hepagen - metabolic management of cow health
TRANSCRIPT
Metabolic Management of Cow Health
• Cow metabolism during transition
• Fatty liver and related disorders• Transcriptional control of lipid/energy
metabolism: PPARs
• PPAR-alpha agonists in veterinary
The Transition Period
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
PregnantNonlactating
NonpregnantLactating
ExtremeCHALLENGE
Hepatic Adaptation to Lactation
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
Energy intake and requirements for a lactation in dairy cows
0 14 28 42 56 70 84 98112
126140
154168
182196
210224
238252
266280
294-10
0
10
20
30
40
Energy Ingested
Energy Required
Neg
ativ
e
Po
siti
ve
Energy Balance = Energy Ingested - Energy Required
DIM
Mca
l/da
y
Adapted from Bauman and Currie 1980
After parturition extra energy requirement for milk production is not met by feed energy intake
Lipolisis
Parturition
KB
AdiposeTissue
TG NEFA
VLDL
CoA
CPT1CPT2
HSL
β-oxidation
KREB’S
CoACoA
CO2
CO2
CoA
CoA
CoA
CO2
CO2Liver
MusclesUdder
CoA
↓ Insulin
↑ epinephrine
Lipolisis
NEB
Lipid Metabolism during NEB
-17 -14 -11 -8 -5 -2 1 4 7 10 13 16 19 22 250
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0%
2%
4%
6%
8%
10%
12%
14%
NEFA Liver TG
Days
NEF
A m
Eq/L
Live
r TG
- %
DM
ParturitionAdapted from Overton 2003
Blood NEFA and Liver TG around calving
Incidence of fatty liver in dairy cows
Fatty liver is a common condition, up to 50 % of dairy cows
Consequences of Fatty Liver
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
Association of fatty liver with health status
Disorder Association ReferenceDisplaced 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
Association of Fatty Liver with impairment of the immune system
Curtis 1989
Mas
titis
inci
denc
e (3
0 da
ys)
Hepatic fat increment(2 wk after vs. 2 wk before calving)
Association of fatty liver with reproductive performance
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
PPARs
Regulation of Lipid Metabolism
Metabolism Regulation• All the cells regulate their metabolism in
response to changes in the environment and metabolize fuels according to their availability
MODERN VIEWNutrients can directly
regulate metabolism in a hormonal independent
manner
CLASSICAL VIEWmetabolic adaptations are controlled only by hormonal or neuronal
signals
Regulation of fat/cell interactions
PPARsPeroxisome Proliferator-Activated Receptors
Fat sensors transducing changes in cellular lipid levels to the transcriptional regulation of target
genes involved in fatty acid metabolism
Lipids control the expression of genes involved in their own metabolism
PPARs are Nuclear receptorsNUCLEAR 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
NUCLEAR RECEPTORS
PPARPeroxisome Proliferator-Activated Receptors
• 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
3 PPAR isotypes act as Fat Sensors
PPARγ
PPARδ
Fat Storage
PPARα
Fat Catabolism
Any changes in endogenous fatty acid profiles modulate the activity of PPAR
PPARs modulate Fat & Energy Metabolism
PPARα PPARδ PPARγ
STORAGE
FATenergy
BURNING
FATenergy
PPAR αActs in liver to maintain hepatic lipid
homeostasis and reduces fat concentrations
Peroxisomalβ-oxidation
Mitochondrialβ-oxidation
NEFATransport
NEFAUptake
Up-regulates genes involved in all aspects of Fat Catabolism
↑ epinephrine
↓ Insulin
KB
AdiposeTissue
TG NEFA
NEB
Lipolisis
HSL
CO2
CO2
MusclesUdder
VLDL
CoA
CPT1CPT2
β-oxidation
KREB’S
CoACoA
CO2
CO2
CoA
CoA
CoA
CoA
BURNING LIVER FAT
Liver
PPARα Activator
PPAR-α activators: Fibrates• 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
HEPAGEN®
2-methyl-2-phenoxy-propionic acid
2-methyl-2-phenoxy-propanoic acid2-Phenoxyisobutyric acid2,2-Dimethylphenoxyacetic acidMefepronic acid
