A hormone (from Greek"impetus") is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one cell to another. All multicellular organisms produce hormones; plant hormones are also called phytohormones. Hormones in animals are often transported in the blood. Cells respond to a hormone when they express a specific receptor for that hormone. The hormone binds to the receptor protein, resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses. Endocrine hormone molecules are secreted (released) directly into the bloodstream, whereas exocrine hormones (or ectohormones) are secreted directly into a duct, and, from the duct, they flow either into the bloodstream or from cell to cell by diffusion in a process known as paracrine signalling. Recently it has been found that a variety of exogenous modern chemical compounds have hormone-like effects on both humans and wildlife. Their interference with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body are responsible of homeostasis, reproduction, development, and/or behavioural changes sameway as the endogenous produced hormones. Hormonal signaling involves the following: Biosynthesis of a particular hormone in a particular tissue Storage and secretion of the hormone Transport of the hormone to the target cell(s) Recognition of the hormone by an associated cell membrane or intracellular receptor protein Relay and amplification of the received hormonal signal via a signal transduction process: This then leads to a cellular response. The reaction of the target cells may then be recognized by the original hormone-producing cells, leading to a down-regulation in hormone production. This is an example of a homeostatic negative feedback loop. Degradation of the hormone. Hormone cells are typically of a specialized cell type, residing within a particular endocrine gland, such as thyroid gland, ovaries, and testes. Hormones exit their cell of origin via exocytosis or another means of membrane transport. The hierarchical model is an oversimplification of the hormonal signaling process. Cellular recipients of a particular hormonal signal may be one of several cell types that reside within a number of different tissues, as is the case for insulin, which triggers a diverse range of systemic physiological effects. Different tissue types may also respond differently to the same hormonal signal. Because of this, hormonal signaling is elaborate and hard to dissect.
Effects of hormonesEdit
Hormones have the following effects on the body: stimulation or inhibition of growth
induction or suppression of apoptosis (programmed cell death)
activation or inhibition of the immune system
regulation of metabolism
preparation of the body for mating, fighting, fleeing, and other activity
preparation of the body for a new phase of life, such as puberty, parenting, and menopause control of the reproductive cycle
A hormone may also regulate the production and release of other hormones. Hormone signals control the internal environment of the body through homeostasis.
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g (0.02 oz.), in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity (sella turcica) covered by a dural fold (diaphragma sellae). The pituitary is functionally connected to the hypothalamus by the median eminence via a small tube called the infundibular stem (Pituitary Stalk). The pituitary fossa, in which the pituitary gland sits, is situated in the sphenoid bone in the middle cranial fossa at the base of the brain. The pituitary gland secretes nine hormones that regulate homeostasis. There is an analogous structure in the octopus brain.
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland. The anterior pituitary regulates several physiological processes including stress, growth, and reproduction. Its regulatory functions are achieved through the secretion of various peptide hormones that act on target organs including the adrenal gland, liver, bone, thyroid gland, and gonads. The anterior pituitary itself is regulated by the hypothalamus and by negative feedback from these target organs. Disorders of the anterior pituitary are generally classified by the presence of over- or underproduction of pituitary hormones. For example, a prolactinoma is a pituitary adenoma that overproduces prolactin. In Sheehan's syndrome of postpartum hypopituitarism, the anterior pituitary uniformly malfunctions and underproduces all hormones. Proper function of the anterior pituitary and of the organs it regulates can often be ascertained via blood tests that measure hormone levels.
The anterior pituitary synthesizes and secretes the following important endocrine hormones:
Adrenocorticotropic hormone (ACTH), release under influence of hypothalamic Corticotropin Releasing Hormone (CRH).
Thyroid-stimulating hormone (TSH), release under influence of hypothalamic Thyrotropin Releasing Hormone (TRH).
Growth hormone (also referred to as 'Human Growth Hormone', 'HGH' or 'GH' or somatotropin), release under influence of hypothalamic Growth Hormone Releasing Hormone (GHRH); inhibited by hypothalamic Somatostatin.
Prolactin (PRL), also known as 'Luteotropic' hormone (LTH), release under influence of multiple hypothalamic Prolactin Releasing Factors (PRH). The two 'Gonadotropins';
Luteinizing hormone (also referred to as 'Lutropin' or 'LH', or in males, 'Interstitial Cell Stimulating Hormone' (ICSH)), and Follicle stimulating hormone (FSH), both released under influence of Gonadotropin Releasing Hormone (GnRH). and;
melanocyte–stimulating hormones (MSH's) or "intermedins" as these are released by the pars intermedia which is "the middle part"; adjacent to the posterior pituitary lobe, pars intermedia is a specific part developed from the anterior pituitary lobe.
These hormones are released from the anterior pituitary under the influence of the hypothalamus. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called the hypothalamic-hypophysial portal system. The anterior pituitary is divided into anatomical regions known as the pars tuberalis, pars intermedia, and pars distalis. It develops from a depression in the dorsal wall of the pharynx (stomodial part) known as Rathke's pouch.
The posterior pituitary (or neurohypophysis) comprises the posterior lobe of the pituitary gland and is part of the endocrine system. Despite its name, the posterior pituitary gland is not a gland, per se; rather, it is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary gland.
The posterior pituitary consists mainly of neuronal projections (axons) extending from the supraoptic and paraventricular nuclei of the hypothalamus. These axons release peptide hormones into the capillaries of the hypophyseal circulation. In addition to axons, the posterior pituitary also contains pituicytes, specialized glial cells resembling astrocytes. Classification of the posterior pituitary varies, but most sources include the three regions below:
Also called the neural lobe or posterior lobe, this region constitutes the majority of the posterior pituitary, and is sometimes (incorrectly) considered synonymous with it. Notable features include Herring bodies and pituicytes.
Also known as the infundibulum or pituitary stalk, the infundibular stalk bridges the hypothalamic and hypophyseal systems.
