGF21 mRNA, or plasma FGF21. These data implicate plasma NEFA as a key factor triggering hepatic production and increased circulating concentrations of FGF21 in early lactation., (Copyright © 2017 the American Physiological Society.)

Study objectives were to evaluate the effects of intentionally reduced intestinal barrier function on productivity, metabolism, and inflammatory indices in otherwise healthy dairy cows. Fourteen lactating Holstein cows (parity 2.6 ± 0.3; 117 ± 18 d in milk) were enrolled in 2 experimental periods. Period 1 (5 d) served as the baseline for period 2 (7 d), during which cows received 1 of 2 i.v. treatments twice per day: sterile saline or a gamma-secretase inhibitor (GSI; 1.5 mg/kg of body weight). Gamma-secretase inhibitors reduce intestinal barrier function by inhibiting crypt cell differentiation into absorptive enterocytes. During period 2, control cows receiving sterile saline were pair-fed (PF) to the GSI-treated cows, and all cows were killed at the end of period 2. Administering GSI increased goblet cell area 218, 70, and 28% in jejunum, ileum, and colon, respectively. In the jejunum, GSI-treated cows had increased crypt depth and reduced villus height, villus height-to-crypt depth ratio, cell proliferation, and mucosal surface area. Plasma lipopolysaccharide binding protein increased with time, and tended to be increased 42% in GSI-treated cows relative to PF controls on d 5 to 7. Circulating haptoglobin and serum amyloid A concentrations increased (585- and 4.4-fold, respectively) similarly in both treatments. Administering GSI progressively reduced dry matter intake (66%) and, by design, the pattern and magnitude of decreased nutrient intake was similar in PF controls. A similar progressive decrease (42%) in milk yield occurred in both treatments, but we observed no treatment effects on milk components. Cows treated with GSI tended to have increased plasma insulin (68%) and decreased circulating nonesterified fatty acids (29%) compared with PF cows. For both treatments, plasma glucose decreased with time while β-hydroxybutyrate progressively increased. Liver triglycerides increased 221% from period 1 to sacrifice in both treatments. No differences were detected in liver weight, liver moisture, or body weight change. Intentionally compromising intestinal barrier function caused inflammation, altered metabolism, and markedly reduced feed intake and milk yield. Further, we demonstrated that progressive feed reduction appeared to cause leaky gut and inflammation., (Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Ketosis is a prevalent periparturient metabolic disorder and we hypothesize that lipopolysaccharide (LPS) infiltration may play a key role in its etiology. Study objectives were to characterize biomarkers of inflammation during the transition period in healthy and clinically diagnosed ketotic cows. Cows were retrospectively categorized into one of two groups: healthy and clinically diagnosed ketotic. Two data sets were utilized; the first dataset (Study A) was obtained as a subset of cows (n=16) enrolled in a larger experiment conducted at the Iowa State University Dairy utilizing Holstein cows (8 healthy; 8 ketotic), and the second dataset (Study B; 22 healthy; 22 ketotic) was obtained from a commercial farm. For both experiments, blood samples were collected prior to and following calving. Ketotic cows in both studies had reduced milk production compared to healthy cows (P<0.01). Post-calving, ketotic cows had increased serum amyloid A (4.2 and 1.8 fold in studies A and B, respectively; P=0.03 and P=0.04), haptoglobin (>6 fold and ~4 fold; P=0.04 and P=0.03), and lipopolysaccharide binding protein (66 and 45%; P<0.01 and P=0.02) compared with their healthy counterparts. Antepartum circulating LPS in ketotic cows was increased (2.3 fold; P=0.01) compared to healthy cows