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I am thinking which hormonal and chemical effects from:
- sex hormones
can be be regarded as metabolites i.e. intermediates or products of metabolism.
I got this question
Account for chemical and hormonal effects on the heart.
and I am thinking if I should include metabolites as a factor as
Metabolites by intrinsic autoregulative system locally
because the autoregulation of heart is very important factor in the physiology of the heart.
Can you regard some metabolites as having hormonal and chemical effects?
Ions are not hormones. Ions are not metabolites either.
Technically, anything that is not directly absorbed from environment but is synthesized/modified in the body is a metabolite. Even if you don't consider polypeptides as metabolites (which for some reason are not classified as metabolites in scientific parlance), all the molecules that you mention are metabolites with known biosynthetic pathways.
Cells of the body require nutrients in order to function, and these nutrients are obtained through feeding. In order to manage nutrient intake, storing excess intake and utilizing reserves when necessary, the body uses hormones to moderate energy stores. Insulin is produced by the beta cells of the pancreas, which are stimulated to release insulin as blood glucose levels rise (for example, after a meal is consumed). Insulin lowers blood glucose levels by enhancing the rate of glucose uptake and utilization by target cells, which use glucose for ATP production. It also stimulates the liver to convert glucose to glycogen, which is then stored by cells for later use. Insulin also increases glucose transport into certain cells, such as muscle cells and the liver. This results from an insulin-mediated increase in the number of glucose transporter proteins in cell membranes, which remove glucose from circulation by facilitated diffusion. As insulin binds to its target cell via insulin receptors and signal transduction, it triggers the cell to incorporate glucose transport proteins into its membrane. This allows glucose to enter the cell, where it can be used as an energy source. However, this does not occur in all cells: some cells, including those in the kidneys and brain, can access glucose without the use of insulin. Insulin also stimulates the conversion of glucose to fat in adipocytes and the synthesis of proteins. These actions mediated by insulin cause blood glucose concentrations to fall, called a hypoglycemic “low sugar” effect, which inhibits further insulin release from beta cells through a negative feedback loop.
This animation describe the role of insulin and the pancreas in diabetes.
Figure 1. The main symptoms of diabetes are shown. (credit: modification of work by Mikael Häggström)
Impaired insulin function can lead to a condition called diabetes mellitus, the main symptoms of which are illustrated in Figure 1. This can be caused by low levels of insulin production by the beta cells of the pancreas, or by reduced sensitivity of tissue cells to insulin. This prevents glucose from being absorbed by cells, causing high levels of blood glucose, or hyperglycemia (high sugar). High blood glucose levels make it difficult for the kidneys to recover all the glucose from nascent urine, resulting in glucose being lost in urine. High glucose levels also result in less water being reabsorbed by the kidneys, causing high amounts of urine to be produced this may result in dehydration. Over time, high blood glucose levels can cause nerve damage to the eyes and peripheral body tissues, as well as damage to the kidneys and cardiovascular system. Oversecretion of insulin can cause hypoglycemia, low blood glucose levels. This causes insufficient glucose availability to cells, often leading to muscle weakness, and can sometimes cause unconsciousness or death if left untreated.
When blood glucose levels decline below normal levels, for example between meals or when glucose is utilized rapidly during exercise, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon raises blood glucose levels, eliciting what is called a hyperglycemic effect, by stimulating the breakdown of glycogen to glucose in skeletal muscle cells and liver cells in a process called glycogenolysis. Glucose can then be utilized as energy by muscle cells and released into circulation by the liver cells. Glucagon also stimulates absorption of amino acids from the blood by the liver, which then converts them to glucose. This process of glucose synthesis is called gluconeogenesis. Glucagon also stimulates adipose cells to release fatty acids into the blood. These actions mediated by glucagon result in an increase in blood glucose levels to normal homeostatic levels. Rising blood glucose levels inhibit further glucagon release by the pancreas via a negative feedback mechanism. In this way, insulin and glucagon work together to maintain homeostatic glucose levels, as shown in Figure 2.
Figure 2. Insulin and glucagon regulate blood glucose levels.
Pancreatic tumors may cause excess secretion of glucagon. Type I diabetes results from the failure of the pancreas to produce insulin. Which of the following statement about these two conditions is true?
- A pancreatic tumor and type I diabetes will have the opposite effects on blood sugar levels.
- A pancreatic tumor and type I diabetes will both cause hyperglycemia.
- A pancreatic tumor and type I diabetes will both cause hypoglycemia.
- Both pancreatic tumors and type I diabetes result in the inability of cells to take up glucose.