Median eminence This is only occasionally included as part of the posterior pituitary. Other sources specifically exclude it from the pituitary. A few sources include the pars intermedia as part of the posterior lobe, but this is a minority view. It is based upon the gross anatomical separation of the posterior and anterior pituitary along the cystic remnants of Rathke's pouch, causing the pars intermedia to remain attached to the neurohypophysis.
Hormones known classically as posterior pituitary hormones are synthesized by the hypothalamus. They are then stored and secreted by the posterior pituitary into the bloodstream.
|Oxytocin||-||OT||Uterus, mammary glands||Uterine contractions; lactation||supraoptic and paraventricular nuclei|
|Vasopressin (antidiuretic hormone)||Arginine vasopressin, argipressin, antidiuretic hormone||VP, AVP, ADH||Kidneys or Arterioles||Stimulates water retention; raises blood pressure by contracting arterioles, induces male aggression||supraoptic and paraventricular nuclei|
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals. Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the cell nucleus. Peptide hormone precursors (pre-prohormones) are then processed in several stages, typically in the endoplasmic reticulum, including removal of the N-terminal signal sequence and sometimes glycosylation, resulting in prohormones. The prohormones are then packaged into membrane-bound secretory vesicles, which can be secreted from the cell by exocytosis in response to specific stimuli e.g increase of calcium and cAMP concentration in cytoplasm.. These prohormones often contain superfluous amino acid residues that were needed to direct folding of the hormone molecule into its active configuration but have no function once the hormone folds. Specific endopeptidases in the cell cleave the prohormone just before it is released into the bloodstream, generating the mature hormone form of the molecule. Mature peptide hormones then diffuse through the blood to all of the cells of the body, where they interact with specific receptors on the surface of their target cells. Some peptide/protein hormones (angiotensin II, basic fibroblast growth factor-2, parathyroid hormone-related protein) also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism. Several important peptide hormones are secreted from the pituitary gland. The anterior pituitary secretes prolactin, which acts on the mammary gland, adrenocorticotrophic hormone (ACTH), which acts on the adrenal cortex to regulate the secretion of glucocorticoids, and growth hormone, which acts on bone, muscle, and the liver. The posterior pituitary gland secretes antidiuretic hormone, also called vasopressin, and oxytocin. Peptide hormones are produced by many different organs and tissues, however, including the heart (atrial-natriuretic peptide (ANP) or atrial natriuretic factor (ANF)) and pancreas (insulin and somatostatin), the gastrointestinal tract cholecystokinin, gastrin), and adipose tissue stores (leptin). Some neurotransmitters are secreted and released in a similar fashion to peptide hormones, and some 'neuropeptides' may be used as neurotransmitters in the nervous system in addition to acting as hormones when released into the blood. When a peptide hormone binds to receptors on the surface of the cell, a second messenger appears in the cytoplasm, which triggers intracellular responses.
The following is a list of hormones found in humans. Spelling is not uniform for many hormones. Current North American|North America and international usage is estrogen, gonadotropin, while British usage retains the Greek diphthong in estrogen and favors the earlier spelling gonadotrophin (from trophē ‘nourishment, sustenance’ rather than tropē ‘turning, change’).
|amine - tryptophan||Image: Melatonin2.svg|thumb|200px||MT||pineal gland||pinealocyte||antioxidant and causes drowsiness|
|amine - tryptophan||thumb|200px||5-HT||CNS, gastrointestinal tract|GI tract||enterochromaffin cell||Controls mood, appetite, and sleep|
|amine - tyrosine||thumb|200px (or tetraiodothyronine) (a thyroid hormone)||T4||thyroid gland||thyroid epithelial cell||direct||less active form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines,
affect protein synthesis
|amine - tyrosine||Triiodothyronine (a thyroid hormone)||T3||thyroid gland||thyroid epithelial cell||direct||potent form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines,
affect protein synthesis
|cat)||thumb|180px||EPI||adrenal medulla||chromaffin cell||Fight-or-flight response:
Boosts the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasodilation, increasing catalysis of glycogen in liver, breakdown of lipids in adipocyte|fat cells. dilate the pupils Suppress non-emergency bodily processes (e.g. digestion) Suppress immune system
|cat)||Norepinephrine (or noradrenaline)||NRE||adrenal medulla||chromaffin cell||Fight-or-flight response:
Boosts the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasoconstriction and increased blood pressure, breakdown of lipids in adipocyte|fat cells. Increase skeletal muscle readiness.
|cat)||Dopamine (or prolactin inhibiting hormone)||DPM, PIH or DA||kidney, hypothalamus||Dopamine neurons of the arcuate nucleus in hypothalamus||TRH from anterior pituitary|
|peptide||Antimullerian hormone (or mullerian inhibiting factor or hormone)||AMH||testes||Sertoli cell||TRH from anterior pituitary|
|peptide||Adrenocorticotropic hormone (or corticotropin)||ACTH||anterior pituitary||corticotrope||cAMP||adrenocortical cells|
|peptide||Angiotensinogen and angiotensin||AGT||liver||IP3||vasoconstriction
release of aldosterone from adrenal cortex dipsogen.
|peptide||Antidiuretic hormone (or vasopressin, arginine vasopressin)||ADH||posterior pituitary||Parvocellular neurosecretory neurons in hypothalamus
Magnocellular neurosecretory cells in posterior pituitary
|varies||ACTH in anterior pituitary|
|peptide||Atrial-natriuretic peptide (or atriopeptin)||ANP||heart||cGMP|
|peptide||On-time Hormone||OTH||Epididymis||Regulates tardiness|
|peptide||Calcitonin||CT||thyroid gland||parafollicular cell||cAMP||Ca2+|
|peptide||Cholecystokinin||CCK||duodenum||Release of digestive enzymes from pancreas
Release of bile from gallbladder hunger suppressant
|peptide||Corticotropin-releasing hormone||CRH||hypothalamus||cAMP||ACTH from anterior pituitary|
|peptide||Erythropoietin||EPO||kidney||Extraglomerular mesangial cells||Stimulate erythrocyte production|
|peptide||Follicle-stimulating hormone||FSH||anterior pituitary||gonadotrope||cAMP||In female: stimulates maturation of Graafian follicles in ovary.
