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Physiology is the study of functions of living body. Every body is made up of cells which constitute tissues that make organs and that make systems. These perform various functions. The optimum levels of these functions is called Homoeostasis. The internal environment of body is called miliu interior.
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Introduction
Growth hormone (GH) or somatotropin, also known as human
growth hormone (hGH or HGH) in its human form, is a peptide hormone that
stimulates growth, cell reproduction, and cell regeneration in humans and other
animals. It is thus important in human development. GH also stimulates
production of insulin-like growth factor 1 (IGF-1) and increases the
concentration of glucose and free fatty acid. It is a type of mitogen which is
specific only to the receptors on certain types of cells. GH is a 191-amino
acid, single-chain polypeptide that is synthesized, stored and secreted by
somatotropic cells within the lateral wings of the anterior pituitary gland. A
recombinant form of HGH called somatropin (INN) is used as a prescription drug
to treat children's growth disorders and adult growth hormone deficiency.
Genes for human growth hormone, known as growth hormone 1
(somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth
hormone; growth hormone variant), are localized in the q22-24 region of
chromosome and are closely related to human chorionic somatomammotropin (also
known as placental lactogen) genes. GH, human chorionic somatomammotropin, and
prolactin belong to a group of homologous hormones with growth-promoting and
lactogenic activity.
Structure
The major isoform of the human growth hormone is a protein
of 191 amino acids and a molecular weight of 22,124 daltons. The structure
includes four helices necessary for functional interaction with the GH
receptor. Several molecular isoforms of GH exist in the pituitary gland and are
released to blood. In particular, a variant of approximately 20 kDa originated
by an alternative splicing is present in a rather constant 1:9 ratio.
Regulation
Secretion of growth hormone (GH) in the pituitary is
regulated by the neurosecretory nuclei of the hypothalamus. These cells release
the peptides growth hormone-releasing hormone (GHRH or somatocrinin) and growth
hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal
venous blood surrounding the pituitary. GH release in the pituitary is
primarily determined by the balance of these two peptides, which in turn is
affected by many physiological stimulators (e.g., exercise, nutrition, sleep)
and inhibitors (e.g., free fatty acids) of GH secretion.
Somatotropic cells in the anterior pituitary gland then
synthesize and secrete GH in a pulsatile manner, in response to these stimuli
by the hypothalamus. The largest and most predictable of these GH peaks occurs
about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL Maximal
secretion of GH may occur within minutes of the onset of slow-wave (SW) sleep
(stage III or IV). Otherwise there is wide variation between days and
individuals. Nearly fifty percent of GH secretion occurs during the third and
fourth NREM sleep stages. Surges of secretion during the day occur at 3- to
5-hour intervals. The plasma concentration of GH during these peaks may range
from 5 to even 45 ng/mL. Between the peaks, basal GH levels are low, usually
less than 5 ng/mL for most of the day and night.
A number of factors are known to affect GH secretion,
such as age, sex, diet, exercise, stress, and other hormones. Young
adolescents secrete GH at the rate of about 700 μg/day, while healthy adults
secrete GH at the rate of about 400 μg/day.[20] Sleep deprivation generally
suppresses GH release, particularly after early adulthood.[21]
Stimulators[quantify] of growth hormone (GH) secretion
include:
·
Peptide hormones
·
GHRH (somatocrinin) through
binding to the growth hormone-releasing hormone receptor (GHRHR)
·
Ghrelin through binding to
growth hormone secretagogue receptors (GHSR)
·
Sex hormones
o
Increased androgen
secretion during puberty (in males from testes and in females from adrenal
cortex)
o
Testosterone and DHEA
o
Estrogen
·
Clonidine, moxonidine and
L-DOPA by stimulating GHRH release, α4β2 nicotinic agonists, including
nicotine, which also act synergistically with clonidine or moxonidine.[
·
Hypoglycemia,
·
arginine, pramipexole,
ornitine, lysine, tryptophan, γ-Aminobutyric acid and propranolol by inhibiting
somatostatin release
·
Deep sleep
·
Glucagon
·
Sodium oxybate or
γ-Hydroxybutyric acid
·
Niacin as nicotinic acid
(vitamin B3)
·
Fasting
·
Insulin
·
Vigorous exercise
Inhibitors[quantify] of GH secretion include:
·
GHIH (somatostatin) from
the periventricular nucleus
·
circulating concentrations
of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)
·
Hyperglycemia
·
Glucocorticoids
·
Dihydrotestosterone
·
Phenothiazines
Functions
Effects of growth hormone on the
tissues of the body can generally be described as anabolic (building up). Like
most other peptide hormones, GH acts by interacting with a specific receptor on
the surface of cells. Increased height during childhood is the most widely
known effect of GH. Height appears to be stimulated by at least two mechanisms-
1.
