Metabolic Modifiers General Summary. Lecture Outline Somatotropin (bST, GH) –What it is –Mechanism agonists –What it is –Mechanims Anabolic Steroids.
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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
• 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
Somatotropin
Pituitary Gland
HYPOTHALAMUS (Growth Hormone Releasing Factor, Somatostatin)
Anterior Pituitary
GH
IndirectGrowth-Promoting Actions
DirectAnti-Insulin Effects
Liver and other organs
(IGF)
Extra-skeletalSkeletal
CarbohydratesFat
chondrogenesis skeletal growth
protein synthesis cell proliferation
Lipolysis↓Lipogenesis
↓ Insulin Sensitivity
-
-
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)
Somatotropin Problems
Mammary
Nutrient Pool
Adipose Tissue
Adipose Tissue
Adipose Tissue
Mammary Mammary
Nutrient Pool
Nutrient PoolST ST ST
IGF Complex IGF Complex
Adequate Nutrition
Moderate Undernutrition
Severe Undernutrition
*Adapted from Bauman and Vernon (1993)
+ +
- --
+
Physiological Situation
Circulating GH Milk kg
ST-Treatment Up Up
Genetically Superior Up Up
Inadequate nutrition Up Down
Poor Management Up Down
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
• 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
-agonists
46 d/132 kg feed
50 d/150.5 kg feed
control
-agonist
Ham 14.3 kg 13.3 kgLoin 11.2 10.7Shoulders 11.9 11.2Belly 10.2 10.3
Carcass lean 43.9 39.4
Moody et al., 2000
75 kg
100 kg /bw
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
• Animal agriculture– Approved for beef– Not as effective in pigs
• Effects– 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
Steroids (Estrogens and Androgens)
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
– C18:2 cis-9, trans- 11– C18:2 trans-7, cis-9– C18:2 trans-10, cis-12– C18:2 cis-8, trans-10
• CLA has been shown to:– Anti-carcinogenic– Anti-atherogenic– Anti-diabetic– Enhanced immune system– Reduces severity of cachexia– Alleviates symptoms of lupus– Improved bone mineralization – Alters lipid metabolism
A B C
c9, t11 CLAt10, c12 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
0
5
10
15
20
25
0 2 4 6 8
Bo
dy
Fat
%
Con
CLA
0
2
4
6
8
0 2 4 6 8
Week on Treatment
Bo
dy
Fat
(g)
Adapted from Park et al., 1999
Effect of CLA on Body Fat in Growing Mice
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
14
16
18
20
0 2 4 6 8
Pro
tein
(%
)
Con
CLA
4
4.5
5
5.5
6
0 2 4 6 8
Week of Treatment
Pro
tein
(g
)
Adapted from Park et al., 1999
Effect of CLA on Body Protein in Mice
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
1Park et al 1997
2DeLany et al 1999
*Calculated by LHB
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
– Blankson et al., 2000– Riserus et al., 2001– Smedman et al., 2001– Thom et al., 2001
• Studies showing no effect on body fat– Medina et al., 2000– Zambell et al., 2000– Atkins et al., 1999
Minor (3-6%)
Potential Mechanisms
Lipolysis Hormone sensitive lipase• Results are inconsistent with most showing no
effect on plasma NEFA concentrations
LipogenesisLPL 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
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