Heart and kidney function
Throughout pregnancy there is an increase in the amount of blood the heart pumps each minute. Dilation and relaxation of blood vessels, due to hormones such as oestrogen and relaxin, results in a lowering of blood pressure. There is also an increase in kidney blood flow.
Activation of the renin-angiotensin system, an important system to control normal fluid balance and blood pressure, leads to fluid retention in the pregnant mother. This can manifest as ankle and hand swelling. Despite more fluid being retained, the mother’s blood pressure normally does not rise. In fact, it falls due to the dilation of blood vessels as discussed above.
Increases in total blood volume and circulating red cells occur throughout pregnancy. This is due to a stimulation of red cell formation caused by increases in erythropoietin, a hormone secreted by the kidney that controls the number of red cells circulating in the blood.
The Endocrine Function of the Heart
The heart is not only considered to be a part of the circulatory or cardiovascular system as most people were taught in biology class but it is also a part of the endocrine system as well. An article published in Scientific American in 1986, The Heart As An Endocrine Gland, by Marc Cantin and Jacques Genest is an account of their discovery of two hormones secreted by the heart that have dramatic effects on the behavior of the cardiovascular system. Researchers have long suspected as far back as 1956 that the heart has other functions in the body besides pumping blood.
These hormones are released by the heart from granules located mostly in the muscular walls of the atrial ( upper chambers) and in lesser amount in the ventricles (lower chambers) of the mammalian heart. These granules, small clusters of particles, are similar to granules found in the cells of other endocrine glands. The hormones are A-type natriuretic peptides or atrial natriuretic peptides (ANP), sometimes called atrial natriuretic factor (ANF), and B-type natriuretic peptides or brain natriuretic peptides (BNP). The latter is also found in the brain hence the name since it was first discovered there and as well as in the central nervous system. But it is predominantly found in the ventricles of the heart. There is also a third hormone in this class called the C-type natriuretic peptides which is found mainly in the walls of the blood vessels.
To control endocrine functions, the secretion of each hormone must be regulated within precise limits. The body is normally able to sense whether more or less of a given hormone is needed.
Many endocrine glands are controlled by the interplay of hormonal signals between the hypothalamus, located in the brain, and the pituitary gland, which sits at the base of the brain. This interplay is referred to as the hypothalamic-pituitary axis. The hypothalamus secretes several hormones that control the pituitary gland.
The pituitary gland, sometimes called the master gland, in turn controls the functions of many other endocrine glands. The pituitary controls the rate at which it secretes hormones through a feedback loop in which the blood levels of other endocrine hormones signal the pituitary to slow down or speed up. So, for example, the pituitary gland senses when blood levels of thyroid hormone are low and releases thyroid stimulating hormone, which tells the thyroid gland to make more hormones. If the level gets too high, the pituitary senses that and decreases the amount of thyroid stimulating hormone, which then decreases the amount of thyroid hormone produced. This back-and-forth adjustment (feedback) keeps hormone levels in proper balance.
Many other factors can control endocrine function. For example, a baby sucking on its mother's nipple stimulates her pituitary gland to secrete prolactin and oxytocin , hormones that stimulate breast milk production and flow. Rising blood sugar levels stimulate the islet cells of the pancreas to produce insulin . Part of the nervous system stimulates the adrenal gland to produce epinephrine .
Hormone, Definitions, Properties and Chemical Natures
The word ‘Hormone’ is derived from Greek word ‘hormao’ which means “I impel” or “I arouse to activity”. William M. Bayliss and Ernest H. Starling (1904) termed that important chemical substance as hormone though it was first proposed by W. B. Hardy.
In animal physiology, it denotes a specific substance which is effective in a very low concentration and it is transported to other part of the organism from their site of synthesis, where they cause specific physiological effects. But the site of synthesis of plant hormone synthesis and their place of action is not differentiable although there are certain evidences indicating their effects are far away from the site of synthesis.
Hormones are active in minute amounts and act as chemical messengers. A hormone can cause a variety of response depending upon the nature of tissue or organ in which that hormone is acting. Plant hormones have been referred to as growth regulators or growth substances.
Definition of Hormone
Hormone is an organic substance which is produced naturally within the organism, controlling growth or other physiological functions at a site remote from its place of origin and active in minute amounts.
According to William M. Bayliss and Ernest H. Starling (1904), Hormone is a chemical agent released from one group of cells which travels through the body fluid to distant places to affect different group of cells.
Actually, hormone is the organic chemical substance synthesized by a specific organ or local group of cells and secreted into the body fluid such as tissue fluid or blood which carries it to other sites of the body where it exerts an effect on the activities of the cells is known as hormone.
