Roy J. Martin

Animal growth regulation.

1 Placental Regulation of Fetal Growth.- 1. Introduction.- 2. Placental Anatomy and Pattern of Blood Flow.- 3. Placental Growth.- 4. Growth of Uteroplacental Blood Flow.- 5. Regulation of Blood Flow.- 6. Placental Transport.- 7. Hormone Secretion.- 8. Conclusions.- References.- 2 Endocrinology of Bone Formation.- 1. Introduction.- 1.1. Unique Aspects of Bone Physiology.- 1.2. Bone Structure.- 1.3. Methods of Investigating Bone Formation.- 2. Hormones.- 2.1. Somatomedins.- 2.2. PTH.- 2.3. Vitamin D.- 2.4. Calcitonin.- 2.5. Insulin.- 2.6. Thyroid Hormones.- 2.7. Sex Steroids.- 2.8 Glucocorticoids.- 3. Local Regulators of Bone Formation.- 3.1. Prostaglandins.- 3.2. Noncollagen Proteins.- 3.3. Growth Factors.- References.- 3 Endocrine Regulation of Adipogenesis.- 1. Introduction.- 2. Insulin.- 3. Growth Hormone.- 4. Insulinlike Growth Factors.- 5. Glucocorticoids.- 6. Indomethacin, Prostaglandins, and AMP.- 7. Thyroid Hormones.- 8. Cachectin.- 9. Autocrine Control.- 10. Perspectives on Integrated Endocrine Control.- References.- 4 Autocrine, Paracrine, and Endocrine Regulation of Myogenesis.- 1. Introduction.- 2. Muscle Structure.- 3. Myogenesis.- 4. Factors Affecting Myogenesis.- 4.1. Insulinlike Growth Factors (Somatomedins).- 4.2. Insulin.- 4.3. Transforming Growth Factor-? (TGF-?) (Differentiation Inhibitor).- 4.4. Transferrin.- 4.5. Fibroblast Growth Factor (FGF).- 4.6. Somatotropin.- 4.7. Glucocorticoids.- 4.8. Thyroid Hormone.- 5. Summary.- References.- 5 The Expression of Protooncogenes in Skeletal Muscle.- 1. Introduction.- 2. Categories of Oncogenes.- 2.1. Tyrosine Kinases.- 2.2. GTP-Binding Proteins.- 2.3. Nuclear Proteins.- 2.4. Peptide Hormones.- 3. Oncogene Expression in Skeletal Muscle.- References.- 6 Regulation of Myofibrillar Protein Gene Expression.- 1. Introduction.- 2. Multigene Families.- 3. Major Myofibrillar Proteins of the Sarcomere.- 3.1. Actin.- 3.2. Tropomyosin (TM).- 3.3. Troponin (TN).- 3.4. Myosin Light Chains (MLC).- 3.5. Myosin Heavy Chains (MHC).- 4. Isolation and Characterization of MHC Sequences.- 5. Effects of Various Stimuli on MHC Gene Expression.- 5.1. Thyroid Hormone.- 5.2. Exercise/Electrical Stimulation.- 6. Alternative Splicing and MHC Gene Structure.- 7. Conclusions.- References.- 7 Regulation of Growth by Negative Growth Regulators.- 1. Introduction.- 2. Transforming Growth Factor-?.- 3. Platelet-Derived Inhibitors.- 3.1. 37-kDa Protein.- 3.2. 27-kDa Protein.- 3.3. Proteins Greater than 200 kDa.- 4. Interferons.- 5. Liver-Derived Inhibitors.- 6. Mammary-Derived Inhibitor.- 7. Glycopeptide Inhibitors.- 8. Density-Dependent Inhibitors.- 9. Summary.- References.- 8 Skeletal Muscle Proteases and Protein Turnover.- 1. Introduction.- 2. General Features of Intracellular Protein Degradation.- 3. Intracellular Degradation of Muscle Proteins.- 4. Neutral and Alkaline Proteolytic Activities.- 4.1. Neutral and Alkaline Proteolytic Activities in Muscle Cells.- 4.2. The ATP-Stimulated and ATP-Dependent Proteinases.- 4.3. The Ca2 +-Dependent Proteinases.- 5. Protease Inhibitors.- 6. Summary.- References.- 9 Regulation of Protein Turnover.- 1. Introduction.- 2. Factors That Affect Tissue Growth and Protein Turnover.- 2.1. Protein Turnover in Different Tissues and the Effect of Developmental Age.- 2.2. Nutrient Intake.- 2.3. Functional Load.- 3. Factors That Control Protein Turnover.- 3.1. Substrates and Hormones and Their Relation to Nutritional Control.- 3.2. The Role of Initiation and Ribosomal Accretion in the Control of Translation.- 3.3. Comments on the Link between Receptor Activation and Protein Synthesis.- 4. Conclusion.- References.- 10 Energy Balance Regulation.- 1. Introduction.- 2. Evidence for Energy Balance Regulation in Farm Animals.- 2.1. Lactation.- 2.2. Growing Animals.- 2.3. Compensatory Growth.- 2.4. Egg Production.- 3. Mechanisms of Energy Balance Regulation.- 3.1. Lactation.