1 Key Points for This Presentation Transition cows undergo extreme - - PDF document

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Metabolic and Management Challenges of Periparturient Cows

Michael Overton, DVM, MPVM

Associate Professor, Dairy Production Medicine University of Georgia, College of Veterinary Medicine

Denise Rich – therichartist.com

Management Timeline for Dairy Cattle

Dry-off

Far dry period

Close-up

(3 weeks prior to calving)

Transition

Calving Fresh period

(3 weeks after calving)

Lactation

Milk Production Reproduction

Transition Period Metabolic Changes and Challenges Facing the Periparturient Cow

Rapid fetal growth Decrease in DMI Initiation of lactation

Hormonal changes

Hypocalcemia Immunosuppression Negative energy balance

Fat mobilization Colostrum production Exposure of teats and uterus to pathogens Sudden demand for calcium

Diet/ rumen changes Pen moves

Liver challenges

Increased risk of…

Ketosis Milk fever Metritis Mastitis Poor milk production Repro challenges Culling/ death Etc

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Key Points for This Presentation

Transition cows undergo extreme changes and

challenges during the transition period

Energy (glucose) and calcium needs dramatically increase

despite drops in feed intake despite drops in feed intake

Excessive mobilization of fat presents challenges to the

liver’s capacity to make glucose

Management needs to focus on ways to improve

metabolic health of transition cows

Overview of the Adaptations at Parturition and Onset of Lactation

(Bauman and Currie, 1980; Bauman, 2000; Ingvartsen and Andersen, 2000)

Rumen: size absorptive capacity rate of nutrient absorption Adipose Tissue: lipolysis de novo fat synthesis uptake of preformed fatty acids re-esterification of fatty acids Liver: size rate of gluconeogenesis protein synthesis ketogenesis Muscle: glucose utilization protein synthesis protein degradation Mammary gland: # secretory cells nutrient use supply of blood

Ruminants are Quite Unique

~ 90% of the carbohydrate carbon that becomes

available for metabolism by the cow is in the form

• f VFA’s

Very little glucose available for absorption Most is modified (fermented) by rumen microbes Cows are very dependent on gluconeogenesis for

maintaining blood glucose levels

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Cows Rely on Hepatic Gluconeogenesis to Meet their Glucose Needs

Propionate

L ct s (milk)

Gluconeogenesis – the pathway consisting of enzyme-catalyzed reactions that primarily take place in the mitochondria or cytoplasm of the liver that takes precursors and forms glucose

Propionate

~ 30 to 70%

Amino acids (Alanine)

Up to ~ 30%

Lactate

Up to ~ 15%

Glycerol

Normally, very small

amounts

Glucose

Lactose (milk) Fetus Nervous tissue Other energy needs

Liver

When Energy Output is Greater than Energy Intake, Negative Energy Balance (NEB)

In response to energy demands, cows undergo

lipolysis – breakdown (or mobilization) of fat stores

Result:

“Free” fatty acids (NEFA’s) circulating in blood Glycerol

Oxidation of NEFA

Fatty acid ß-oxidation:

Provides ATP for glucose synthesis Stimulates gluconeogenesis from lactate and alanine (via acetyl-CoA

activation of pyruvate carboxylase)

ß-Oxidation: pathway that sequentially removes two-carbon

acetyl-CoA units from a long-chain fatty acid (acyl-CoA)

Complete combustion (oxidation) of NEFA generates Acetyl-Co A

that can be used to generate energy via the Krebs Cycle

If Krebs Cycle gets overloaded, acetyl Co A is shunted off to

produce ketones (acetoacetic acid, acetone, and BHBA)

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Fetal Needs During Late Pregnancy

Fetal metabolic rate (weight-specific oxygen consumption) ~

2X the dam

Most energy and nitrogen needs of the fetus for growth/

metabolism supplied by glucose (and lactate) and amino acids from maternal circulation acids from maternal circulation

Glucose uptake – passive AA uptake via active placental transport (independent of maternal

blood concentration)