A class of thyroid hormone metabolites has dramatic physiological effects on metabolism and heart rate by still-unknown mechanisms of action. A recent study has discovered that thyronamines can inhibit neuronal reuptake of neurotransmitters and prevent the intracellular transport of monoamines for release. This discovery presents a third signaling pathway for thyroid hormone, expands the role that thyroid plays in the central nervous system, and suggests mechanisms of action for the effects of thyronamine-derived neuromodulators.
Thyroid hormone is a key regulator of metabolism and energetics in the body and is well-known to both chemists and biologists for its unique iodine-containing structure and for the deleterious physiological effects seen when thyroid hormone concentrations are either excessive or deficient. The potential physiological roles for thyroid increased greatly with the discovery that thyronamines, decarboxylated and partially deiodinated metabolites of thyroid hormone, cause a 50% decrease in heart rate and an 8 °C drop in body temperature in mice 30 min after dosing (1). Finding molecular mechanisms to explain these physiological effects is key to understanding and potentially exploiting this signaling pathway. On page 390 of this journal, Scanlan and coworkers present evidence that thyronamines inhibit dopamine and norepinephrine transporters, preventing neuronal reuptake of these neurotransmitters, and also inhibit the action of vesicular monoamine transporter 2 (VMAT2), the intracellular transporter responsible for loading secretory vesicles with intracellular monoamines for exocytotic release (2). These neuromodulatory effects could help explain the physiological effects of thyronamines and give more evidence on how thyroid hormone acts as a switch for maintaining metabolic homeostasis.
Thyroid hormone is biosynthesized from tyrosine and is originally produced in a tetraiodinated form (T4) that is then deiodinated to the more potent triiodothyronine (T3). It binds to the thyroid hormone receptor, a nuclear receptor that regulates transcription of genes containing thyroid response elements in their promoter region (3, 4). Through this pathway, T3 is known to increase heart rate, basal metabolism, and body temperature (5, 6). Because of their common biosynthetic precursor, tyrosine, T3 is also structurally similar to biogenic amines such as dopamine and norepinephrine, if T3 were decarboxylated to the thyronamine. Although the concept of a thyroid metabolite as a neuromodulator has been mentioned previously (7), identifying the nature of the metabolite and its physiological relevance was not achieved. In previous work, a panel of thyronamines was synthesized with different degrees of iodination and screened against various biogenic amine receptors (1). A number of compounds were found to bind to an isoform of the trace amine-associated receptor (TAAR1), an orphan G-protein-coupled receptor that had not previously been linked with an endogenous ligand. One of these thyronamines, 3-iodothyronamine (T1AM), was found to activate the receptor at concentrations that were found to be present in rodent brain. This thyronamine was then shown to cause rapid decrease in heart rate and body temperature in mice that were reversible over time without negative long-term effects on the mice. The effects of T1AM on heart rate and body temperature were generally the opposite of those of T3, an indication that T3 and its iodothyronamine metabolite act to maintain a balance in homeostasis, with T1AM acting as a quick brake to the more gradual increases seen with T3.
This work suggests that the thyronamine scaffold is capable of selective modulation of the different monoamine transporters.
Although this finding was important, it also raised a number of questions, including the key question of whether TAAR1 was the mediator of the physiological effects seen in the animal models. The trace amine receptors are a fairly new receptor family whose functions are still poorly understood (8, 9). The possibility remains that other receptors that were not tested in the initial screen could also respond to thyronamines. A very relevant family of receptors to consider when testing monoamine action is the monoamine transporter family. At the synapse, neurotransmitters are released from presynaptic neurons through an exocytotic mechanism in which secretory vesicles containing high concentrations of neurotransmitter are shuttled to the plasma membrane for release. After release, neurotransmitters can then bind to receptors on postsynaptic neurons, or they can be inactivated by reuptake into the presynaptic neuron and neighboring neurons by monoamine transporters. There are monoamine transporters specific for dopamine, serotonin, and norepinephrine (named DAT, SERT, and NET, respectively) and an intracellular transporter that packs the monoamines into secretory vesicles for release (VMAT2) (10, 11). The monoamine transporters have been vitally important in the development of central nervous system drugs. Most clinically used antidepressants inhibit either the norepinephrine or serotonin transporters (or both), and the dopamine transporter is a major target of amphetamine and cocaine. Various psychostimulants can also inhibit VMAT2, a sign that VMAT2 could be targeted as a strategy to potentially mitigate abuse of these drugs (Figure 1).