in Study B. In summary, increased biomarkers of inflammation appear to be closely associated with ketosis in transition dairy cows., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Nonlactating Holstein cows (n=12) in late pregnancy were used to determine effects of plane of nutrition followed by feed deprivation on metabolic responses to insulin. Beginning 48 d before expected parturition, cows were fed to either a high plane (HP) or a low plane (LP) of nutrition (162 and 90% of calculated energy requirements, respectively). Cows were subjected to an intravenous glucose tolerance test [GTT; 0.25 g of dextrose/kg of body weight (BW)] on d 14 of treatment and a hyperinsulinemic-euglycemic clamp (HEC; 1 μg/kg of BW/h) on d 15. Following 24 h of feed removal, cows were subjected to a second GTT on d 17 and a second HEC on d 18 after 48 h of feed removal. During the feeding period, plasma nonesterified fatty acid (NEFA) concentrations were higher for cows fed the LP diet compared with those fed the HP diet (163.6 vs. 73.1 μEq/L), whereas plasma insulin was higher for cows fed the HP diet during the feeding period (11.1 vs. 5.2 μIU/mL). Glucose areas under the curve during both GTT were higher for cows fed the LP diet than for those fed the HP diet (4,213 vs. 3,750 mg/dL × 60 min) and was higher during the GTT in the feed-deprived state (4,878 vs. 3,085 mg/dL × 60 min) than in the GTT during the fed state, suggesting slower clearance of glucose during negative energy balance either pre-or post-feed deprivation. This corresponded with a higher dextrose infusion rate during the fed-state HEC than during the feed-deprived-state HEC (203.3 vs. 90.1 mL/h). Plasma NEFA decreased at a faster rate following GTT during feed deprivation compared with that during the fed state (8.7 vs. 2.9%/min). Suppression of NEFA was highest for cows fed the HP diet during the GTT conducted during feed deprivation, and lowest for cows fed the HP diet during the fed-state GTT (68.6 vs. 50.3% decrease from basal). Plasma insulin responses to GTT were affected by feed deprivation such that cows had a much lower insulin response to GTT by 24 h after feed removal (995 vs. 3,957 μIU/mL × 60 min). During the fed-state HEC, circulating concentrations of NEFA were 21% below basal for cows fed the HP diet and 62% below basal for cows fed the LP diet; during feed deprivation, NEFA were 79 and 59% below basal for the HP and LP diets, respectively (diet × HEC). Cows that are fed below energy requirements or are feed deprived have slower clearance of glucose and greater NEFA responses to glucose challenge. Additionally, feed deprivation had a large effect on insulin secretion. Overall, effects of feed deprivation were larger than effects of plane of nutrition., (Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

In many mammals, lactation success depends on substantial use of lipid reserves and requires integrated metabolic activities between white adipose tissue (WAT) and liver. Mechanisms responsible for this integration in lactation are poorly understood, but data collected in other conditions of elevated lipid use suggest a role for fibroblast growth factor-21 (FGF21). To address this possibility in the context of lactation, we studied high-yielding dairy cows during the transition from late pregnancy (LP) to early lactation (EL). Plasma FGF21 was nearly undetectable in LP, peaked on the day of parturition, and then stabilized at lower, chronically elevated concentrations during the energy deficit of EL. Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. Gene expression studies showed that liver was a major source of plasma FGF21 in EL with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT. Overall, these data suggest a model whereby liver-derived FGF21 regulates the use of lipid reserves during lactation via focal actions on liver and WAT.