In male: spermatogenesis, enhances production of androgen-binding protein by the Sertoli cells of the testes
|peptide||Gastrin||GRP||stomach, duodenum||G cell||Secretion of gastric acid by parietal cells|
|peptide||Ghrelin||stomach||P/D1 cell||Stimulate appetite,
secretion of growth hormone from anterior pituitary gland
|peptide||Glucagon||GCG||pancreas||alpha cells||cAMP||glycogenolysis and gluconeogenesis in liver
increases blood glucose level
|peptide||Gonadotropin-releasing hormone||GnRH||hypothalamus||IP3||FSH and Luteinizing hormone|LH from anterior pituitary.|
|peptide||Growth hormone-releasing hormone||GHRH||hypothalamus||IP3||GH from anterior pituitary|
|peptide||Human chorionic gonadotropin||hCG||placenta||syncytiotrophoblast cells||cAMP||promote maintenance of corpus luteum during beginning of pregnancy
Inhibit immune system|immune response, towards the human embryo.
|peptide||Human placental lactogen||HPL||placenta||increase production of insulin and IGF-1
increase insulin resistance and carbohydrate intolerance
|peptide||Growth hormone||GH or hGH||anterior pituitary||somatotropes||growth and cell (biology)|cell reproduction
Release Insulin-like growth factor 1 from liver
|peptide||Inhibin||testes, ovary, fetus||Sertoli cells of testes
granulosa cells of ovary
trophoblasts in fetus
|peptide||Insulin||INS||pancreas||beta cells||tyrosine kinase||Intake of glucose, glycogenesis and glycolysis in liver and muscle from blood
intake of lipids and synthesis of triglycerides in adipocytes Other anabolism|anabolic effects
|peptide||Insulin-like growth factor (or somatomedin)||IGF||liver||Hepatocytes||tyrosine kinase||insulin-like effects
regulate cell growth and development
|peptide||Leptin||LEP||adipose tissue||decrease of appetite and increase of metabolism.|
|peptide||Luteinizing hormone||LH||anterior pituitary||gonadotropes||cAMP||In female: ovulation
In male: stimulates Leydig cell production of testosterone
|peptide||Melanocyte stimulating hormone||MSH or α-MSH||anterior pituitary/pars intermedia||Melanotroph||cAMP||melanogenesis by melanocytes in skin and hair|
|peptide||Orexin||hypothalamus||wakefulness and increased energy expenditure, increased appetite|
|peptide||Oxytocin||OXT||posterior pituitary||Magnocellular neurosecretory cells||IP3||release breast milk|
|peptide||Parathyroid hormone||PTH||parathyroid gland||parathyroid chief cell||cAMP||Ca2+: *indirectly stimulate osteoclasts
(Slightly) decrease blood phosphate:
|peptide||Prolactin||PRL||anterior pituitary, uterus||lactotrophs of anterior pituitary
Decidual cells of uterus
|sexual gratification after Human sexual behavior|sexual acts|
|peptide||Relaxin||RLN||uterus||Decidual cells||Unclear in humans|
|peptide||Secretin||SCT||duodenum||S cell||Secretion of bicarbonate from liver, pancreas and duodenal Brunner's glands
Enhances effects of cholecystokinin Stops production of gastric juice
|peptide||Somatostatin||SRIF||hypothalamus, islets of Langerhans, gastrointestinal system||delta cells in islets
Neuroendocrince cells of the Periventricular nucleus in hypothalamus
|GH and Thyrotropin-releasing hormone|TRH from anterior pituitary
Suppress release of gastrin, cholecystokinin (CCK), secretin, motilin, vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide (GIP), enteroglucagon in gastrointestinal system
Lowers rate of gastric emptying
Reduces smooth muscle contractions and blood flow within the intestine
|peptide||Thrombopoietin||TPO||liver, kidney, striated muscle||Myocytes||megakaryocytes||produce platelets|
|peptide||Thyroid-stimulating hormone (or thyrotropin)||TSH||anterior pituitary||thyrotropes||cAMP||thyroid gland||secrete thyroxine (T4) and triiodothyronine (T3)|
|peptide||Thyrotropin-releasing hormone||TRH||hypothalamus||Parvocellular neurosecretory neurons||IP3||anterior pituitary||Release thyroid-stimulating hormone (primarily)
Stimulate prolactin release
|glu.||Cortisol||adrenal cortex (zona fasciculata and zona reticularis cells)||direct||Stimulation of gluconeogenesis
Inhibition of glucose uptake in muscle and adipose tissue Mobilization of amino acids from Wiktionary:extrahepatic|extrahepatic tissues Stimulation of fat breakdown in adipose tissue anti-inflammatory and immunosuppressive
|min.||Aldosterone||adrenal cortex (zona glomerulosa)||direct||Increase blood volume by reabsorption of sodium in kidneys (primarily)
Potassium and Hydrogen ion|H+ secretion in kidney.
|and)||Testosterone||testes||Leydig cells||direct||libido, Anabolic: growth of muscle mass and strength, increased bone density, growth and strength,
Virilizing: maturation of sex organs, formation of scrotum, deepening of voice, growth of beard and axillary hair.
|and)||Dehydroepiandrosterone||DHEA||testes, ovary, kidney||Zona fasciculata and Zona reticularis cells of kidney
theca cells of ovary
Leydig cellss of testes
|and)||Androstenedione||adrenal glands, gonads||direct||Substrate for estrogen|
|est)||Estradiol||E2||females: ovary, males testes||females: granulosa cells, males: Sertoli cell||direct||Females:
Increase high density lipoprotein|HDL, triglyceride, height growth Decrease low density lipoprotein|LDL, fat deposition Fluid balance:
Cancer: support hormone-sensitive breast cancers  Suppression of production in the body of estrogen is a treatment for these cancers.
