Metabolic Modifiers General Summary. Lecture Outline Somatotropin (bST, GH) –What it is –Mechanism agonists –What it is –Mechanims Anabolic Steroids.

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