Because polypeptide
hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH
exerts some of its effects by binding to receptors on target cells, where it
activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates
division and multiplication of chondrocytes of cartilage.
2.
GH also stimulates, through
the JAK-STAT signaling pathway, the production of insulin-like growth factor 1
(IGF-1, formerly known as somatomedin C), a hormone homologous to
proinsulin.[40] The liver is a major target organ of GH for this process and is
the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on
a wide variety of tissues. Additional IGF-1 is generated within target tissues,
making it what appears to be both an endocrine and an autocrine/paracrine
hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte
activity to promote bone growth.
In addition to increasing height
in children and adolescents, growth hormone has many other effects on the body:
·
Increases calcium
retention, and strengthens and increases the mineralization of bone
·
Increases muscle mass
through sarcomere hypertrophy
·
Promotes lipolysis
·
Increases protein synthesis
·
Stimulates the growth of
all internal organs excluding the brain
·
Plays a role in homeostasis
·
Reduces liver uptake of
glucose
·
Promotes gluconeogenesis in
the liver
·
Contributes to the
maintenance and function of pancreatic islets
·
Stimulates the immune
system
·
Increases deiodination of
T4 to T3
·
Induces insulin resistance
Introduction
Leptin (from Greek λεπτός leptos, "thin" or
"light" or "small"), also known as obese protein, is a
protein hormone predominantly made by adipocytes (cells of adipose tissue). Its
primary role is likely to regulate long-term energy balance.
As one of the major signals of energy status, leptin levels
influence appetite, satiety, and motivated behaviors oriented toward the
maintenance of energy reserves (e.g., feeding, foraging behaviors).
The amount of circulating leptin correlates with the amount
of energy reserves, mainly triglycerides stored in adipose tissue. High leptin
levels are interpreted by the brain that energy reserves are high, whereas low
leptin levels indicate that energy reserves are low, in the process adapting
the organism to starvation through a variety of metabolic, endocrine,
neurobiochemical, and behavioral changes. Leptin is coded for by the LEP gene.
Leptin receptors are expressed by a variety of brain and peripheral cell types.
These include cell receptors in the arcuate and ventromedial nuclei, as well as
other parts of the hypothalamus and dopaminergic neurons of the ventral
tegmental area, consequently mediating feeding.
Although regulation of fat stores is deemed to be the
primary function of leptin, it also plays a role in other physiological
processes, as evidenced by its many sites of synthesis other than fat cells,
and the many cell types beyond hypothalamic cells that have leptin receptors.
Many of these additional functions are yet to be fully defined.
In obesity, a decreased sensitivity to leptin occurs
(similar to insulin resistance in type 2 diabetes), resulting in an inability
to detect satiety despite high energy stores and high levels of leptin.
Sites of synthesis
Leptin is produced primarily in the adipocytes of white
adipose tissue. It also is produced by brown adipose tissue, placenta
(syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of
the fundic glands), mammary epithelial cells, bone marrow,[19] gastric chief
cells, and P/D1 cells.
Blood levels
Leptin circulates in blood in free form and bound to
proteins. Leptin levels vary exponentially, not linearly, with fat mass. Leptin
levels in blood are higher between midnight and early morning, perhaps
suppressing appetite during the night. The diurnal rhythm of blood leptin
levels may be modified by meal-timing. Increased levels of melatonin causes a
downregulation of leptin, however, melatonin also appears to increase leptin
levels in the presence of insulin, therefore causing a decrease in appetite
during sleeping. Partial sleep deprivation has also been associated with
decreased blood leptin levels.