Males: Prevent apoptosis of germ cells
|est)||Estrone||ovary||granulosa cells, Adipocytes||direct|
|pro)||Progesterone||ovary, adrenal glands, placenta (when pregnant)||theca cells of ovary||direct||Support pregnancy:
Convert uterine lining|endometrium to secretory stage Make Cervix#Cervical mucus|cervical mucus permeable to sperm. Inhibit immune system|immune response, e.g. towards the human embryo. Decrease uterine smooth muscle contractility Inhibit lactation Inhibit onset of labor (childbirth)|labor. Support fetal production of adrenal mineralo- and glucosteroids.
Other: Raise epidermal growth factor-1 levels Increase core temperature during ovulation Reduce spasm and relax smooth muscle (widen bronchi and regulate mucus) Inflammation|Antiinflammatory Reduce gall-bladder activity Normalize blood clotting and vascular tone, zinc and copper levels, cell (biology)|cell oxygen levels, and use of fat stores for energy. Assist in thyroid function and bone growth by osteoblasts Relsilience in bone, teeth, gingiva|gums, joint, tendon, ligament and skin Healing by regulating collagen Nerve function and healing by regulating myelin Prevent endometrial cancer by regulating effects of estrogen.
|sterol||Calcitriol (1,25-dihydroxyvitamin D3)||skin/proximal tubule of kidneys||direct||vitamin D3
Increase absorption of calcium and phosphate from gastrointestinal tract and kidneys inhibit release of parathyroid hormone|PTH
|sterol||Calcidiol (25-hydroxyvitamin D3)||skin/proximal tubule of kidneys||direct||vitamin D3|
|eicosanoid||Leukotrienes||LT||white blood cells|
|peptide||Prolactin releasing hormone||PRH||hypothalamus||Release prolactin from anterior pituitary|
|peptide||Lipotropin||PRH||anterior pituitary||Corticotropes||lipolysis and steroidogenesis,
stimulates melanocytes to produce melanin
|peptide||Brain natriuretic peptide||BNP||heart||Cardiac myocytes||(To a minor degree than ANP) reduce blood pressure by:
reducing systemic circulation|systemic vascular resistance, reducing blood water, sodium and blood fats|fats
|peptide||Neuropeptide Y||NPY||Stomach||increased food intake and decreased physical activity|
|amine - histidine||Histamine||Stomach||ECL cells||stimulate gastric acid secretion|
|Endothelin||Stomach||X cells||Smooth muscle contraction of stomach |
|peptide||Pancreatic polypeptide||Pancreas||PP cells||self regulate the pancreas secretion activities (endocrine and exocrine), it also effects on hepatic glycogen levels and gastrointestinal secretions.|
|peptide||Renin||Kidney||Juxtaglomerular cells||Activates the renin-angiotensin system by producing angiotensin I of angiotensinogen|
|peptide||Enkephalin||Kidney||Chromaffin cells||Regulate pain|
In 1869, Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a microscope when he identified some previously unnoticed tissue clumps scattered throughout the bulk of the pancreas. The function of the "little heaps of cells", later known as the islets of Langerhans, was unknown, but Edouard Laguesse later suggested they might produce secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term "insulin" origins from insula, the Latin word for islet/island.
In 1889, the Polish-German physician Oscar Minkowski, in collaboration with Joseph von Mering, removed the pancreas from a healthy dog to test its assumed role in digestion. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine, they found there was sugar in the dog's urine, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by Eugene Opie, when he clearly established the link between the islets of Langerhans and diabetes: "Diabetes mellitus . . . is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed." Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets. Over the next two decades, several attempts were made to isolate whatever it was the islets produced as a potential treatment. In 1906, George Ludwig Zuelzer was partially successful treating dogs with pancreatic extract, but was unable to continue his work. Between 1911 and 1912, E.L. Scott at the University of Chicago used aqueous pancreatic extracts, and noted "a slight diminution of glycosuria", but was unable to convince his director of his work's value; it was shut down. Israel Kleiner demonstrated similar effects at Rockefeller University in 1915, but his work was interrupted by World War I, and he did not return to it.
In the spring of 1921, Banting traveled to Toronto to explain his idea to J.J.R. Macleod, who was Professor of Physiology at the University of Toronto, and asked Macleod if he could use his lab space to test the idea. Macleod was initially skeptical, but eventually agreed to let Banting use his lab space while he was on vacation for the summer. He also supplied Banting with ten dogs on which to experiment, and two medical students, Charles Best and Clark Noble, to use as lab assistants, before leaving for Scotland. Since Banting required only one lab assistant, Best and Noble flipped a coin to see which would assist Banting for the first half of the summer. Best won the coin toss, and took the first shift as Banting's assistant. Loss of the coin toss may have proved unfortunate for Noble, given that Banting decided to keep Best for the entire summer, and eventually shared half his Nobel Prize money and a large part of the credit for the discovery of insulin with the winner of the toss. Had Noble won the toss, his career might have taken a different path.
