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  • 1. Roberto Farina - Fatro
  • 2. • Cow metabolism during transition • Fatty liver and related disorders • Transcriptional control of lipid/energy metabolism: PPARs • PPAR-alpha agonists in veterinary
  • 3. The last 3 wk before to 3 wk after parturition  Tremendous metabolic adaptations to support lactation  Most diseases occur during or soon after this time
  • 4. Prepartum Postpartum Increase Hepatic Blood Flow 1140 l/h 2099 l/h + 84% DMI 9.8 kg/d 14.1 kg/d + 44 % Liver Oxygen Utilization 1619 mmol/h 3159 mmol/h + 95 % Daily Metabolic Activity per gram of liver 4.4 mmol O2/g 8.6 mmol O2/g X 2 Glucose Release from Liver 1356 g/d 2760 g/d X 2 Big changes over a very short time highlight the tremendous metabolic adaptations necessary to adequately support lactation
  • 5. -10 0 10 20 30 40 0 35 70 105 140 175 210 245 280 Energy Ingested Energy Required NegativePositive Energy Balance = Energy Ingested - Energy Required DIM Mcal/day Adapted from Bauman and Currie 1980 After parturition extra energy requirement for milk production is not met by feed energy intake Lipolisis Parturition
  • 6. HSL CO2 CO2 CO2 CO2 ↓ Insulin ↑ epinephrine Lipolisis
  • 7. 0% 2% 4% 6% 8% 10% 12% 14% 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 -17 -10 -3 4 11 18 25 LiverTG-%DM NEFAmEq/L Days NEFA Liver TGParturition Adapted from Overton 2003
  • 8. Fatty liver is a common condition, up to 50 % of dairy cows
  • 9. Fatty liver has detrimental effects on health, productivity and fertility The Liver sits at the crossroads of metabolism Its integrity is vital to all physiological processes
  • 10. Disorder Association Reference Displaced abomasum +++ Wada et al., 1995; Rehage et al., 1996 Impaired immunoreactivity ++ Wentink et al., 1997; Zerbe et al., 2000 Ketosis +++ Gröhn et al., 1987; Veenhuizen et al., 1991 Laminitis + Fronk et al., 1980; Rehage et al., 1996 Mastitis ++ Morrow et al., 1979 Metritis ++ Haraszti et al., 1982; Heinonen et al., 1987 Milk fever + Higgins and Anderson, 1983; Gröhn et al., 1987 Retained placenta + Haraszti et al., 1982; Heinonen et al., 1987 Bobe 2004
  • 11. Curtis 1989 Mastitisincidence(30days) Hepatic fat increment (2 wk after vs. 2 wk before calving)
  • 12. Parameter Association Reference First ovarian activity ++ Reid et al., 1983; Rukkwamsuk et al., 1999c First ovulation + Reid et al., 1983 First estrus + Paulová et al., 1990; Jorritsma et al., 2000 First insemination + Reid et al., 1983 Days open ++ Heinonen et al., 1987; Paulová et al., 1990 Pregnancy rate ++ Haraszti et al., 1982; Jorritsma et al., 2000 Services/cow + Schäfer et al., 1988; Paulová et al., 1990 Bobe 2004
  • 13. • All the cells regulate their metabolism in response to changes in the environment and metabolize fuels according to their availability MODERN VIEW Nutrients can directly regulate metabolism in a hormonal independent manner CLASSICAL VIEW metabolic adaptations are controlled only by hormonal or neuronal signals
  • 14. PPARs Peroxisome Proliferator-Activated Receptors Fat sensors transducing changes in cellular lipid levels to the transcriptional regulation of target genes involved in fatty acid metabolism
  • 15. NUCLEAR RECEPTOR LIGAND Thyroid hormone R Thyroid hormone Glucocorticoid R Cortisol Estrogen R Estrogen Progesterone R Progesterone Androgen R Testosterone PPAR Lipids Receptors found within the nucleus Bind directly to DNA and regulate gene expression Ligand activated transcription factors
  • 16. • Nuclear receptors involved in the transcriptional regulation of lipid metabolism and energy balance • Fatty acids and their derivatives (Acyl-CoA & eicosanoids) are the natural ligands of PPAR ANIMATION
  • 17. PPARα PPARδ PPARγ STORAGE FAT energy BURNING FAT energy
  • 18. Acts in liver to maintain hepatic lipid homeostasis and reduces fat concentrations Peroxisomal β-oxidation Mitochondrial β-oxidation NEFA Transport NEFA Uptake
  • 19. ↑ epinephrine ↓ Insulin Lipolisis HSL CO2 CO2 CO2 CO2