Functions
1.
Predominantly, the
"energy expenditure hormone" leptin is made by adipose cells, and is
thus labeled fat cell-specific. The central location of action (effect) of the
fat cell-specific hormone leptin is the hypothalamus. The primary function of
the hormone leptin is the regulation of adipose tissue mass through central
hypothalamus mediated effects on hunger, food energy use, physical exercise,
and energy balance.
2.
Outside the brain, in the
periphery of the body, leptin's secondary functions are: modulation of energy
expenditure, modulation between fetal and maternal metabolism, and that of a
permissive factor in puberty, activator of immune cells, activator of beta
islet cells, and growth factor.
3.
Leptin along with
kisspeptin controls the onset of puberty. High levels of leptin, as usually
observed in obese females, can trigger neuroendocrine cascade resulting in
early menarche. This may eventually lead to shorter stature as estrogen
secretion starts during menarche and causes early closure of epiphyses.
4.
Leptin can affect bone
metabolism via direct signalling from the brain. Leptin decreases cancellous
bone, but increases cortical bone. This "cortical-cancellous
dichotomy" may represent a mechanism for enlarging bone size, and thus
bone resistance, to cope with increased body weight.
5.
Factors that acutely affect
leptin levels are also factors that influence other markers of inflammation,
e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat
levels. While it is well-established that leptin is involved in the regulation
of the inflammatory response, it has been further theorized that leptin's role
as an inflammatory marker is to respond specifically to adipose-derived
inflammatory cytokines.
6.
Similar to what is observed
in chronic inflammation, chronically elevated leptin levels are associated with
obesity, overeating, and inflammation-related diseases, including hypertension,
metabolic syndrome, and cardiovascular disease. While leptin is associated with
body fat mass, the size of individual fat cells, and overeating, it is not
affected by exercise.
specific conditions
In humans, many instances are seen where leptin dissociates
from the strict role of communicating nutritional status between body and brain
and no longer correlates with body fat levels:
·
Leptin plays a critical
role in the adaptive response to starvation.
·
Leptin level is decreased
after short-term fasting (24–72 hours), even when changes in fat mass are not
observed.
·
Serum level of leptin is
reduced by sleep deprivation.
·
Leptin levels are
paradoxically increased in obesity.
·
Leptin level is increased
by emotional stress.
·
Leptin level is chronically
reduced by physical exercise training.
·
Leptin level is decreased
by increases in testosterone levels and increased by increases in estrogen
levels.
·
Leptin level is increased
by insulin.
·
Leptin release is increased
by dexamethasone.
·
In obese patients with
obstructive sleep apnea, leptin level is increased, but decreased after the
administration of continuous positive airway pressure.[119][120] In non-obese
individuals, h
Introduction
Ghrelin (/ˈɡrɛlɪn/; or
lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of
the gastrointestinal tract, especially the stomach, and is also dubbed the
"hunger hormone" because it increases the drive to eat.[6] Blood
levels of ghrelin are highest before meals when hungry, returning to lower
levels after mealtimes. 4Ghrelin may help prepare for food intake by increasing
gastric motility and stimulating the secretion of gastric acid. Ghrelin
activates cells in the anterior pituitary gland and hypothalamic arcuate
nucleus, including neuropeptide Y neurons that initiate appetite. Ghrelin
stimulates brain structures having a specific receptor – the growth hormone
secretagogue receptor 1A (GHSR-1A). Ghrelin also participates in regulation of
reward cognition, learning and memory, the sleep-wake cycle, taste sensation,
reward behavior, and glucose metabolism.
Ghrelin was discovered after the ghrelin receptor (called
growth hormone secretagogue type 1A receptor or GHS-R) was determined in 1999.
The hormone name is based on its role as a growth hormone-releasing peptide- gʰre-, meaning "to
grow".