Banting's method was to tie a ligature around the pancreatic duct; when examined several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called "isletin" (what we now know as insulin), and tested this extract on the dogs. Banting and Best were then able to keep a pancreatectomized dog named Alpha alive for the rest of the summer by injecting her with the crude extract they had prepared. Removal of the pancreas in test animals essentially mimics diabetes, leading to elevated blood glucose levels. Alpha was able to remain alive because the extracts, containing isletin, were able to lower her blood glucose levels. Banting and Best presented their results to Macleod on his return to Toronto in the fall of 1921, but Macleod pointed out flaws with the experimental design, and suggested the experiments be repeated with more dogs and better equipment. He then supplied Banting and Best with a better laboratory, and began paying Banting a salary from his research grants. Several weeks later, the second round of experiments clearly was also a success; and Macleod helped publish their results privately in Toronto that November. However, they needed six weeks to extract the isletin, which forced considerable delays. Banting suggested they try to use fetal calf pancreas, which had not yet developed digestive glands; he was relieved to find this method worked well. With the supply problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited the biochemist James Collip to help with this task, and, within a month, the team felt ready for a clinical test. On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin. However, the extract was so impure, Thompson suffered a severe allergic reaction, and further injections were canceled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on January 23. This was completely successful, not only in having no obvious side effects, but also in completely eliminating the glycosuria sign of diabetes. The first American patient was Elizabeth Hughes Gossett, the daughter of the governor of New York.The first patient treated in the U.S. was future woodcut artist James D. Havens; Dr. John Ralston Williams imported insulin from Toronto to Rochester, New York, to treat Havens. Children dying from diabetic ketoacidosis were kept in large wards, often with 50 or more patients in a ward, mostly comatose. Grieving family members were often in attendance, awaiting the (until then, inevitable) death. In one of medicine's more dramatic moments, Banting, Best, and Collip went from bed to bed, injecting an entire ward with the new purified extract. Before they had reached the last dying child, the first few were awakening from their coma, to the joyous exclamations of their families. Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left the project soon after. Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm Eli Lilly and Company had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. In November, Lilly made a major breakthrough and were able to produce large quantities of highly refined insulin. Insulin was offered for sale shortly thereafter. Purified animal-sourced insulin was the only type of insulin available to diabetics until genetic breakthroughs occurred later with medical research. The amino acid structure of insulin was characterized in the 1950s, and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the early 1960s.
The first genetically-engineered, synthetic "human" insulin was produced in a laboratory in 1977 by Herbert Boyer using E. coli. Partnering with Genentech founded by Boyer, Eli Lilly and Company went on in 1982 to sell the first commercially available biosynthetic human insulin under the brand name Humulin. The vast majority of insulin currently used worldwide is now biosynthetic recombinant "human" insulin or its analogs.
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle. Insulin stops the use of fat as an energy source by inhibiting the release of glucagon. When insulin is absent, glucose is not taken up by body cells and the body begins to use fat as an energy source or gluconeogenesis; for example, by transfer of lipids from adipose tissue to the liver for mobilization as an energy source. As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). In addition, it has several other anabolic effects throughout the body. When control of insulin levels fails, diabetes mellitus will result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with type 2 diabetes are often insulin resistant, and because of such resistance, may suffer from a "relative" insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately, though this is somewhat uncommon. Insulin also influences other body functions, such as vascular compliance and cognition. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular. Enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting central nervous insulin contributes to the control of whole-body energy homeostasis in humans. Insulin is a peptide hormone composed of 51 amino acids and has a molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. The name comes from the Latin insula for "island". Insulin's structure varies slightly between species of animals. Insulin from animal sources differs somewhat in "strength" (in carbohydrate metabolism control effects) in humans because of those variations. Porcine insulin is especially close to the human version.
Image:Glucagon.png|thumb|right|Glucagon ball and stick model, with the carboxyl terminus above and the amino terminus below Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar (glucose) levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. Glucagon also stimulates the release of insulin, so glucose can be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level. Glucagon belongs to a family of several other related hormones.
Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH. The polypeptide has a molecular weight of 3485 daltons. Glucagon is a peptide (nonsteroid) hormone.
The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet.
Increased secretion of glucagon is caused by:
Decreased plasma glucose (indirectly)
Increased catecholamines - norepinephrine and epinephrine
Increased plasma amino acids (to protect from hypoglycemia if an all-protein meal is consumed) Sympathetic nervous system
Decreased secretion (inhibition) of glucagon is caused by:
Increased free fatty acids and keto acids into the blood
Increased urea production
Mechanism of action and Function of GlucagonEdit
Glucagon helps maintain the level of glucose in the blood. Glucose is stored in the liver in the form of glycogen, which is a starch-like polymer chain made up of glucose molecules. Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen polymer into individual glucose molecules, and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis. Glucagon also regulates the rate of glucose production through lipolysis.
Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase. Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which, in turn, phosphorylates glycogen phosphorylase, converting into the active form called phosphorylase A. Phosphorylase A is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.
Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure (see structure to the right). GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases that are caused by an overactive immune system, such as allergies, asthma, autoimmune diseases and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over-the-counter.
A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in the pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water; see also: renal physiology). Because they permeate the intestines easily, they are administered primarily per os (by mouth), but also by other methods, such as topically on skin. More than 90 percent of them bind different plasma proteins, however with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin (also called CBG, corticosteroid-binding globulin), whereas all of them bind albumin. In the liver, they quickly metabolise by conjugation with a sulfate or glucuronic acid, and are secreted in the urine. Glucocorticoid potency, duration of effect, and overlapping mineralocorticoid potency varies. Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol. Data refer to oral dosing, except when mentioned. Oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Fludrocortisone, DOCA (Deoxycorticosterone acetate), and aldosterone are, by definition, not considered glucocorticoids, although they may have minor glucocorticoid potency, and are included in this table to provide perspective on mineralocorticoid potency.
Monoamine and Monoamine neurotransmittersEdit
Monoamines derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan by the action of aromatic amino acid decarboxylase enzymes.
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and the thyroid hormones by the action of aromatic amino acid decarboxylase enzymes.
* Histamine * Catecholamines: o Dopamine (DA) o Norepinephrine (NE) (noradrenaline, NA) o Epinephrine (Epi) (adrenaline) * Tryptamines: o Serotonin (5-HT) o Melatonin * Trace amines: o β-Phenylethylamine (PEA, β-PEA) o Tyramine o Tryptamine o Octopamine o 3-iodothyronamine o Thyronamines, a new group of compounds derived from thyroid hormones
Epinephrine or AdrenalineEdit
|Heart||Increases heart rate|
|Lungs||Increases respiratory rate|
|Nearly all tissues||Vasoconstriction or vasodilation|
|N/A, systemic||Triggers lipolysis|
|N/A, systemic||Muscle contraction|
Epinephrine (also known as adrenaline) is a hormone and a neurotransmitter.It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. Chemically, epinephrine is a catecholamine, a monoamine produced only by the adrenal glands from the amino acids phenylalanine and tyrosine.