Secondary Metabolites: Meaning, Role and Types
Plants produce thousands types of chemicals. Some of the organic compounds like carbohydrates, fats, proteins, nucleic acids, chlorophylls, hemes are required for their basic metabolic processes and found throughout the plant kingdom. These organic com­pounds are called primary metabolites or biomolecules. These are produced in large quantities and can easily be extracted from the plants.
Many plants, fungi and microbes of certain genera and families synthesize a number of organic compounds which are not involved in primary metabolism (pho­tosynthesis, respiration, and protein and lipid metabolism) and seem to have no direct function in growth and development of plants. Such compounds are called secondary metabolites (secondary plant products or natural products) (Table 9.7).
These compounds are accessary rather than central to the functioning of the plants in which they are found. These compounds are produced in small quantities and their extraction from the plant is difficult and expensive.
They accumulate in small quantities only in specific parts of plants. These are derivatives of primary metabolites. By the cultivation of plant cells in culture media, secondary metabolites can be produced on large scale.
Role of Secondary Metabolites:
(1) Some of them attract animals for pollination and seed dispersal.
(2) They are used by the plants in their defence against herbivores and pathogens.
(3) They act as agents of plant-plant competition.
(4) They are used in making drugs, insecticides, flavours, pigments, scents, rubber, spices and other industrial materials like gums, resins for human welfare.
Types of Secondary Metabolites:
These secondary metabolites are highly numerous in number, chemically diverse in nature and belong to three groups.
Parts of the endocrine system
The endocrine system consists of
Many other organs, such as the liver, skin, kidney, and parts of the digestive and circulatory systems, produce hormones in addition to their other physiological functions.
Endocrine vs. exocrine glands
Endocrine glands are ductless glands that secrete hormones directly into the bloodstream, whereas exocrine glands release their secretions through ducts or tubes.
Examples of exocrine glands are sweat glands, salivary glands, and tear (lacrimal) glands.
Video: Endocrine glands and hormones review
Glucagon is a peptide hormone that is produced in the α-cells of the pancreatic islets. Epinephrine is produced in the medulla, and cortisol in the cortex of the adrenal glands. All these hormones are antagonists of insulin.
Glucagon and epinephrine act via G-protein-coupled receptors
The cognate receptors of glucagon and epinephrine belong to the class of G protein-coupled receptors (GPCRs). Like receptor tyrosine kinases (RTKs), GPCRs are located in the cytoplasmic membrane. In contrast to RTKs, however, GPCRs do not have any enzymatic activity themselves. A GPCR functions solely by changing conformation in response to the binding of its cognate agonist, which occurs on the extracellular side (1). This conformational change is recognized on the intracellular side by a heterotrimeric G protein (2), which becomes bound to the receptor and is thereby activated. The active state of the G protein is stabilized by the non-covalent binding of GTP, which replaces a GDP molecule that was left behind in a previous round of activation (3). Upon GTP binding, the G protein dissociate into the α-subunit and the βγ-dimer, each of which then seeks out its cognate effector protein (4).
The α-subunit has a built-in, slow GTPase activity. When this activity kicks in and cleaves the bound GTP molecule (5), the activated state is terminated, 87 and the α-subunit rejoins a βγ-dimer (6). The inactive trimer then awaits the next round of activation by the same or another GPCR molecule.
The glucagon and epinephrine receptors activate adenylate cyclase and protein kinase A
One type of G protein can couple to several types of GPCR this is the case with the the so-called stimulatory G protein (GS), which couples to both the glucagon receptor and the β-adrenergic receptor, which binds epinephrine. The α-subunit of this G protein (αS) activates adenylate cyclase, which converts ATP to cyclic AMP (cAMP). This second messenger then binds and activates protein kinase A (PKA), which phosphorylates a number of target enzymes.
Adenylate cyclase is also targeted by the α-subunit an inhibitory G protein, Gi, which is activated downstream of other GPCRs, such as for example α2-adrenergic receptors or several serotonin receptor subtypes. Another major signaling cascade that is controlled by GPCRs is the phospholipase C/protein kinase C pathway, which is activated for example by vasopressin and oxytocin receptors. In these notes, however, we will confine the discussion to epinephrine, glucagon, and protein kinase A.