The ghrelin cell is also known as an A-like cell (pancreas),
X-cell (for unknown function), X/A-like cell (rats), Epsilon cell (pancreas),
P/D sub 1 cell (humans) and Gr cell (abbreviation for ghrelin cell).
Ghrelin cells are found mainly in the stomach and duodenum,
but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex,
placenta, and kidney. It has also been shown that ghrelin is produced locally
in the brain. Additionally, research suggests that ghrelin may be produced in
the myocardium and have an 'autocrine/ paracrine' like effect within the heart.
Ghrelin cells are also found in oxyntic glands (20% of cells), pyloric glands,
and small intestine.
Function and mechanism of action
1.
Ghrelin is a participant in
regulating the complex process of energy homeostasis which adjusts both energy
input – by adjusting hunger signals – and energy output – by adjusting the
proportion of energy going to ATP production, fat storage, glycogen storage,
and short-term heat loss. The net result of these processes is reflected in
body weight, and is under continuous monitoring and adjustment based on
metabolic signals and needs. At any given moment in time, it may be in
equilibrium or disequilibrium. Gastric-brain communication is an essential part
of energy homeostasis, and several communication pathways are probable,
including the gastric intracellular mTOR/S6K1 pathway mediating the interaction
among ghrelin, nesfatin and endocannabinoid gastric systems, and both afferent
and efferent vagal signals.
2.
Ghrelin and synthetic
ghrelin mimetics (growth hormone secretagogues) increase body weight and fat
mass by triggering receptors in the arcuate nucleus that include neuropeptide Y
(NPY) and agouti-related protein (AgRP) neurons. Ghrelin responsiveness of
these neurons is both leptin- and insulin-sensitive. Ghrelin reduces the
sensitivity of gastric vagal afferents, so they are less sensitive to gastric
distension.
3.
In addition to its function
in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic
reward link in inputs to the ventral tegmental area and in the mesolimbic
pathway, a circuit that communicates the hedonic and reinforcing aspects of
natural rewards, such as food and addictive drugs such as ethanol. Ghrelin
receptors are located on neurons in this circuit. Hypothalamic ghrelin signaling
is required for reward from alcohol and palatable/rewarding foods.
4.
Ghrelin has been linked
to inducing appetite and feeding behaviors. Circulating ghrelin levels are
the highest right before a meal and the lowest right after. Injections of
ghrelin in humans have been shown to increase food intake in a dose-dependent
manner. So the more ghrelin that is injected the more food that is consumed.
However, ghrelin does not increase meal size, only meal number. Ghrelin also
increases motivation to seek out food.
5.
Body weight is regulated
through energy balance, the amount of energy taken in versus the amount of
energy expended over an extended period of time. Studies have shown that
ghrelin levels are positively correlated with weight. This data suggests that
ghrelin functions as an adiposity signal, a messenger between the body's energy
stores and the brain.
6.
Action on Glucose
metabolism
The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a
gluco-regulatory action,
7.
Effects of and on Sleep
Preliminary research indicates that ghrelin participates in
the regulation of circadian rhythms. A review reported finding strong evidence
that sleep restriction affected ghrelin or leptin levels, or energy
expenditure.
8.
Effects on Cardiovascular
system
Ghrelin functions as a cardio-protective peptide by being an
anti-inflammatory agent, promoting angiogenesis, inhibiting arrhythmia, and
improving heart failure.
Thyroid hormones are two hormones produced and released by
the thyroid gland: triiodothyronine (T3) and thyroxine (T4). They are
tyrosine-based hormones that are primarily responsible for regulation of
metabolism. T3 and T4 are partially composed of iodine, which is derived from
food American chemist Edward Calvin Kendall was responsible for the isolation
of thyroxine in 1915. Levothyroxine, a synthetic derivative of Thyroxine, is on
the World Health Organization's List of Essential Medicines.