Specific mechanisms by which dry period dietary energy affects transition cow metabolism have been intensively investigated but those of thiazolidinedione (TZD) administration have not. We hypothesized that effects of both are mediated via changes in insulin, glucose, or fatty acid metabolism. The objective of this experiment was to determine the effects of the insulin-sensitizing agent TZD and dietary energy level on glucose and fatty acid metabolism during late gestation in dairy cows. Multiparous Holstein cows (n=32) approximately 50 d before expected calving date were dried-off and assigned to 1 of 2 dietary energy levels for 3 wk (high: 1.52 Mcal/kg of NE(L), or low: 1.34 Mcal/kg of NE(L)) and treated daily during the final 14 d with 4.0 mg of TZD/kg of body weight (BW) or saline in a completely randomized design. Cows fed the low energy diet had lower dry matter intake (12.8 vs. 16.1 kg/d) and higher plasma nonesterified fatty acid (NEFA) concentrations (103.3 vs. 82.4 μEq/L) compared with cows fed the high energy diet. Cows administered TZD had higher plasma glucose concentrations (62.5 vs. 59.6 mg/dL) than saline controls and cows fed the high energy diet had higher plasma insulin concentrations (35.1 vs. 25.3 μU/mL) compared with those fed the low energy diet. After 2 wk of TZD treatment, all cows were subjected to an intravenous glucose tolerance test (GTT; 0.25 g of dextrose/kg of BW) followed 110 min later by an insulin challenge (IC; 1.0 μg of insulin/kg of BW). Differences in plasma glucose response to GTT were minimal based on diet; however, cows fed the low energy diet had more negative NEFA areas under the curve (AUC; -4,838 vs. -2,137 μEq/L × min over 90 min) and greater rates of NEFA decrease (1.35 vs. 0.63%/min) during GTT, suggesting differential responses of tissue glucose and fatty acid metabolism in response to dietary energy level. During IC, the TZD-treated cows tended to have more negative glucose AUC (-45.0 vs. -12.1mg/dL × min over 15 min) than controls, suggesting that TZD-treated cows had greater responses to insulin. Limited interactions were observed between dietary and TZD treatments in all response variables measured. Adipose tissue biopsies performed on the final day of treatment suggested higher expression of peroxisome proliferator-activated receptor-γ (0.71 vs. 0.50 relative expression) and lipoprotein lipase (0.71 vs. 0.40 relative expression) in cows fed the high energy diet as measured by quantitative real-time PCR. These results indicate that energy level and insulin-sensitizing agents affect glucose and lipid metabolism during the dry period., (Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Administration of peroxisome proliferator-activated receptor gamma (PPARγ) ligands, thiazolidinediones (TZD), to prepartum dairy cattle has been shown to improve dry matter intake and decrease circulating nonesterified fatty acids (NEFA) around the time of calving. The objective of this work was to elucidate mechanisms of TZD action in transition dairy cattle by investigating changes in plasma leptin, tumor necrosis factor-α (TNFα), the revised quantitative insulin sensitivity check index (RQUICKI), and adipose tissue gene expression of leptin, PPARγ, lipoprotein lipase (LPL), and fatty acid synthase (FAS). Multiparous Holstein cows (n=40) were administered 0, 2.0, or 4.0 mg of TZD/kg of body weight (BW) by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples collected daily from 22 d before expected parturition through 21 d postpartum were analyzed for glucose, NEFA, and insulin. Plasma samples collected on d -14, -3, -1, 1, 3, 7, 14, and 49 relative to parturition were also analyzed for leptin and TNFα. Adipose tissue was collected on d 7 before expected parturition from a subset of cows, and gene expression was examined via quantitative real-time PCR. A tendency for a treatment by time effect on plasma leptin prepartum was observed such that values were similar on d -14 but cows receiving 2.0 mg/kg of BW of TZD tended to have lower circulating leptin as calving approached. Postpartum leptin tended to be increased linearly (2.3, 2.4, and 2.5±0.1 ng/mL for 0, 2.0, and 4.0 mg/kg treatments, respectively) in cows that received TZD prepartum. Plasma TNFα increased linearly (2.6, 3.7, and 4.0±0.1 pg/mL) in response to TZD treatment and decreased through the first week postpartum. Calculation of RQUICKI 1/[log(glucose)+log(insulin)+log(NEFA)] suggested altered insulin sensitivity in cows administered TZD that may depend on day relative to calving. Administration of TZD increased adipose tissue expression of PPARγ mRNA (11.0, 13.3, and 12.8±1.9). Administration of TZD had a quadratic effect on gene expression of leptin (16.2, 10.7, and 17.4±1.6) and no effect on LPL expression, and expression of FAS was lower for TZD-treated cows than for controls (8.2, 4.2, and 6.1±1.8, respectively). Results imply altered expression and plasma concentrations of leptin, increased plasma TNFα concentrations, and increased expression of PPARγ in adipose tissue as potential mechanisms for the effects of TZD administration on transition dairy cattle., (Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)