1. Metabolic Modifiers General Summary

2. 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

3. Reasons for interest Agriculture –Maximize efficiency –Feed the hungry –Economic reasons Dieting –Thin obsession Athletics –Track and field –Baseball/football –Horseracing –Body Building

4. 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

5. 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

6. 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

7. Pituitary Gland

8. HYPOTHALAMUS (Growth Hormone Releasing Factor, Somatostatin) Anterior Pituitary GH Indirect Growth-Promoting Actions Direct Anti-Insulin Effects Liver and other organs (IGF) Extra-skeletalSkeletal CarbohydratesFat  chondrogenesis skeletal growth  protein synthesis  cell proliferation  Lipolysis ↓Lipogenesis ↓ Insulin Sensitivity - -

10. 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

14. Mammary Nutrient Pool Adipose Tissue Mammary Nutrient Pool ST IGF Complex Adequate Nutrition Moderate Undernutrition Severe Undernutrition *Adapted from Bauman and Vernon (1993) + + - - - + Physiological Situation Circulating GHMilk kg ST-TreatmentUp Genetically SuperiorUp Inadequate nutritionUpDown Poor ManagementUpDown

16. Somatotropin and Pig Growth Parameters

17. 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

18. Reasons for interest: –Human medicine Branchodialators –Agriculture Increase growth –Enhanced muscle –Decreased fat –Approved for pigs and cattle –Feed supplement »Orally active  -agonists

19. 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

20. 46 d/132 kg feed 50 d/150.5 kg feed control  -agonist Ham 14.3 kg 13.3 kg Loin 11.2 10.7 Shoulders 11.9 11.2 Belly 10.2 10.3 Carcass lean 43.9 39.4 Moody et al., 2000 75 kg 100 kg /bw

21.  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

22. Steroids (Estrogens and Androgens) Classification –Estrogenic –Androgenic Predominate illegal steroid in humans –Progestin –Non-steroidal

23. 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)

24. Mechanisms: not well understood –Mediated via somatotropin? Increase ST/GH Increase ST/GH receptors Increase IGF-1 Increase thyroid hormones Steroids (Estrogens and Androgens)

25. 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

26. 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

27. Conjugated Linoleic Acid (CLA) Many isomers (n=24) found in ruminant food products –C 18:2 cis-9, trans- 11 –C 18:2 trans-7, cis-9 –C 18:2 trans-10, cis-12 –C 18:2 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 c9, t11 CLAt10, c12 CLAc9, c12 C 18:2

28. 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

29. Adapted from Park et al., 1999 Effect of CLA on Body Fat in Growing Mice

30. Effect of Dietary CLA on Body Fat of Growing Gilts Dietary CLA, %Backfat Thickness, mm 021.0 0.12517.1 0.25016.1 0.50016.9 0.75015.4 1.00014.6 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.

31. CLA Effect During Growth Lean tissue metabolism –CLA supplements increase protein percentage Mice Rats Pigs

32. Adapted from Park et al., 1999 Effect of CLA on Body Protein in Mice

33. Effects of CLA on Body Composition of Mice 1 Park et al 1997 2 DeLany et al 1999 *Calculated by LHB

34. CLA Products Available in “Health Stores”

35. 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%)

36. 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

37. 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

38. 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