The term adrenaline is derived from the Latin roots ad- and renes and literally means "on the kidney", in reference to the adrenal gland's anatomic location on the kidney. The Greek roots epi and nephros have similar meanings, and give rise to "epinephrine". The term epinephrine is often shortened to epi in medical jargon. Adrenaline is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the amino acid tyrosine into a series of intermediates and ultimately adrenaline. Tyrosine is first oxidized to L-DOPA, which is subsequently decarboxylated to give dopamine. Oxidation gives norepinephrine, which is methylated to give epinephrine.
Adrenaline is synthesized via methylation of the primary distal amine of noradrenaline by phenylethanolamine N-methyltransferase (PNMT) in the cytosol of adrenergic neurons and cells of the adrenal medulla (so-called chromaffin cells). PNMT is only found in the cytosol of cells of adrenal medullary cells. PNMT uses S-adenosylmethionine (SAMe) as a cofactor to donate the methyl group to noradrenaline, creating adrenaline. The biosynthesis of adrenaline involves a series of enzymatic reactions.
For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.
In liver cells, adrenaline binds to the β-adrenergic receptor which changes conformation and helps Gs, a G protein, exchange GDP to GTP. This trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits. Gs alpha binds to adenyl cyclase, thus converting ATP into cyclic AMP. Cyclic AMP binds to the regulatory subunit of protein kinase A: Protein kinase A phosphorylates phosphorylase kinase. Meanwhile, Gs beta/gamma binds to the calcium channel and allows calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin proteins, a protein present in all eukaryotic cells, which then binds to phosphorylase kinase and finishes its activation. Phosphorylase kinase phosphorylates glycogen phosphorylase which then phosphorylates glycogen and converts it to glucose-6-phosphate. Image:Catecholamines biosynthesis.svg|thumb|centre|450px|The biosynthesis of adrenaline involves a series of enzymatic reactions.
As a hormone, epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, epinephrine causes smooth muscle relaxation in the airways, but causes contraction of the smooth muscle that lines most arterioles.
Epinephrine acts by binding to a variety of adrenergic receptors. Adrenaline is a nonselective agonist of all adrenergic receptors, including α1, α2, β1, β2, and β3 receptors.Epinephrine's binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis in muscle. β-Adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.
In addition to these metabolic changes, epinephrine also leads to broad alterations throughout all organ systems.
The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high ambient temperature. All of these stimuli are processed in the central nervous system.
Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine-β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of adrenaline (and noradrenaline) into the bloodstream.
Adrenaline (as with noradrenaline) does exert negative feedback to down-regulate its own synthesis at the presynaptic alpha-2 adrenergic receptor. Abnormally elevated levels of adrenaline can occur in a variety of conditions, such as surreptitious epinephrine administration, pheochromocytoma, and other tumors of the sympathetic ganglia.
Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-o-methyl transferase
Cortisol (hydrocortisone) is a steroid hormone, or glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat, protein and carbohydrate metabolism. It also decreases bone formation. During pregnancy, increased production of cortisol between weeks 30-32 initiates production of fetal lung surfactanct to promote maturation of the lungs. Various synthetic forms of cortisol are used to treat a variety of different diseases.
Cortisol's primary functions in the body are:
* increasing blood sugar through gluconeogenesis * suppressing the immune system * aiding in fat, protein, and carbohydrate metabolism
It surpresses the immune system by "muting" the white blood cells
Another function is to decrease bone formation. Cortisol is used to treat diseases such as Addison’s disease, inflammatory and rheumatoid diseases, and allergies. Low-potency hydrocortisone, available over the counter in some countries, is used to treat skin problems such as rashes, eczema and others.
Cortisol prevents the release of substances in the body that cause inflammation. It stimulates gluconeogenesis (the breakdown of protein and fat to provide metabolites that can be converted to glucose in the liver) and it activates anti-stress and anti-inflammatory pathways.
Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of the adrenal cortex. (The name cortisol is derived from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.
The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); ACTH production is in turn stimulated by corticotropin-releasing hormone (CRH), which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the STAR (steroidogenic acute regulatory) protein. It also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by Cytochrome P450SCC (side chain cleavage enzyme).
Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.
* 11-beta HSD1 utilizes the cofactor NADPH to convert biologically-inert cortisone to biologically-active cortisol * 11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone
Overall, the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically-active cortisol in a given tissue; 11-beta HSD2 serves to decrease local concentrations of biologically-active cortisol.
Cortisol is also metabolized into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), reactions for which 5-alpha reductase and 5-beta reductase are the rate-limiting factors respectively. 5-beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone (THE).
An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance known as metabolic syndrome.
An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME).
Leptin (Greek leptos meaning thin) is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones.The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.
Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf) which in turn are encoded by a single gene, LEPR. Ob-Rb is the only receptor isoform that can signal intracellularly via the JAK-STAT signaling pathway|Jak-Stat and MAPK signal transduction pathways, and is present in hypothalamic nuclei.
It is unknown whether leptin can cross the blood-brain barrier to access receptor neurons, because the blood-brain barrier is attenuated in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are. It is generally thought that leptin might enter the brain at the choroid plexus, where there is intense expression of a form of leptin receptor molecule that could act as a transport mechanism.
Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to, presumably, effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible for increasing appetite. There are other intracellular pathways activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them. There is some recognition that leptin action is more decentralized than previously assumed. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a paracrine mediator.
Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by
(1) counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus);
(2) counteracting the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC, the primary active ingredient of marijuana); and
(3) promoting the synthesis of α-MSH, an appetite suppressant. This inhibition is long-term, in contrast to the rapid inhibition of eating by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled food intake and resulting obesity. Several studies have shown that fasting or following a very-low-calorie diet (VLCD) lowers leptin levels. It might be that on short-term leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding; leptin levels change more when food intake decreases than when it increases. It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually to food intake. Although this is a new hypothesis, there are already some data that support it.