- 3.2. Brown Adipose Tissue Metabolism.- 3.3. Compensatory Growth.- 4. CNS Control of Food Intake.- 4.1. Brain Areas Involved.- 4.2. Mechanisms of Action.- 5. CNS Control of Peripheral Metabolism.- 5.1. Brain Areas Involved.- 5.2. Direct Regulation.- 5.3. Indirect Regulation.- 6. Theories of Signals Regulating Food Intake.- 6.1. Short-Term Mechanisms.- 6.2. Long-Term Mechanisms.- 7. Role of Neurotransmitters and Neuropeptides.- 8. Summary.- References.- 11 Central Regulation of Growth Hormone Secretion.- 1. Introduction.- 2. Patterns of GH Secretion.- 3. Hypothalamic Peptides Involved in GH Regulation.- 3.1. Somatostatin.- 3.2. GH-Releasing Factor (GRF).- 3.3. Other Peptides That Increase GH Secretion.- 4. Hypothalamic Regions Involved in GH Regulation.- 5. Interaction of Somatostatin and GRF in Episodic GH Secretion.- 6. Neuropharmacological Regulation of GH Secretion.- 6.1. Norepinephrine (NE).- 6.2. Dopamine (DA).- 6.3. Serotonin (5-HT).- 6.4. Other Neurotransmitters.- 7. Gonadal Steroid Modulation of GH Secretion.- 8. Feedback Regulation of GH Secretion.- References.- 12 Mechanisms of Action for Somatotropin in Growth.- 1. Introduction.- 2. Chemical Nature of Somatotropin.- 2.1. Variants of Somatotropin.- 2.2. Fragments of Somatotropin.- 2.3. Receptor Mediation of Somatotropin Effects.- 3. Biological Response to Somatotropin.- 3.1. Nutrient Partitioning.- 3.2. Pattern of Administration.- 3.3. Dose-Response Relationships: Growth Model.- 4. Mechanisms of Action.- 4.1. General Considerations.- 4.2. Carbohydrate Metabolism.- 4.3. Bone and Mineral Metabolism.- 4.4. Adipose Tissue Lipid Metabolism.- 4.5. Muscle and Protein Metabolism.- 5. Summary and Perspectives.- References.- 13 Regulation of Somatomedin Production, Release, and Mechanism of Action.- 1. Origin of the Somatomedin Hypothesis.- 2. Methods of Analyses.- 3. Gene Expression and the Insulin Peptide Family.- 4. Site of Synthesis.- 5. Somatomedin Research in Domestic Animals.- References.- 14 Sexual Differentiation and the Growth Process.- 1. Introduction.- 2. Rats.- 3. Cattle and Sheep.- 4. Swine.- 5. Chickens.- 6. Sexual Differences in Growth-Related Endocrine Processes.- 7. Conclusions.- References.- 15 Potential Mechanisms for Repartitioning of Growth by ss-Adrenergic Agonists.- 1. Introduction.- 2. Biology of Adrenergic Hormones and Neurotransmitters.- 2.1. Endogenous Adrenergic Agents.- 2.2. Synthesis and Removal.- 2.3. Adrenergic Receptors.- 2.4. Coupling of Adrenergic Receptors to Intracellular Function.- 2.5. Physiological Effects of Adrenergic Agonists.- 3. Administration of ss-Adrenergic Agonists to Animals.- 3.1. Effects.- 3.2. Adipose Tissue.- 3.3. Muscle.- 3.4. Other Mechanisms.- References.- 16 Gene Transfer for Enhanced Growth of Livestock.- 1. Introduction.- 2. Identification of Genes for Transfer.- 3. Methods of Producing Transgenic Animals.- 3.1. Microinjection into Fertilized Ova.- 3.2. Retroviral Insertion of Genes.- 3.3. Insertion via Pluripotent Cells.- 3.4. Insertion by Transposons.- 4. Production of Transkaryotic Animals.- 5. Transfer of Growth-Related Genes into Livestock.- 5.1. Integration of Growth-Related Genes.- 5.2. Expression of Integrated Genes.- 5.3. Growth Performance of Transgenic Livestock.- 5.4. Germline Transmission of Fusion Genes.- 5.5. Expression in Animals with Transkaryotic Implants.- 6. Conclusions.- References.- 17 Status of Current Strategies for Growth Regulation.- 1. Introduction.- 2. Steroid Hormone and Xenobiotic Regulation of Animal Growth.- 3. Manipulation of Animal Growth with Exogenous Somatotropin.- 4. Use of Growth Hormone-Releasing Factor (GRF) to Alter Animal Growth.- 5. Use of ?-Adrenergic Agonists to Manipulate Animal Growth.- 5.1. Effects of Adrenergic Agonists in Sheep.- 5.2. Effects of Adrenergic Agonists in Cattle.- 5.3. Effects of Adrenergic Agonists in Swine.- 6. Use of Immunization to Manipulate Animal Growth.- 7. Summary and Perspectives.- References.