During hypoglycemia, fetus makes up by using more AA for energy

Fetus cannot take direct advantage of mobilized maternal

lipids

Bell, 1995

Despite Increasing Needs, Feed Intake Drops Dramatically Prior to Calving

DMI Drop is Greater in Mature Cows and in Fat Cows Normal cows:

• Often see drops of

25% (i DMI

Ex: 13 kg to 9 kg

Grummer

25% (i.e., DMI declines to 70-75%

• f original level)

Fat cows (BCS >3.75):

• May drop by > 40%
• f DMI at -21 days

Around Calving, Cortisol Levels Increase

Cortisol induces changes in mammary cells Promotes maturation of the fetal lungs

Promotes maturat on of the fetal lungs

Promotes production of surfactant that is

necessary for normal lung function after birth

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Short Term Increases In Cortisol Help With Gluconeogenesis

Mobilize amino acids from extrahepatic tissues Stimulate gluconeogenesis, particularly in the liver

Results in the production of glucose from amino acids

Inhibits uptake of glucose by muscle and fat tissue

Tries to conserve glucose (glucose-sparing effect)

Stimulates the breakdown of fat

The fatty acids released by lipolysis are used for production of

energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis

Periparturient Immunosuppression

• Increased cortisol
• migration of leukocytes
• phagocytosis
• IGF-1
• Protein/ energy/ vitamin/ mineral

deficiencies:

• neutrophil migration and killing ability
• lymphocyte function
• Spike in estradiol level
• Suppress cell-mediated immunity
• Depresses appetite
• Lower levels of vitamin A & E at calving
• Partly from colostrum demands
• Higher consumption due to metabolic/

immunologic stress

Goff and Horst, 1997

Periparturient Calcium Needs

Dry cow Ca needs – only ~ 10-12 g/ day Around calving – cow must bring ~ 30 g Ca/ d into

the Ca pool

A cow producing ~ 2.5 gallons colostrum loses ~ 23 g Ca

A cow producing 2.5 gallons colostrum loses 23 g Ca in a single milking

~ 9 X the total plasma level of Ca in a cow To make up the difference, cows need to absorb more

from intestine and mobilize bone

Hypocalcemia (clinical and subclinical) impact DMI

and immune function)

Horst et al, 1997

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After Calving, There is a Rapid Acceleration in Nutrient Needs

Within a few days of calving, mammary requirements are

increased as compared to uterine demands just before calving:

Glucose

• 2.7 X gravid uterus

Glucose .7 X grav d uterus

Amino acids

• 2.0 X gravid uterus

Fatty acids

• 4.5 X gravid uterus

Total “Energy”

– ~3 X gravid uterus

Despite these needs, feed intake is low

Negative energy balance: -10 to -15 Mcal/ d (or more) Negative protein balance: - 500 to -600 g/d (or more)

Predicted Whole-Body Glucose Demand and Supply During Transition

Adapted from T.R. Overton, 2001

During late pregnancy, uterus is taking ~ 50% of total maternal supply

Glucose Availability is Key

Mammary uptake of glucose at 1 DIM ~ 9X that at 1 week prior to calving Glucose is required to make lactose Glucose is required to make lactose Lactose is the osmotic driver for milk production

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Liver is Crucial in These Adaptations

The liver actually increases in size and metabolic activity

Day relative to calving

• 21

11 22

Glucose release from liver increases from ~ 1300 g/d at

11-d prepartum to over 2700 g/d at 11-d postpartum

Liver weight (lbs) ~ 19 ~ 19 ~ 21 Oxygen uptake (moles/d) 35 76 80

Bell, 1995 and Reynolds et al, 2000

Cows Adapt to the Increasing Demand for Glucose by Shifting into a Glucose-Sparing Mode

• 1. Increased hepatic gluconeogenesis but reduced

glucose uptake by maternal peripheral tissues

Mobilizes body protein (amino acids) for glucose production Mobilizes large amounts of body fat