There is some controversy regarding the regulation of leptin by melatonin during the night. One research group suggested that increased levels of melatonin caused a downregulation of leptin. However, in 2004, Brazilian researchers found that melatonin increases leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.
Mice with type 1 diabetes treated with leptin alone or in conjunction with insulin did better (blood sugar did not fluctuate as much; cholesterol levels decreased; mice formed less body fat) than mice with type 1 diabetes treated with insulin alone, raising the prospect of a new treatment for diabetes.
To date, only leptin and insulin are known to act as an adiposity signal. In general,
- Leptin circulates at levels proportional to adipose tissue|body fat.
- It enters the central nervous system (CNS) in proportion to its blood plasma|plasma concentration.
- Its receptors are found in brain neurons involved in regulating energy intake and expenditure.
- It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus
Interaction with amylinEdit
Co-administration of two neurohormones known to have a role in body weight control, amylin (produced by beta cells in the pancreas) and leptin (produced by fat cells), results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesity.
Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus, in such a way that decreases the activity of these neurons. Leptin signals to the brain that the body has had enough to eat, producing a feeling of satiety. A very small group of humans possess homozygous mutations for the leptin gene that leads to a constant desire for food, resulting in severe obesity. This condition can be treated somewhat successfully by the administration of recombinant human leptin. However, extensive clinical trials using recombinant human leptin as a therapeutic agent for treating obesity in humans have been inconclusive because only the most obese subjects who were given the highest doses of exogenous leptin produced statistically significant weight loss. It was concluded that large and frequent doses were needed to provide only modest benefit because of leptin’s low circulating half-life, low potency, and poor solubility. Furthermore, these injections caused some participants to drop out of the study due to inflammatory responses of the skin at the injection site. Some of these problems can be alleviated by a form of leptin called Fc-leptin, which takes the Fc fragment from the immunoglobulin gamma chain as the N-terminal fusion partner and follows it with leptin. This Fc-leptin fusion has been experimentally proven to be highly soluble, more biologically potent, and contain a much longer serum half-life. As a result, this Fc-leptin was successfully shown to treat obesity in both leptin-deficient and normal mice, although studies have not been undertaken on human subjects. This makes Fc-leptin a potential treatment for obesity in humans after more extensive testing. Circulating leptin levels give the brain input regarding energy storage so it can regulate appetite and metabolism. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and by increasing the activity of neurons expressing melanocyte-stimulating hormone|α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexia (symptom)|anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the receptor at which α-MSH acts in the brain are linked to obesity in humans.
The role of leptin/leptin receptors in modulation of T cell activity in immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, which is a predisposing factor in patients with obesity.
Leptin promotes angiogenesis by increasing vascular endothelial growth factor (VEGF) levels.
In some epidemiological studies, hyperleptinemia is considered as a risk factor. However, recently a handful of animal experiments demonstrated that systemic hyperleptinemia produced by infusion or adenoviral gene transfer decrease blood pressure in rats.  
Lung surfactant activityEdit
In fetal lung leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.
In mice, leptin is also required for male and female fertility. Leptin has a lesser effect in humans. In mammals such as humans, ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning that a woman is starving) or energy flux is very high (meaning that a woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Some studies have indicated that leptin levels outside an ideal range can have a negative effect on egg quality and outcome during IVF.
The body's fat cells, under normal conditions, are responsible for the constant production and release of leptin. This can also be produced by the placenta. Leptin levels rise during pregnancy and fall after parturition (childbirth). Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.
There is also evidence that leptin plays a role in hyperemesis gravidarum (severe morning sickness), in polycystic ovary syndrome and a 2007 research suggests that hypothalamic leptin is implicated in bone growth.
Effects on boneEdit
The fact that leptin, a hormone released from fat tissue, can regulate bone mass first came to prominence in 2000. It is now well established that leptin can affect bone metabolism via direct signalling from the brain and that although leptin acts to reduce cancellous bone, it conversely increases cortical bone. A number of theories have been put forward concerning the cortical-cancellous dichotomy including a recent theory suggesting that increased leptin during obesity may represent a mechanism for enlarging bone size and thus bone resistance to cope with increased body weight.
Bone metabolism is under direct control of the brain and thus nerve fibres are present in bone tissue. A number of brain signalling molecules (neuropeptides and neurotransmitters) have been found in bone including adrenaline, noradrenaline, serotonin, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y. This evidence supports a direct signalling system between the brain and bone with accumulating evidence suggesting that these molecules are directly involved in the regulation of bone metabolism. Leptin, once released from fat tissue, can cross the blood-brain barrier and bind to its receptors in the brain where it acts through the sympathetic nervous system to regulate bone metabolism. It is also possible that, in addition to its effects through the brain, leptin may act directly on cells in the bone to regulate bone metabolism. In reality, leptin probably signals to bone on multiple levels, with local and systemic checks and balances impacting the final outcome. As a result, the clinical utility of leptin for treatment of bone diseases remains open but ongoing research may yet provide much needed therapies for stimulating bone formation.
- John Davis (23 Apr 2010). "OnTime-hormone produced in Epididymis". http://www.physicsforums.com/showthread.php?t=397764.
- Kosfeld M et al. (2005) Oxytocin increases trust in humans. Nature (journal)|Nature 435:673-676. PDF PMID 15931222
- Scientific American Mind, "Rhythm and Blues"; June/July 2007; Scientific American Mind; by Ulrich Kraft
- Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med 2006;354:2034-45. PMID 16687716.
- Hormonal Therapy
- Massaro D, Massaro GD (2004). "Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice". American Journal of Physiology. Lung Cellular and Molecular Physiology 287 (6): L1154–9. doi:10.1152/ajplung.00228.2004. PMID 15298854. http://ajplung.physiology.org/cgi/content/full/287/6/L1154.
