CNS Control of Metabolism and Growth

Hypothalamic-Anterior Pituitary Axis Hypothalamic neurons secrete releasing factor or release-inhibiting factor (usually a small peptide) into hypothalamic-anterior pituitary portal system Releasing factor targets specific cell population in ant. pituitary, which releases ant.pituitary hormone (a large peptide or glycopeptide) into general circulation. In many cases, the ant. pituitary hormone is a tropic hormone that controls the activity of an endocrine gland

The hypothalamic -hypophyseal control systems

Major Anterior Pituitary Hormones Target Effects Growth Hormone (Somatotropin) Whole Body Growth, substrate mobilization – most effects mediated by tissue-specific somatomedins Thyroid-stimulating H. TSH Thyroid Increase secretion of thyroxine (T4) – increase basal metabolism Adrenocorticotropin (ACTH) Adrenal Cortex Increase secretion of cortisol (mainly); aldosterone and androgen (secondarily) Gonadotropins (Luteinizing H., Follicle-Stimulating H.) Gonads Gonadal steroids (estrogen, progesterone, testosterone); gametogenesis; sexuald differentiation Prolactin Breasts Milk production Melanocyte-stimulating H. Melanocytes in skin Increase in pigmentation – for animals that undergo seasonal color change

Negative-feedback control loops Tropic hormone Final Hormone

Thyroid Hormones are derivatives of tyrosine

Control Factors for plasma levels of T4 and T3 Increased TSH secretion: Cold adaptation (non-tropical mammals) Birth (humans) Increased conversion of T4 to T3 (peripheral deiodinase activity) Food – especially carbohydrate

Metabolic Effects of T3 and T4 Action via nuclear receptors controlling the expression of specific genes Although there is about 50X more T4 in circulation than T3, T3 is much more effective than T4 Essential for normal growth and development Both hormone forms increase basal metabolic rate and heat production by stimulating futile cycles of catabolism-anabolism Na/K pump – Na and K leak Gluconeogenesis – glycolysis Protein synthesis – protein catabolism Lipogenesis-lipolysis

Human Energy Budget Total of about 2,500 Kcal/day Cold exposure, diet, stress, energy requirements associated with digestion Age, sex, lean body mass, genetic factors

Thyroid Disorders Hyperthyroidism (Grave’s Disease) Hypothyroidism autoantibody to TSH receptor acts like TSH - thyroid enlarges, (goiter) hypermetabolic state with heart and CNS symptoms, exopthalmia ‘Thyroid storms’ may occur diagnosis: high T4,low T3, low TSH Hypothyroidism Idiopathic: atrophy preceded by inflammation; TSH levels high Iodine-deficiency – thyroid unable to synthesize T4, so TSH levels elevated – thyroid hyperplasia leads to goiter Symptoms: weight gain, cold intolerance, bradycardia, lethargy, retarded growth and mental development Diagnosis: T4 low, T3 high

Growth Hormone (somatotropin or hGH) Effects: increased protein synthesis increased carbohydrate and lipid mobilization i.e., hGH is potentially diabetogenic Action by inducing liver and other tissues to synthesize specific somatomedins or insulin-like growth factors, somatomedin C (IGF I) which stimulates cartilage growth IGF2 epidermal growth factor NGF nerve growth factor

Control of hGH secretion Developmental program, sleep, stress, starvation, exercise, protein meal Obesity blunts effect of GHrh hGH secretion occurs in brief pulses, so that it is not possible to have accurate information about secretion rates on the basis of single plasma samples. In both children and adults, hGH secretion is promoted by dietary protein. Ant. Pituitary hHG IGF1

Daily Pattern of hGH Release In adolescence, almost all daily secretion occurs just after sleep begins Secretion continues in adulthood, but at much lower levels - triggered by eating a protein meal or by exercise – levels are almost unmeasureable in bed-resting subjects after an overnight fast.

