Metabolic Modifiers
General Summary
Lecture Outline
• Somatotropin (bST, GH)
– What it is
– Mechanism
•  agonists
– What it is
– Mechanims
• Anabolic Steroids
– What are they
– How do the work
• CLA
– What it is
– Mechanism
Reasons for interest
• Agriculture
– Maximize efficiency
– Feed the hungry
– Economic reasons
• Dieting
– Thin obsession
• Athletics
–
–
–
–
Track and field
Baseball/football
Horseracing
Body Building
Why Alter Metabolism?
• Animal Agriculture
– Leaner animal is more efficient
– Consumers demand a leaner product
– Improve energy balance
•  Production,  Reproduction,  Metabolic Disorders
– Design animal lipid with “healthy” fatty acid profile
•  PUFA,  SFA,  Trans
• Human Health
–
–
–
–
–
–
Obesity (60% of Americans are overweight or obese)
Hyperlipidemia
Atherosclerosis
High blood pressure
Diabetes
Cancer
Somatotropin or Growth Hormone
•
•
•
•
Produced by the anterior pituitary
Protein hormone (~190 amino acids)
Approved in dairy cattle in 1994
Causes:
– During Growth
• Increased protein synthesis
• Decreased fat synthesis
– During Lactation
• Increased milk yield
• Increase feed intake
Somatotropin
• Mechanism: Direct and indirect (mediated by IGF-1)
– Lactation
• Increases mammary cell activity
• May increase mammary cell life span
• Increase liver secretion of IGF-1
– Insulin like growth factor-1 (IGF-1): potent stimulator of cell growth
– Growth: Depending upon EBAL
•
•
•
•
•
Increase protein synthesis
Decrease fat synthesis (lipogenesis)
Increase bone growth
Increase liver output of glucose (gluconeogenesis)
Increase liver secretion of IGF-I
Pituitary Gland
HYPOTHALAMUS
(Growth Hormone Releasing Factor, Somatostatin)
-
Anterior Pituitary
GH
Indirect
Growth-Promoting Actions
Direct
Anti-Insulin Effects
Liver and
other organs
Fat
(IGF)
Lipolysis
↓Lipogenesis
Skeletal
Extra-skeletal
 chondrogenesis
skeletal growth
 protein synthesis
 cell proliferation
Carbohydrates
↓ Insulin Sensitivity
Somatotropin Problems
Under production
or  sensitivity
Over production
Growing Animals
DWARFISM
Small size, juvenile
proportions (jaw)
Normal shape at maturity but
stunted (German shepherd)
Pygmies:
 responsiveness to GH
 IGF-I
GIANTS
Andre the Giant
Adults
ALOPECIA
Thin skin, hair loss (poodles)
Cushing’s Syndrome cortisol inhibits GH
synthesis
ACROMEGALY
Thickening of
bones/joints and skin
Enlargement of
internal organs
(tongue, liver, spleen)
Physiological
Situation
ST-Treatment
Genetically Superior
Inadequate nutrition
Poor Management
Circulating GH
Up
Up
Up
Up
Milk kg
Up
Up
Down
Down
Adequate
Nutrition
Moderate
Undernutrition
Mammary
Mammary
IGF Complex
Nutrient
Pool
ST
Severe
Undernutrition
Mammary
IGF Complex
Nutrient
Pool
+
ST
Nutrient
Pool
+
+
-
-
-
Adipose
Tissue
ST
Adipose
Tissue
Adipose
Tissue
*Adapted from Bauman and Vernon (1993)
Somatotropin and Pig Growth Parameters
Somatotropin Summary
• Produced in Anterior pituitary gland
– Protein hormone
– Completely digested in GIT
• Therefore must be injected
• Causes increased growth and milk yield
– Increase lean deposition and decrease fat
• Most effects mediated by IGF-I
• Commercially available (rbST)
• Most intensely studied drug (human or animal) in
the history of the pharmaceutical industry
-agonists
• Reasons for interest:
– Human medicine
• Branchodialators
– Agriculture
• Increase growth
–
–
–
–
Enhanced muscle
Decreased fat
Approved for pigs and cattle
Feed supplement
» Orally active
-agonists
• Molecules that structurally resemble epinephrine
– Caffeine, ephedrine, aspirin
• Easily made in the lab
• Muscle:
– Increase in muscle synthesis
– Decrease in muscle breakdown
• Fat
– Decrease in lipogenesis
– Increase in lipolysis
control
50 d/150.5 kg feed
100 kg /bw
-agonist
46 d/132 kg feed
75 kg
Moody et al., 2000
Ham
14.3 kg
Loin
11.2
Shoulders 11.9
Belly
10.2
13.3 kg
10.7
11.2
10.3
Carcass lean 43.9
39.4
 Agonist summary
• Structurally resembles epinephrine
• Increases muscle synthesis
– Need to increase the protein % of diet
•
•
•
•
Decreases fat content
Orally active
Desensitization
Recently approved for pigs
Steroids (Estrogens and Androgens)
• Classification
– Estrogenic
– Androgenic
• Predominate illegal steroid in humans
– Progestin
– Non-steroidal
Steroids (Estrogens and Androgens)
• Animal agriculture
– Approved for beef
– Not as effective in pigs
• Effects
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–
–
–
Increased protein accretion
Decreased fat accretion
Increased average daily gain
Increased feed efficiency
Steroids (Estrogens and Androgens)
• Mechanisms: not well understood
– Mediated via somatotropin?