Metabolic effects of protein kinase A
|glycogen synthase||↓||glucose is not locked up in glycogen, remains available|
|phosphorylase kinase||↑||phosphorylase is activated, glucose is released from glycogen storage|
|PFK-2 / Fructose-2,6-bisphosphatase||↓ / ↑||Fructose-2,6-bisphosphate drops glycolysis is inhibited, gluconeogenesis is activated|
|hormone-sensitive lipase||↑||fatty acids are mobilized for β-oxidation and ketogenesis|
This slide summarizes downstream effects of PKA activation that were already discussed in detail earlier. The roles of PKA in gluconeogenesis and in glycogen synthesis are shown in slides 7.5.4 and 8.4.2 , respectively. PKA also activates hormone-sensitive lipase in fat tissue, which induces the release of free fatty acids and glycerol (slide 10.3.7 ).
Glucocorticoids and thyroid hormones act on nuclear hormone receptors to activate transcription
While they are inactive, nuclear hormone receptors are located in the cytosol. When activated by ligand binding, they translocate to the nucleus and bind to cognate DNA sequences, recruit a number of other regulatory proteins (not shown) and ultimately induce the transcription of genes in the vicinity of their target DNA sequences.
DNA binding by thyroid hormone receptors
Nuclear hormone receptors function as dimeric molecules. This picture illustrates the binding of a thyroid hormone receptor homodimer (TRβ left) and of a heterodimer of TRβ with retinoid X receptor (RXR yellow) to specific target sequences in the DNA. The structures of the receptor molecules (rendered from 3m9e.pdb and 2nll.pdb) are not complete the hormone-binding domains are missing, and only the DNA-binding domains are shown.
Note that TRβ and RXR bind to the same hexanucleotide motif. Nevertheless, the two receptor dimers recognize different DNA target sequences, since the two instances of the hexanucleotide differ in orientation and spacing. Therefore, the two dimers bind to different sites on the DNA and control different sets of genes.
One key mechanism through which thyroid hormones affect energy metabolism is the transcriptional induction of mitochondrial uncoupling proteins. As discussed earlier (slide 6.3.1 ), uncoupling proteins mediate the conversion of metabolic energy to heat and therefore increase the burn rate of glucose and other energy-rich substrates. Nevertheless, thyroid hormones do not reduce blood glucose, since they also induce the expression of β-adrenergic receptors, and they therefore amplify the glucose-enhancing effect of epinephrine.
Metabolic effects of glucocorticoid hormones
- induction of enzymes for glycogen synthesis, glycogen breakdown, as well as gluconeogenesis
- induction of enzymes for protein breakdown, which supplies substrates for gluconeogenesis
- induction of adrenergic receptors
…overall, glucocorticoids increase blood glucose
In addition to their role in metabolic regulation, glucocorticoids also inhibit inflammation and immune responses. They are used as drugs in the treatment of various inflammatory and autoimmune diseases their metabolic effects then become unwanted side effects of such therapy.
Glucocorticoid receptor agonists and antagonists
Dexamethasone and prednisolone are synthetic glucocorticoid receptor agonists that exert both antiinflammatory and metabolic effects. Mifepristone is a glucocorticoid receptor antagonist. In the experiment shown on the right, the activities of these conventional drugs were compared to those of the experimental drug RU 24858. Downregulation of interleukin-1β (IL-1β) measures antiinflammatory activity, whereas the activity of tyrosine transaminase (TAT), an enzyme that participates in amino acid degradation (see slide 12.4.5 ), represents metabolic regulation. Figure prepared from original data in  .
With dexamethasone, prednisolone and mifepristone, the antiinflammatory and metabolic effects are similarly weak or strong. In contrast, with RU 24858, they are clearly distinct, suggesting that this drug selectively triggers the antiinflammatory glucocorticoid effect but avoids the side effects on metabolic regulation. Such selective glucocorticoid receptor agonists are promising but not yet in clinical use. The biochemical mechanism that underlies the dissociation of metabolic and antiinflammatory glucocorticoid effects is quite interesting  .
Note that mifepristone is an antagonist not only at the glucocorticoid receptor but also at the progestin receptor its typical medical applications relate to the latter activity.
Control of food intake by leptin
Leptin is a peptide hormone produced by fat tissue, in proportion to its abundance and current triacylglycerol content. It acts upon receptors in the hypothalamus and reduces appetite. This slide illustrates the effect of genetic leptin knock-out in mice (no brownie points for correctly identifying the knock-out and the wild-type mouse).
While leptin is important in long-term regulation of metabolism and body weight, initial expectations that leptin substitution or leptin receptor agonists might be useful in the treatment of obesity in humans have not been fulfilled. It appears that in adipose patients there is no leptin deficiency, but rather an insensitivity to it, similar to the insensitivity to insulin in type 2 diabetes (see next chapter).