Cow’s body shifts more toward energy utilization from circulating

fats

Fetus benefits indirectly – receives disproportionate amount

• f glucose
• 2. Changes in insulin levels and sensitivity

Normal Roles of Insulin

General (normal) role is to increase nutrient storage

and decrease blood glucose concentrations

Liver Muscle Fat Carbohydrate Metabolism Glucose uptake, Glycogen synthesis X X X Glycogenolysis X X X Gluconeogenesis X Fat (Lipid) Metabolism Lipogenesis X X Lipolysis X X Protein Metabolism Amino acid uptake X Protein synthesis X Protein degradation X Gluconeogenesis X

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Insulin Changes in Periparturient Cows

Insulin decreases around calving Initiation of lactation is accompanied by insulin

resistance, mediated by increased somatotropin

Since mammary gland does not require insulin for

S nc mammary g an

• s not r qu r

nsu n for nutrient uptake, mammary gland is given priority for glucose use

Mammary receptors up-regulated, adipose and other

tissue receptors are down-regulated

High Producing Dairy Cow are Unique: NEB – Attenuation of Somatotropic Axis

Normally, GH binds to GHR IGF-1 In Periparturient dairy cow:

GHR expression IGF-1 GH

Gluconeogenic efforts from the liver Antagonizes insulin – creates “insulin resistance” Utilization of glucose by “non-essential” tissues

(Glucose sparing for lactose production)

M.C. Lucy, Reprod Dom Anim, 2008

Consequences of Attenuation of the Somatotropic Axis – Catabolic State

Low insulin and low IGF-1:

Lypolysis – breakdown of fat Increase in NEFA’s Repartitioning of nutrients – spare glucose for mammary gland for

milk production

Reduced GnRH / LH secretion Reduced ovarian responsiveness to gonadotropins

If transition mgmt/ cow health are good, temporary issue If mgmt is poor, leads to compromised liver function and

prolonged recovery

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Lance Baumgard, 2007

Underfed/ Peripartum

Metabolic Flexibility: Decreased Insulin Sensitivity

Lance Baumgard, 2007

Gluconeogenesis from Amino Acids Also Increases

All amino acids except leucine and lysine can be

used to support gluconeogenesis

Alanine and glutamine usually account for 40-60%

• f the gluconeogenic potential of all amino acids

Alanine is greatest contributor

Released by peripheral tissues Contribution toward gluconeogenesis is limited by their

supply (correlated to daily protein intake)

Drackley et al., 2001

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Quick Review: Metabolic Changes Associated with Lactogenesis

Function Metabolic Change Tissues Affected Milk Synthesis Use of nutrients (partitioning) Mammary Lipid Metabolism Lipolysis, Lipogenesis Adipose tissue Glucose Metabolism Gluconeogenesis, Glycogenolysis Liver Use of glucose, Use of lipids for energy Body tissues Protein Metabolism Mobilization of protein sources Muscle Mineral Metabolism Absorption and mobilization of calcium Kidney, liver, gut, and bone (Bauman and Currie, 1980)

Feed Intake and NEFA Levels

30 40 50 600 800 1000

23 18 14

mol/l) Burhans and Bell, 1998

10 20

• 29 -22 -15
• 8
• 1

6 13 20 27 200 400 DMI (lbs) NEFA

9 4.5 kg (kg)

(um

Energy Balance

• Negative energy

balance

• Energy intake

< energy outflow

• “Normal” cows may

experience NEB for 2 months or more

• But reach NEB

nadir within first 3 weeks

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During NEB (and High Stress), Cortisol and Stress Hormones are Elevated

Cows breakdown body tissue (fat and protein) in an attempt to make up the energy gap

Catabolism

Fats

Hormone-sensitive Lipase Stimulated by:

Fats “Free” fatty acids

(NEFA’s) circulating in blood

Glycerol Amino acids – from

muscle tissue

Stimulated by: Epinephrine Norepinephrine Glucagon Thyroxine Inhibited by: Insulin

Glycerol Increases As a Source for Gluconeogenesis

May support 15-20% of glucose demand at 4-d

postpartum

Level of contribution is dependent on amount of fat Level of contribution is dependent on amount of fat

mobilized

Double-edged sword – increased fat mobilization

yields more glycerol, but liver must also deal with extra fat

Bell, 1995

Bovine Liver Has 3 Major Options For Disposition Of Fatty Acids

Complete oxidation to

carbon dioxide

Partial oxidation to ketone

bodies

Acylglycerol synthesis and

storage in the liver

Limited ability to export out

• f liver via lipoproteins

Minor option – secretion in

bile

(Encyclopedia of Animal Science by Wilson G. Pond & Alan W. Bell, Published by CRC Press, 2005)

