Download CNS Control of Metabolism and Growth

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
Hormone
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
hypothalamus
Final
Hormone
Anterior pituitary
Peripheral gland
Effector organs
Tropic
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 catabolismanabolism
–
–
–
–
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
basal metabolism
Exercise
thermogenesis
Age, sex, lean
body mass,
genetic factors
Thyroid Disorders
• Hyperthyroidism (Grave’s Disease)
– 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
Hypothalamus
GHrh (ghrelin)
Obesity blunts
effect of GHrh
GHrih (somatostatin)
Ant. Pituitary
hHG
IGF1
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.
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
Result from excess or
deficiency starting in
childhood
– 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.
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 malelethal – 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? 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. 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?