A Comparison of the Enzyme Levels and the In Vitro Utilization of Various Substrates for Lipogenesis in Pair-Fed Lean and Obese Pigs

Summary In this study of spontaneous obesity of pigs, specific metabolic shifts were observed, which explain an increase in fat deposition. Liver tissue utilization of pyruvate and glucose for oxidation and lipogenesis showed no significant difference between lean and obese pigs. Adipose tissue utilization of glucose, acetate and glycerol for triglyceride and fatty acid synthesis was greater in obese pigs than lean pigs (P < 0.01). No significant difference in leucine incorporation into lipid fractions was found. Of the substrates utilized, glucose supplied 86 and 94% of the glyceride-glycerol synthesized in lean and obese pigs, respectively. Glycerol was not a major contributor to glyceride-glycerol synthesis (3.5 to 5.5%), in spite of the presence of adipose tissue glycerokinase. An increase (P < 0.05) in alanine incorporation into glucose was observed in liver tissue from obese pigs. In general, the levels of enzyme activities associated with gluconeogenesis, glycolysis, and lipogenesis supported the findings of in vitro utilization of these substrates. The authors wish to express their gratitude to V. Hazlett, J. Watkins, P. Lamprey, and P. Hartman for their assistance in conduct of this study and in the preparation of this manuscript.

Invivo lipogenesis and enzyme levels in adipose and liver tissues from pair-fed genetically obese and lean rats☆☆☆

Abstract Genetically obese Zucker rats pair-fed to lean controls were similar in body weight and food intake, however, epididymal fat pads were considerably larger than lean controls. In vivo incorporation of acetate-14C into adipose tissue lipid was not significantly different, however, in vivo liver lipogenesis was elevated in the obese rat. Characterization of enzyme profiles in both liver and adipose tissues revealed that enzymes normally associated with lipogenesis were elevated in liver tissue from obese rats. Malic enzyme and citrate cleavage enzyme were both depressed in adipose tissue of obese animals. From these data, it appears that the liver may be prominently involved in the development of excessive blood lipid and enlarged fat cells in the Zucker obese rat.

Characterization of an obese syndrome in the pig.

Summary Metabolic abnormalities associated with obesity were studied with two strains of pigs possessing varying propensities for lipid and protein deposition. The lean strain has a subcutaneous fat thickness of 2.8 cm and the obese strain, 8.0 cm. Adipose tissue enzymes associated with lipogenesis were elevated severalfold in the obese pig. The same enzymes in the liver were not altered. Gluconeogenic enzymes were elevated in the obese pig indicating a shift in the metabolism of amino acids. Enzymatic response to fasting and refeeding appears to be more dynamic in the lean type pig.

The influence of age and fasting on serum hormones in the lean and obese-Zucker rat.

Summary Genetically obese Zucker rats (fa/fa) and their nonobese littermates (Fa/?) were studied during the active phase of obesity onset to characterize serum levels of immunoreactive growth hormone, prolac-tin, thyroid-stimulating hormone, and corti-costerone. The effect of fasting on serum hormone levels in lean and obese rats was also investigated. Fasting reduced insulin levels in both lean and obese rats but the fasted levels in the obese rat were still 9 to 10 times higher than the lean littermates. Growth hormone levels were lower in the obese and were reduced by fasting. In the lean rat serum growth-hormone levels increased with age (25 to 480 ng/ml); however, the obese rat showed only marginal increases (25 to 65 ng/ml) during the same period. Corticosterone levels decreased with age and were higher in the obese rat at 11 weeks of age only. Thyroid-stimulating hormone increased with age and was lower in the obese rat at 9 weeks of age. During 5 and 7 weeks of age, serum prolactin was decreased in the obese rat but was similar by 11 weeks of age. These changes are discussed in relationship to their potential role in excessive lipid deposition in genetically induced obesity. The radioimmunoassay kits for rat growth hormone, prolactin, and TSH were supplied through the generosity of the Hormone Distribution Office, NIAMD, NIH, Bethesda, Maryland.

Adipose and liver tissue enzyme profiles in obese hyperglycemic mice.