The major form of thyroid hormone in the blood is thyroxine
(T4), whose half-life of around one week, is longer than that of T3. In humans,
the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is
converted to the active T3 (three to four times more potent than T4) within
cells by deiodinases (5′-deiodinase). These are further processed by
decarboxylation and deiodination to produce iodothyronamine (T1a) and
thyronamine (T0a). All three isoforms of the deiodinases are
selenium-containing enzymes, thus dietary selenium is essential for T3
production. Calcitonin, a peptide hormone produced and secreted by the thyroid,
is usually not included in the meaning of "thyroid hormone".
Thyroid hormones are one of the factors responsible for the
modulation of energy expenditure. This is achieved through several mechanisms,
such as mitochondrial biogenesis and adaptive thermogenesis.
Central metabolism
- Thyroglobulin is synthesized in the rough endoplasmic
reticulum and follows the secretory pathway to enter the colloid in the lumen
of the thyroid follicle by exocytosis.
- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide
(I−) actively into the cell, which previously has crossed the endothelium by
largely unknown mechanisms.
- This iodide enters the follicular lumen from the cytoplasm
by the transporter pendrin, in a purportedly passive manner.
- In the colloid, iodide (I−) is oxidized to iodine (I0) by
an enzyme called thyroid peroxidase.
- Iodine (I0) is very reactive and iodinates the
thyroglobulin at tyrosyl residues in its protein chain (in total containing
approximately 120 tyrosyl residues).
- In conjugation, adjacent tyrosyl residues are paired
together.
- Thyroglobulin re-enters the follicular cell by
endocytosis.
- Proteolysis by various proteases liberates thyroxine and
triiodothyronine molecules
- Efflux of thyroxine and triiodothyronine from follicular
cells, which appears to be largely through monocarboxylate transporter 8 (MCT
8) and 10, and entry into the blood.
Thyroid hormones (T4 and T3) are produced by thyroid
epithelial cells (a.k.a. thyroid follicular cells) and are regulated by
thyroid-stimulating hormone (TSH) made by the thyrotropes of the anterior
pituitary gland. The effects of T4 in vivo are mediated via T3 (T4 is converted
to T3 in target tissues). T3 is three to five times more active than T4. T4,
thyroxine (3,5,3′,5′-tetraiodothyronine), is produced by follicular cells of
the thyroid gland. It is produced from the precursor thyroglobulin (this is not
the same as thyroxine-binding globulin [TBG]), which is cleaved by enzymes to
produce active T4.
The steps in this process are as follows:
The Na+/I− symporter transports two sodium ions across the
basement membrane of the follicular cells along with an iodide ion. This is a
secondary active transporter that utilises the concentration gradient of Na+ to
move I− against its concentration gradient. This is called iodide trapping.[36]
Sodium is cotransported with iodide from the basolateral side of the membrane
into the cell,[clarification needed] and then concentrated in the thyroid
follicles to about thirty times its concentration in the blood.
I− is moved across the apical membrane into the colloid of
the follicle by pendrin. Hydrogen peroxide is also introduced into the follicle
by the action of DUX (Dual Oxidase).
Iodide is non-reactive, and the reactive I2 species is
required for the next step. Thyroid peroxidase (TPO) reduces hydrogen peroxide
to water by transferring one electron from two I− atoms that react to form I2.
Iodine (I2) is converted into HOI, by hydration with water.
Both I2 and HOI iodinate specific tyrosyl residues of the thyroglobulin within
the colloid to form 3-monoiodityrosyl (MIT-yl) and 3,5-diiodityrosyl (DIT-yl)
residues—introducting iodine atoms at one or both locations ortho to the
hydroxyls of tyrosine. The thyroglobulin was synthesised in the ER of the
follicular cell and secreted into the colloid.
TPO also converts tyrosyl, MIT-yl, and DIT-yl residues into
their free radical forms. These forms attack other MIT-yl and DIT-yl residues.
When a DIT-yl radical attacks a DIT, T4-yl (peptidic T4) is formed. When a
MIT-yl radical attacks a DIT, T3-yl is formed. Other reactions are possible,
but do not form physiologically active products.
Iodinated thyroglobulin binds megalin for endocytosis back
into the cell.
TSH released from the anterior pituitary (a.k.a. the
adenohypophysis) binds the TSH receptor (a Gs protein-coupled receptor) on the
basolateral membrane of the cell and stimulates the endocytosis of the colloid.