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When Relatively Little Fat is Mobilized – Health is Maintained – No Real Issues

Ci l tin

(muscle and other tissues)

Circulating NEFA’s Liver *Complete oxidation (ATP and CO2)

Incomplete oxidation (Ketones) Re-esterification (triglycerides)

VLDL’s

Continued/ excessive

mobilization of fat (NEFA’s)

Too many C-2 compounds

relative to C-3 compounds

With Continued DMI Depression

(Specifically, Insufficient Glucose Precursors)…

A mismatch of Acetyl-CoA

and Oxaloacetate

Additional Acetyl-CoA is

diverted to production of ketone bodies (BHBA)

Result – ketosis and

elevated BHBA levels

(van Knegsel et al., 2005)

Hepatic Lipidosis (Fatty Liver)

Occurs when there is excessive influx of NEFA’s

into the liver and rate of triglyceride synthesis exceeds the rate of oxidation and export

Healthy Liver Fatty Liver

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Cows with Fatty Liver Have a Decreased Ability to Produce Glucose

Propionate

~ 30 to 70%

Amino acids (Alanine)

Up to ~ 30%

Lactate Lactose (milk) Fetus Nervous tissue Other energy needs Lactate

Up to ~ 15%

Glycerol

Normally, very small

amounts

Glucose

gy

Liver Therefore:

• Reduced milk production
• Increased risk of metabolic disorders

Other Consequences of Fatty Liver

Reduced disease resistance and prolonged recovery

from disease

Increased culling risk Increased culling risk Depressed appetite Possible reduction in reproductive efficiency due

to hypocholesterolemia

(Review by Emery et al., 1992)

Management Efforts are Directed at Reducing the Mobilization of Fat

Management Efforts

Reduce stress

Causes increased

energy demands d f

Body fat NEFA Fat NEFA NEFA Liver Insulin Epi

+

Drackley, 1999

Causes increased fat

mobilization

Increase insulin

response

Decreases lipolysis Promotes lipogenesis Fat TG Fat VLDL Ketone Bodies Milk Fat Mammary Gland CO2 Propionate Mitochondrial Fuel use Glucose (precursors)

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Strategies for Managing NEFA’s in Transition Cows – 2 Main Approaches

Approach # 1: Decrease supply of NEFA through diet and management

*Maintain/ maximize feed intake (incl/ fermentable carbs) *Diminish excess maintenance needs – heat stress, mud stress, standing times, etc Targeted feeding/ supplementation of gluconeogenic precursors

Propylene glycol Calcium propionate

Strategies for Managing NEFA’s in Transition Cows

Approach # 2: Optimize ability of liver to handle NEFA’s

Increase ability to burn them for fuel

Process is sensitive to carnitine supply (quasi-vitamin required pp y (q m q for transport of NEFA into mitochondria where they are burned) Synthesized in rumen via methionine and lysine

Increase ability to export them back as triglycerides in VLDL’s

Rate limiting step – apoprotein B – stabilizes VLDL particle – Increased by additional methionine and lysine Choline – quasi-vitamin that facilitates export via VLDL

In Summary:

Transition cows undergo extreme changes and challenges during the transition period

Cow modify how their body metabolizes glucose

Changes in whole-body metabolism Liver-specific adaptations for glucose synthesis Increased reliance on amino acids for glucose production Increased reliance on amino acids for glucose production

Fat mobilization and resulting NEFA’s present challenges to

the liver’s capacity to make glucose

Management needs to focus on ways to improve metabolic

health of transition cows

Minimize risk of excessive fat mobilization Improve supply-side manipulations

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Thanks For Your Attention!

Michael Overton, DVM, MPVM Department of Population Health University of Georgia

Any Questions?

y g College of Veterinary Medicine (706) 542-0177 moverton@uga.edu