O C
CH3
CH3
C
OH
O
CLINICAL TRIALSEffects of PPARα
activation in dairy cows
Effects of Hepagen on liver function and fertility
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
50 m
l/co
w
50 m
l/co
w
50 m
l/co
w
Calv
ing 3 d 5 d
Biopsy
1 d
Biopsy
Biopsy
15 d 30 d
Liver fat in control and Hepagen treated cows
Liver sections stained with toluidine blue
Sciorsci 2009
30 μm
CO
NT
RO
LT
RE
AT
ED
1 d 15 d 30 d
15 d 30 d0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
8.6%9.0%
0.3% 0.1%
Liver Fat
ControlTreated
P < 0.001
Liver glycogen in control and Hepagen treated cows
Liver sections stained with haematoxylin-PAS to highlight the presence of glycogen (purple). Sciorsci 2009
30 μm
CO
NT
RO
LT
RE
AT
ED
1 d 15 d 30 d
Albumins – Protein Synthesis
1 3 5 10 15 30 4026
27
28
29
30
31
32
33
34
35
36
ControlLinear (Control)HepagenLinear (Hepagen)
Days from parturition
g/L
• Albumin concentration significantly higher in the treated group• Albumin concentration in the control group slightly lower than the normal range
Reproductive Parameters
11 d 13 d -
1 2 3 4 5 6 7
3.70 4.24 5,46
6.47
Progesterone
ng/m
l
-
20
40
60
80
74 50
Days to 1° Heat
days
- 20 40 60 80
100 120 140
12192
Days open
days
-
20
40
60
80
50 6457 71
Pregnancy rate
days
Sciorsci 2009p<0.05HEPAGENCONTROL
Hepagen Effects on Ketosis36 Holstein cows (2°- 4° lactation)
50 m
l/co
w
50 m
l/co
w
50 m
l/co
w
Calv
ing
10 d-6/10 d
BHB
30 d 40 d
BHB
BHB
BHB
Bouda et al. 2008
Hepagen Effects on Ketosis
-10 10 30 400.40.50.60.70.80.91.01.11.2
Serum BHB Concentrations
BHB
mm
ol/L
10 30 400%
25%
50%
44%39%
28%17%
6% 6%
Subclinical Ketosis BHB > 1.4
CONTROLHEPAGEN
Bouda et al. 2008
p<0.05
Open days: lower in Control than in Treated group 109.9 vs. 118.5 days
Hepagen Effects on Ketosis57 Pluriparous Holstein cows
50 m
l/co
w
50 m
l/co
w
Calv
ing
2 hours-7/10 d
BHB
10 d 21 d
BHB
BHB
Aparicio et al. 2009
-5/8 d
BHB
2 dBH
B
CONTROL BCS: 3.25 – 3.75 TREATED BCS: 3.25 – 3.75
CONTROL BCS: ≥ 4 TREATED BCS: ≥ 4
Serum BHB Concentrations
-10 -7 2 10 210
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
CONTROL BCS ≥ 4
CONTROL BCS: 3.25 – 3.75
HEPAGEN BCS ≥ 4
HEPAGEN BCS: 3.25 – 3.75
Use Of Hepagen® in the Transition Dairy Cow : Practical Experiences
200 “Parmigiano-Reggiano” cows
50 m
l/co
w
50 m
l/co
wCa
lvin
g-20 d
Gorrieri 2009
BHB once/week
Follow Up (postpartum diseases, fertility)
Use Of Hepagen® in the Transition Dairy Cow : Practical Experiences
0%5%
10%15%20%25%30%35%
30 %15 %
Postpartum Diseases
0.00.20.40.60.81.0
0.86
0.35
Milk BHB
BHB
mg/
dl
50 60 70 80 90
100
8976
Days open
days
0%5%
10%15%20%25%30%
25 %
10 %
BHB +
metritis, displaced abomasum
Gorrieri 2009
HEPAGENPreventive and
Therapeutic Protocols for the Transition Cow
Preventive protocols in close-up dry cows
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
50
ml/
cow
7-10 days before expected time of Calving
50
ml/
cow
Day of calving
Preventive protocols in close-up dry cows
Preventive Protocols in Fresh Cows
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
50
ml/
cow
Calving
50
ml/
cow
After 2-3 days
Preventive Protocols in Fresh Cows
Therapeutic Protocols in Fresh cows
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
Diagnosis of Fatty Liver
• Difficult • No specific symptoms• Diagnosed by biopsy – invasive technique–hemorrhage, infection, death
• New promising ultrasound technology
Diagnosis of Fatty Liver• 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
50
ml/
cow
Early Identify and Treat
Follow up and repeat where appropriate
50
ml/
cow
After 24 h
Therapeutic Protocols in Fresh cows
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