•
•
•
•
Increase ST/GH
Increase ST/GH receptors
Increase IGF-1
Increase thyroid hormones
Negative side effects (humans)
• Both Genders
– Increased heart disease, liver cancer, acne, male
pattern baldness
• Females:
– Decreased breast size, deepening of voice, increase in body hair
• Males:
– reduced sperm production, shrinking of the testicles, impotence,
difficulty or pain in urinating, baldness, and irreversible breast
enlargement, testicular shrinking
Steroid summary
• Improves animal performance
– Approved for beef cattle
• Taken illegally by body builders
• Used legally for many health reasons
• Mechanism
– Via ST/GH system
Conjugated Linoleic Acid (CLA)
• Many isomers (n=24) found in ruminant food products
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–
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C18:2 cis-9, trans- 11
C18:2 trans-7, cis-9
C18:2 trans-10, cis-12
C18:2 cis-8, trans-10
A
B
C
• CLA has been shown to:
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–
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Anti-carcinogenic
Anti-atherogenic
Anti-diabetic
Enhanced immune system
Reduces severity of cachexia
Alleviates symptoms of lupus
Improved bone mineralization
Alters lipid metabolism
t10, c12 CLA
c9, t11 CLA
c9, c12 C18:2
CLA Effect During Growth
• Adipose tissue metabolism
– CLA supplement decreased body fat of mice by >
50 % (Park et al., 1997).
– CLA supplements reduce body fat content of
growing
•
•
•
•
•
Rats
Mice
Hamsters
Pigs
Dogs
Body Fat %
Effect of CLA on Body Fat in Growing Mice
25
Con
20
CLA
15
10
5
0
0
2
4
0
2
4
6
8
Body Fat (g)
8
6
4
2
0
6
8
Week on Treatment
Adapted from Park et al., 1999
Effect of Dietary CLA on Body Fat of Growing Gilts
Dietary CLA, %
Backfat Thickness, mm
0
21.0
0.125
17.1
0.250
16.1
0.500
16.9
0.750
15.4
1.000
14.6
White x Landrace gilts received dietary supplement of CLA for 8 weeks
(final body weight 100-105 kg). Significant at P<0.024. Adapted from
Ostrowska et al. 1999.
CLA Effect During Growth
• Lean tissue metabolism
– CLA supplements increase protein
percentage
• Mice
• Rats
• Pigs
Effect of CLA on Body Protein in Mice
Con
20
Protein (%)
CLA
18
16
14
0
2
4
6
8
0
2
4
6
8
6
Protein (g)
5.5
5
4.5
4
Week of Treatm ent
Adapted from Park et al., 1999
Effects of CLA on Body Composition
of Mice
CLA
Body fat
Body protein
Days
% of diet
%
g
%
g
321
0.0
0.5
18.7a
7.5b
4.7*
1.7*
17.7a
20.1b
4.4*
4.6*
392
0.00
0.25
0.50
0.75
1.00
28.8a
27.4b
22.8b
22.8b
18.8c
9.9a
9.3a
7.5b
7.1c
5.7c
15.5a
16.3a
16.6a
16.6a
18.2b
5.3
5.5
5.4
5.1
5.5
*Calculated by LHB
1Park
et al 1997
2DeLany
et al 1999
CLA Products Available in “Health Stores”
CLA Effect on Human Body
Composition
• No indication of increase in body lean
• Studies showing decrease in body fat
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–
–
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Blankson et al., 2000
Riserus et al., 2001
Smedman et al., 2001
Thom et al., 2001
Minor (3-6%)
• Studies showing no effect on body fat
– Medina et al., 2000
– Zambell et al., 2000
– Atkins et al., 1999
Potential Mechanisms
•  Lipolysis
•  Hormone sensitive lipase
• Results are inconsistent with most showing no
effect on plasma NEFA concentrations
•  Lipogenesis
• LPL activity; observed in many studies
Conjugated linoleic acid summary
• Naturally found in diet
– Meat and milk
• Decreases fat accretion
– Decreases lipogenesis and increases lipolysis
• No effect on protein metabolism
• In experimental phase, not yet approved for
animal agriculture
Metabolic modifiers
• Improve production
– Increase protein synthesis
– Decrease fat synthesis
– Increase milk yield
• Improve farm economics
– Increased feed efficiency
• Enhance human performance
• Most studied molecules in pharmaceutical history
• Animals supplemented with modifiers are
completely safe to eat
• Improving the efficiency of food (animal and
plant) production is essential to feed the worlds
growing population