The endocytosed vesicles fuse with the lysosomes of the
follicular cell. The lysosomal enzymes cleave any MIT, DIT, T3, T4 as well as
the inactive analogues from the iodinated thyroglobulin.
The thyroid hormones cross the follicular cell membrane
towards the blood vessels by monocarboxylate transporter 8 (MCT 8) and 10 which
play major roles in the efflux of the thyroid hormones from thyroid cells.
Thyroglobulin (Tg) is a 660 kDa, dimeric protein produced by
the follicular cells of the thyroid and used entirely within the thyroid gland.
Thyroxine is produced by attaching iodine atoms to the ring structures of this
protein's tyrosine residues; thyroxine (T4) contains four iodine atoms, while
triiodothyronine (T3), otherwise identical to T4, has one less iodine atom per
molecule.[48] The thyroglobulin protein accounts for approximately half of the
protein content of the thyroid gland.[49] Each thyroglobulin molecule contains
approximately 100–120 tyrosine residues, a small number (<20) of which are
subject to iodination catalysed by thyroperoxidase. The same enzyme then
catalyses "coupling" of one modified tyrosine with another, via a
free-radical-mediated reaction, and when these iodinated bicyclic molecules are
released by hydrolysis of the protein, T3 and T4 are the result. Therefore,
each thyroglobulin protein molecule ultimately yields very small amounts of
thyroid hormone (experimentally observed to be on the order of 5–6 molecules of
either T4 or T3 per original molecule of thyroglobulin).
Hydrolysis (cleavage to individual amino acids) of the
modified protein by proteases then liberates T3 and T4, as well as the
non-coupled tyrosine derivatives MIT and DIT. The hormones T4 and T3 are the
biologically active agents central to metabolic regulation.
Peripheral metabolism
Thyroxine is believed to be a prohormone and a reservoir for
the most active and main thyroid hormone, T3. T4 is converted as required in
the tissues by iodothyronine deiodinase. Deficiency of deiodinase can mimic
hypothyroidism due to iodine deficiency.T3 is more active than T4,[56] though
it is present in less quantity than T4.
Initiation of production in fetuses
Thyrotropin-releasing hormone (TRH) is released from
hypothalamus by 6–8 gestational weeks, and thyroid-stimulating hormone (TSH)
secretion from the fetal pituitary gland is evident by 12 gestational weeks;
fetal production of thyroxine (T4) reaches a clinically significant level at
18–20 weeks. Fetal triiodothyronine (T3) remains low (less than 15 ng/dL) until
30 weeks of gestation, and increases to 50 ng/dL at term. Fetal
self-sufficiency of thyroid hormones protects the fetus against, for example,
neurodevelopmental abnormalities caused by maternal hypothyroidism
Circulation and transport
Plasma transport
Most of the
thyroid hormone circulating in the blood is bound to transport proteins, and
only a very small fraction is unbound and biologically active. Therefore,
measuring concentrations of free thyroid hormones is important for diagnosis,
while measuring total levels can be misleading.
Thyroid
hormone in the blood is usually distributed as follows:
|
Type |
Percent |
|
bound to thyroxine-binding globulin (TBG) |
70% |
|
bound to transthyretin or
"thyroxine-binding prealbumin" (TTR or TBPA) |
10–15% |
|
15–20% |
|
|
unbound T4 (fT4) |
0.03% |
|
unbound T3 (fT3) |
0.3% |
Despite being
lipophilic, T3 and T4 cross the cell membrane via
carrier-mediated transport, which is ATP-dependent
Membrane
transport
thyroid
hormones cannot traverse cell membranes in a passive manner like other
lipophilic substances. The iodine in o-position makes the phenolic OH-group
more acidic, resulting in a negative charge at physiological pH. However, at
least 10 different active, energy-dependent and genetically regulated
iodothyronine transporters have been identified in humans. They guarantee that
intracellular levels of thyroid hormones are higher than in blood plasma or
interstitial fluids.