Long-Bone Growth is controlled by IGF I and Gonadal Steroids Growth in stature is result of elongation of bone shafts at epiphyseal plate (cartilage), stimulated by IGF I Growth termination occurs when cartilage is replaced by solid bone (epiphyseal closure) Bone elongation is stimulated by gonadal steroid – especially testosterone – but gonadal steroid also tends to terminate bone growth by accelerating epiphyseal closure – for this reason, hypogonadism or castration before puberty tends to increase stature.

hGH and IGF-1 have effects throughout the life cycle Age 3-4 through puberty: IGF-1 levels rise continuously, peaking at about age 12 in girls and age 15 in boys, simultaneous with the highest rate of increase in stature. Post adolesence: hGH and IGF-1 levels gradually fall by about 2/3 between teens and middle life, but hGH and IGF-1 remain important regulators of body composition. In adults, supplementation with recombinant hGH can cause significant increases in muscle mass, decrease in fat mass, and metabolic rate. However, increased levels of IGF-1 may also promote cancer and diabetes.

growth defects related to hGH: at least 5 basic types Defects of hGh secretion Hyperpituitary giantism Hypopituitary dwarfism Acromegaly – excessive growth of flat bones resulting from hGH excess after adult growth has been completed – people with acromegaly frequently have diabetes-like symptoms as well hGH receptor defect operative throughout life – Laron dwarfism Deficiency of IGF I or IGF I receptor around the time of puberty with no deficiency of IGF II – short stature but normal body proportions. Efe pygmies of northeast Zaire – decreased expression of IGF I receptor starts in late childhood – rise in testosterone levels at puberty is normal but does not lead to growth spurt. But not all pygmy populations appear to share this mechanism. Result from excess or deficiency starting in childhood

Laron dwarfism There are about 300 Laron dwarfs in the world – about 100 of them are in Ecuador. Laron dwarfs are characterized by low levels of IGF-1 (the result of a hypofunctional hGH receptor) and high levels of hGH. They are almost free of cancer and diabetes and have enhanced longevity.

The little women of Loja – another form of Laron-type dwarfism also found in Ecuador In this form, the trait is recessive sex-linked male-lethal – almost all affected males die before birth, and thus the number of female children in families where the mother is a carrier tends to be twice the number of males. As for the classical form of Laron dwarfism, hGH levels are high and IGF-1 and IGF-2 levels are barely detectible in most patients.

How did these variant genes for hGH receptors get to Ecuador How did these variant genes for hGH receptors get to Ecuador? Paintings can provide a clue The Spanish artist Diego Velasquez (1599-1660) was painting the court of Philip IV around the time that Spain was colonizing the Americas. His paintings include several recognizable Laron dwarfs. The custom of keeping dwarfs as court entertainment was continued in Spain long after it had vanished from more progressive European courts. One might hypothesize that Spanish colonists carried genes for dwarfism to the New World.

The Dwarf Francisco Lezcano, Called "El Nino de Vallecas" c The Dwarf Francisco Lezcano, Called "El Nino de Vallecas" c. 1642-45 (130 Kb); Oil on canvas, 107 x 83 cm (42 1/8 x 32 5/8 in); Museo del Prado, Madrid; No. 1204

The Dwarf Sebastian de Morra (90 Kb); Museo del Prado, Madrid

Las Meninas (Maids of Honor) 1656-57 (120 Kb); Museo del Prado, Madrid The little girl in white is the Infanta Margarita Teresa, who was married at quite a young age to her uncle Leopold I, the Holy Roman Emperor.

Growth defects unrelated to the GHrh-hGH-IGF axis Achondroplastic dwarves – the most common type of dwarfism - defect in conversion of cartilage to bone – results from a single point mutation inherited as a dominant autosomal trait. There are a number of related disorders of osteogenesis.

GH is not the only hormone needed for normal growth Thyroid hormones Sex steroids – the effect is paradoxical – bone growth is stimulated but so is epiphyseal closure – most of the time, the dominant effect is to narrow the time window in which the growth spurt of puberty can occur. Glucocorticoids Insulin – in lower vertebrates, insulin is the growth hormone

Pharmacological growth control raises ethical and social issues In men, stature correlates strongly with perceived attractiveness, social success and economic success. Above-average stature is a prerequisite for success in certain sports. Recombinant hGH is now readily available Should pharmaceutical firms designate some fraction of the population of otherwise healthy children as growth-deficient and promote prescription of hGH for these children to increase sales? Should parents be allowed to obtain hGH prescriptions for their healthy children to promote their potential for success in the NBA, or in life generally? Should ‘normal’ aging be regarded as a disease, and older adults be able to get hGH to mitigate the effects of aging?