  • 20. • fenofibrate, gemfibrozil • used to lower triglycerides and raise HDL-C in dyslipidemia to reduce risk of cardiovascular events • 2-phenoxy-2-methyl-propionic acid • Hepagen • used to treat fatty liver, related metabolic disorders and improve energy balance
  • 21. 2-methyl-2-phenoxy-propionic acid 2-methyl-2-phenoxy-propanoic acid 2-Phenoxyisobutyric acid 2,2-Dimethylphenoxyacetic acid Mefepronic acid O C CH3 CH3 C OH O
  • 22. 40 Holstein cows (2°-5° lactation) • Treated group: 50 ml of Hepagen® I.M. at calving, 3d postpartum and 5d postpartum • Control group: 50 ml of physiological solution (NaCl 0.9%)/ head at calving, 3d postpartum and 5d postpartum 50ml/cow 50ml/cow 50ml/cow Biopsy Biopsy Biopsy
  • 23. Liver sections stained with toluidine blue Sciorsci 2009 30 μm CONTROLTREATED 1 d 15 d 30 d 8.6% 9.0% 0.3% 0.1% 0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% 15 d 30 d Liver Fat Control Treated P < 0.001
  • 24. Liver sections stained with haematoxylin-PAS to highlight the presence of glycogen (purple). Sciorsci 2009 30 μm CONTROLTREATED 1 d 15 d 30 d
  • 25. 26 27 28 29 30 31 32 33 34 35 36 1 3 5 10 15 30 40 g/L Days from parturition Control Hepagen • Albumin concentration significantly higher in the treated group • Albumin concentration in the control group slightly lower than the normal range
  • 26. 3.70 4.24 5,46 6.47 - 2 4 6 8 11 d 13 d ng/ml Progesterone 74 50 - 20 40 60 80 days Days to 1° Heat 121 92 - 50 100 150 days Days open 50 6457 71 - 20 40 60 80 days Pregnancy rate Sciorsci 2009p<0.05 HEPAGENCONTROL
  • 27. 36 Holstein cows (2°- 4° lactation) 50ml/cow 50ml/cow 50ml/cow BHB BHB BHB BHB Bouda et al. 2008
  • 28. 0.4 0.6 0.8 1.0 1.2 -10 10 30 40 BHBmmol/L 44% 39% 28% 17% 6% 6% 0% 25% 50% 10 30 40 CONTROL HEPAGEN Bouda et al. 2008 p<0.05 Open days: lower in Control than in Treated group 109.9 vs. 118.5 days
  • 29. 57 Pluriparous Holstein cows 50ml/cow 50ml/cow BHB BHB BHB Aparicio et al. 2009 BHB BHB CONTROL BCS: 3.25 – 3.75 TREATED BCS: 3.25 – 3.75 CONTROL BCS: ≥ 4 TREATED BCS: ≥ 4
  • 30. 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 -10 -7 2 10 21 CONTROL BCS ≥ 4 CONTROL BCS: 3.25 – 3.75 HEPAGEN BCS ≥ 4 HEPAGEN BCS: 3.25 – 3.75
  • 31. 200 “Parmigiano-Reggiano” cows 50ml/cow 50ml/cow Gorrieri 2009 BHB once/week Follow Up (postpartum diseases, fertility)
  • 32. 30 % 15 % 0% 10% 20% 30% 40% Postpartum Diseases 0.86 0.35 0.0 0.2 0.4 0.6 0.8 1.0 BHBmg/dl Milk BHB 89 76 50 60 70 80 90 100 days Days open 25 % 10 % 0% 10% 20% 30% BHB + metritis, displaced abomasum Gorrieri 2009
  • 33. Monitor and record for diseases occurring during the early lactation period in the herd: • Lactational incidence risk (LIR): #affected / # of calvings (at risk) in the same time period • Case definitions/Confidence of diagnosis grade • Define targets for acceptable levels of incidence Reduce risk of postpartum diseases To complement transition cow management programs and herd preventive health care programs
  • 34. 50ml/cow 50ml/cow
  • 35. Cows at a higher risk of fatty liver and metabolic disordes:  Over-conditioned  Underfed  Quick weight loss  Calving difficulties, Twins  Predisposing diseases (Infections, RP, etc.) Identify primary target for prevention
  • 36. 50ml/cow 50ml/cow
  • 37. Daily Monitoring of Each Cow for First 10 Days after Calving (Temperature and Physical Exam) Early Identification and Treatment of Problem Cows Best with Fresh Cow Medicine Programs
  • 38. • Difficult • No specific symptoms • Diagnosed by biopsy –invasive technique –hemorrhage, infection, death • New promising ultrasound technology
  • 39. • Cows having problems from the beginning of lactation • Rapid weight and BCS loss, reduced feed intake • Presence of ther diseases • Diseases more severe and less responsive – Milk fever cows that relapse and become downers – Ketotic cows that don’t respond to treatment – Chronic mastitis cows – Repeat breeders that defy all treatments – Cows that relapse or go from one disease to another – Reduced milk production – Cows that are frequently culled
  • 40. 50ml/cow Follow up and repeat where appropriate 50ml/cow