Mechanism of action
The thyroid hormones function via a well-studied set of
nuclear receptors, termed the thyroid hormone receptors. These receptors,
together with corepressor molecules, bind DNA regions called thyroid hormone
response elements (TREs) near genes. This receptor-corepressor-DNA complex can
block gene transcription. Triiodothyronine (T3), which is the active form of
thyroxine (T4), goes on to bind to receptors. The deiodinase catalyzed reaction
removes an iodine atom from the 5′ position of the outer aromatic ring of
thyroxine's (T4) structure. When triiodothyronine (T3) binds a receptor, it
induces a conformational change in the receptor, displacing the corepressor
from the complex. This leads to recruitment of coactivator proteins and RNA
polymerase, activating transcription of the gene.
Functions of Thyroid Hormones
Thyroid hormones act on nearly every cell in the
body. They act to
·
increase the basal
metabolic rate
·
affect protein synthesis
·
help regulate long bone
growth in synergy with growth hormone
·
effect neural maturation
·
increase the body's
sensitivity to catecholamines (such as norepinephrine and epinephrine) by
permissiveness, especially under cold exposure.
·
essential to proper
development and differentiation of all cells of the human body.
·
These hormones also
regulate protein, fat, and carbohydrate metabolism, affecting how human cells
use energetic compounds.
·
They stimulate vitamin metabolism.
·
Thyroid hormones lead to
heat generation in humans.
Functions of triiodothyronine
Effects of triiodothyronine (T3) which is the metabolically
active form:
·
Increases cardiac output
·
Increases heart rate
·
Increases ventilation rate
·
Increases basal metabolic
rate
·
Potentiates the effects of
catecholamines (i.e. increases sympathetic activity)
·
Potentiates brain
development
·
Thickens endometrium in
females
·
Increases catabolism of
proteins and carbohydrates.
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Melatonin,
an indoleamine, is a natural compound produced by various organisms, including
bacteria and eukaryotes. In 1917, Carey Pratt McCord and Floyd P. Allen found
that feeding extracts from the pineal glands of cows caused the skin of
tadpoles to lighten by contracting the dark epidermal melanophores.
The hormone
melatonin was isolated from
bovine pineal gland extracts in 1958 by Aaron B. Lerner, a dermatology
professor, and his team at Yale University. Lerner and his colleagues proposed the name melatonin,
derived from the Greek words melas, meaning 'black' or 'dark', and tonos,
meaning 'labour', 'colour' or 'suppress' as it was found to lighten skin
colour. Subsequent research in the
mid-1970s by Lynch and others demonstrated that melatonin production follows a
circadian rhythm in human pineal glands. This compound was later identified as
a hormone secreted in the brain during the night, playing a crucial role in
regulating the sleep-wake cycle, also known as the circadian rhythm, in human.
Biosynthesis
The
biosynthesis of melatonin in animals involves a sequence of enzymatic reactions
starting with L-tryptophan, which can be synthesized through the shikimate
pathway from chorismate, found in plants, or obtained from protein catabolism.
The initial step in the melatonin biosynthesis pathway is the hydroxylation of
L-tryptophan's indole ring by the enzyme tryptophan hydroxylase, resulting in
the formation of 5-hydroxytryptophan (5-HTP). Subsequently, 5-HTP undergoes
decarboxylation, facilitated by pyridoxal phosphate and the enzyme
5-hydroxytryptophan decarboxylase, yielding serotonin.
Serotonin, itself
an essential neurotransmitter, is further converted into N-acetylserotonin by
the action of serotonin N-acetyltransferase, using acetyl-CoA. The final step
in the pathway involves the methylation of N-acetylserotonin's hydroxyl group
by hydroxyindole O-methyltransferase, with S-adenosyl methionine as the methyl
donor, to produce melatonin.
Regulation
of secretion
In human,
the secretion of melatonin is regulated through the activation of the beta-1
adrenergic receptor by the hormone norepinephrine. Norepinephrine increases the
concentration of intracellular cAMP via beta-adrenergic receptors, which in
turn activates the cAMP-dependent protein kinase A (PKA). PKA then
phosphorylates arylalkylamine N-acetyltransferase (AANAT), the penultimate
enzyme in the melatonin synthesis pathway. When exposed to daylight,
noradrenergic stimulation ceases, leading to the immediate degradation of the
protein by proteasomal proteolysis.