Summary In order to determine metabolic abnormalities associated with obesity in the obese hyperglycemic mouse, enzyme levels in adipose and liver tissue were measured in three groups of mice. One lean group and one obese group were fed ad libitum. The third group consisted of obese mice subjected to weight gain control by dietary restriction and exercise. Levels of adipose tissue enzymes associated with lipogenesis were higher in obese mice than the lean mice. The data also indicated that obob mouse adipose tissue enzymes were not appreciably affected by diet restriction and exercise. However, liver tissue enzymes associated with lipogenesis and gluconeogenesis, which are normally elevated in obese mice, were restored to normal levels when the obese mice were on a weight gain control schedule. These data indicate that some differences in enzyme profiles observed in a genetically obese mouse are secondary adaptations caused by changes in either dietary intake or spontaneous activity.

Changes in liver and adipose tissue enzymes and lipogenic activities during the onset of hypothalamic obesity in mice

Abstract Introduction of hyperphagia by injection of aurothioglucose resulted in rapid deposition of tissue lipid. The changes in tissue enzyme levels and in vivo rates of lipogenesis from U-14C glucose were measured at 2, 4, and 8-week intervals post-aurothioglucose injection. Rapid increases of both enzyme activity and in vivo lipogenesis were observed during the onset of obesity. The elevated levels of adipose tissue enzyme activities were restored to normal levels 8 weeks post-injection. However, some lipogenic enzymes in liver tissue remained elevated throughout the experimental period. Liver tissue enzymes normally associated with glucogenesis were slightly elevated during the onset of obesity.

Effect of a high fat diet on body composition, cellularity, and enzyme levels during early development of the rat.

Abstract A high fat (60%) and a low fat (5%) diet were fed to female rats during gestation and lactation and to their male and female offspring for 3 weeks postweaning. The cellular effects of feeding all combinations of the two diets during the three growth periods (gestation, lactation, and rapid growth) were determined in Wistar rats. “Nutritional imprinting” of earlier dietary regimes on enzyme profiles and adipose cell number was not observed after rats were fed a control diet to maturity. The high fat diet caused reduced fat deposition during gestation. During lactation, the high fat diet caused increased fat deposition. Post-weaning rats had increased carcass fat, decreased protein, and lower carcass weight due to the high fat diet. Serum glucose was lower for fat-fed males during lactation and also for postweaning males and females. Fat feeding in lactation caused a decrease in adipose cell numbers which was not evident until rats were 6 weeks of age. The effect was only transient when rats were fed the chow diet until 21 weeks of age. Fat feeding for 3 weeks postweaning caused a significant decrease in liver DNA of 21-week-old male and female rats.

Characterization of tissue enzyme activities in rats with dorsomedial hypothalamic lesions and their sham-operated controls

Abstract The dorsomedial hypothalamic lesions (DMNL) resulted in a depression in food intake and linear and ponderal growth. The present study was designed to examine basic enzymatic adaptations to the lesions produced in the dorsomedial hypothalamus. Liver glucose-6-PO 4 dehydrogenase, citrate cleavage enzyme and malic enzyme were depressed in DMNL rats. These observations suggest a depression in fatty acid synthesis in liver tissue; however, no change in the enzyme fatty acid synthetase was observed. Adipose tissue enzymes involved in the conversion of dietary carbohydrate to fatty acid were not significantly altered in the DMN syndrome. Subtle changes in enzyme activity may be responsible for the development of the DMN syndrome. The mechanisms of the induced changes in enzyme activity remain to be elucidated.

The effects of metyrapone and ACTH on the development of gluconeogenesis in the neonatal pig.

Summary Pigs taken by Caesarean delivery on either 111th or 112th day of gestation were assigned to three treatment groups, each receiving im injections. The control group (C) received saline injections; the cortisol-deficient group (M) received 5 mg/kg body weight of metyrapone, and the ACTH group (A) received 1 U/kg body weight of ACTH. Pigs in group M demonstrated hypoglycemia at ages 22, 30, and 38 hr. The metryapone-treated pigs had the lowest liver glycogen levels at ages 30 and 38 hr. Liver glucose-6-phosphatase activity increased 5-fold by 30 hr of age in groups C and A, and about 3-fold in group M. The development of liver serine dehydratase was dependent on an adequate level of plasma Cortisol. Liver and kidney fructose-1,6-diphosphatose, alanine aminotransferase, and aspartate aminotransferase were not drastically altered by the cortisol status of the neonatal pig. Gluconeogenesis from pyruvate and glycerol in kidney cortex slices from pigs in group M was consistently lower than both groups A and C pigs. These studies indicate that the rapid development of liver gluconeogenic enzymes in young pigs after birth is not dependent on high levels of cortisol during the period of development. However, maximum development of gluconeogenic capacity was prevented by cortisol deficiency. The authors wish to acknowledge the excellent technical assistance of Mrs. Patricia Lamprey.