Blue light,
especially within the 460–480 nm range, inhibits the biosynthesis of melatonin,
with the degree of suppression being directly proportional to the intensity and
duration of light exposure. Historically, humans in temperate climates
experienced limited exposure to blue daylight during winter months, primarily
receiving light from sources that emitted predominantly yellow light, such as
fires. The incandescent light bulbs used extensively throughout the 20th
century emitted relatively low levels of blue light. It has been found that
light containing only wavelengths greater than 530 nm does not suppress
melatonin under bright-light conditions. The use of glasses that block blue
light in the hours preceding bedtime can mitigate melatonin suppression.
Additionally, wearing blue-blocking goggles during the last hours before
bedtime is recommended for individuals needing to adjust to an earlier bedtime
since melatonin facilitates the onset of sleep.
Metabolism
Melatonin is
metabolized in liver by liver enzymes, with an elimination half-life ranging
from 20 to 50 minutes. The primary metabolic pathway transforms melatonin into
6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine
as a waste product.
Measurement
For both
research and clinical purposes, melatonin levels in humans can be determined
through saliva or blood plasma analysis.
Physiological
functions
Circadian
rhythm
In human,
melatonin is critical for the regulation of sleep–wake cycles, or circadian
rhythms. The establishment of regular melatonin levels in human infants occurs
around the third month after birth, with peak concentrations observed between
midnight and 8:00 am. It has been documented that melatonin production
diminishes as a person ages. Additionally, a shift in the timing of melatonin
secretion is observed during adolescence, resulting in delayed sleep and wake
times, increasing their risk for delayed sleep phase disorder during this
period.
Antioxidant
Properties
The
antioxidant properties of melatonin were first recognized in 1993. In vitro
studies reveal that melatonin directly neutralizes various reactive oxygen
species, including hydroxyl (OH•), superoxide (O2−•), and reactive nitrogen
species such as nitric oxide (NO•).
Melatonin's
concentration in the mitochondrial matrix is significantly higher than that
found in the blood plasma, emphasizing its role not only in direct free radical
scavenging but also in modulating the expression of antioxidant enzymes and
maintaining mitochondrial integrity. This multifaceted role shows the
physiological significance of melatonin as a mitochondrial antioxidant, a
notion supported by numerous scholars.
Furthermore,
the interaction of melatonin with reactive oxygen and nitrogen species results
in the formation of metabolites capable of reducing free radicals. These
metabolites, including cyclic 3-hydroxymelatonin,
N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and
N1-acetyl-5-methoxykynuramine (AMK), contribute to the broader antioxidative
effects of melatonin through further redox reactions with free radicals.
Immune
system
Melatonin's
interaction with the immune system is recognized, yet the specifics of these
interactions remain inadequately defined. An anti-inflammatory effect appears
to be the most significant. The efficacy of melatonin in disease treatment has
been the subject of limited trials, with most available data deriving from
small-scale, preliminary studies. It is posited that any beneficial
immunological impact is attributable to melatonin's action on high-affinity
receptors (MT1 and MT2), which are present on immunocompetent cells.
Preclinical investigations suggest that melatonin may augment cytokine
production and promote the expansion of T cells, thereby potentially mitigating
acquired immunodeficiencies.
Weight
regulation
Melatonin's
potential to regulate weight gain is posited to involve its inhibitory effect
on leptin, a hormone that serves as a long-term indicator of the body's energy
status.
Use as a
medication and supplement
As a
medicine it is used in following conditions under medical supervision-
1.
Insomnia- in persons above 55 years
2.
Circadian rhythm sleep disorders like- delayed sleep phase syndrome and to reduce jet lag syndrome
3.
REM sleep behavior disorders- like Parkinson's disease and dementia
with Lewy bodies.
4.
Dementia- melatonin may improve sleep in minimal cognitive impairment
only in cases of dementia.