- Pentikäinen V, Erkkilä K, Suomalainen L, Parvinen M, Dunkel L. Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in vitro. The Journal of Clinical Endocrinology & Metabolism 2006;85:2057-67 PMID 10843196
- Placental Hormones
- Hould F, Fried G, Fazekas A, Tremblay S, Mersereau W (1988). "Progesterone receptors regulate gallbladder motility". J Surg Res 45 (6): 505–12. doi:10.1016/0022-4804(88)90137-0. PMID 3184927.
- Diabetes-related changes in contractile responses of stomach fundus to endothelin-1 in streptozotocin-induced diabetic rats Journal of Smooth Muscle Research Vol. 41 (2005) , No. 1 35-47. Kazuki Endo1), Takayuki Matsumoto1), Tsuneo Kobayashi1), Yutaka Kasuya1) and Katsuo Kamata1)
- Wang MY, Zhou YT, Newgard CB, Unger RH (August 1996). "A novel leptin receptor isoform in rat". FEBS Lett. 392 (2): 87–90. doi:10.1016/0014-5793(96)00790-9. PMID 8772180.
- Malendowicz W, Rucinski M, Macchi C, Spinazzi R, Ziolkowska A, Nussdorfer GG, Kwias Z (October 2006). "Leptin and leptin receptors in the prostate and seminal vesicles of the adult rat". Int. J. Mol. Med. 18 (4): 615–8. PMID 16964413. http://www.spandidos-publications.com/ijmm/article.jsp?article_id=ijmm_18_4_615.
- Studies include:
- Dubuc G, Phinney S, Stern J, Havel P (1998). "Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women". Metab. Clin. Exp. 47 (4): 429–34. PMID 9550541.
- Pratley R, Nicolson M, Bogardus C, Ravussin E (1997). "Plasma leptin responses to fasting in Pima Indians". Am. J. Physiol. 273 (3 Pt 1): E644–9. PMID 9316457.
- Weigle D, Duell P, Connor W, Steiner R, Soules M, Kuijper J (1997). "Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels". J. Clin. Endocrinol. Metab. 82 (2): 561–5. doi:10.1210/jc.82.2.561. PMID 9024254.
- Chin-Chance C, Polonsky K, Schoeller D (2000). "Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake". J. Clin. Endocrinol. Metab. 85 (8): 2685–91. doi:10.1210/jc.85.8.2685. PMID 10946866.
- Keim N, Stern J, Havel P (1998). "Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women". Am. J. Clin. Nutr. 68 (4): 794–801. PMID 9771856.
- Mars M, de Graaf C, de Groot C, van Rossum C, Kok F (2006). "Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet". International journal of obesity (Lond) 30 (1): 122–8. doi:10.1038/sj.ijo.0803070. PMID 16158086.
- Kus I, Sarsilmaz M, Colakoglu N, et al. (2004). "Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study". Physiological research / Academia Scientiarum Bohemoslovaca 53 (4): 403–8. PMID 15311999.
- Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB (April 2005). "Melatonin enhances leptin expression by rat adipocytes in the presence of insulin". Am. J. Physiol. Endocrinol. Metab. 288 (4): E805–12. doi:10.1152/ajpendo.00478.2004. PMID 15572654.
- Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH (March 2010). "Leptin therapy in insulin-deficient type I diabetes". Proc. Natl. Acad. Sci. U.S.A. 107 (11): 4813–9. doi:10.1073/pnas.0909422107. PMID 20194735. Lay summary – medicinenet.com.
- Williams KW, Scott MM, Elmquist JK (March 2009). "From observation to experimentation: leptin action in the mediobasal hypothalamus". Am. J. Clin. Nutr. 89 (3): 985S–990S. doi:10.3945/ajcn.2008.26788D. PMID 19176744.
- Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD (May 2008). "Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies". Proc. Natl. Acad. Sci. U.S.A. 105 (20): 7257–62. doi:10.1073/pnas.0706473105. PMID 18458326.
- OMIM - LEPTIN; LEP
- Friedman JM, Halaas JL (October 1998). "Leptin and the regulation of body weight in mammals". Nature 395 (6704): 763–70. doi:10.1038/27376. PMID 9796811.
- Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M (October 1999). "Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial". JAMA 282 (16): 1568–75. doi:10.1001/jama.282.16.1568. PMID 10546697.
- Lo KM, Zhang J, Sun Y, Morelli B, Lan Y, Lauder S, Brunkhorst B, Webster G, Hallakou-Bozec S, Doaré L, Gillies SD (January 2005). "Engineering a pharmacologically superior form of leptin for the treatment of obesity". Protein Eng. Des. Sel. 18 (1): 1–10. doi:10.1093/protein/gzh102. PMID 15790575.
- Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clément K, Holvoet P, Tedgui A, Mallat Z. (2007). "Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis". Arterioscler Thromb Vasc Biol. 27 (12): 2691–8. doi:10.1161/ATVBAHA.107.149567. PMID 17690315.
- Zhang W, Telemaque S, Augustyniak R, Anderson P, Thomas G, An J, Wang Z, Newgard C, Victor R. (2010). "Adenovirus-mediated leptin expression normalises hypertension associated with diet-induced obesity". J Neuroendocrinol. 22 (3): 175–80. doi:10.1111/j.1365-2826.2010.01953.x. PMID 20059648.
- Knight W, Seth R, Boron J, Overton J. (2009). "Short-term physiological hyperleptinemia decreases arterial blood pressure". Regul Pept. 154 (1-3): 60–8. doi:10.1016/j.regpep.2009.02.001. PMID 19323984.
- John S. Torday, Virender K. Rehan (2006). "Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network". Pediatr. Res. 60 (4): 382–8. doi:10.1203/01.pdr.0000238326.42590.03. PMID 16940239. — published online before print as DOI 10.1203/01.pdr.0000238326.42590.03
- Anifandis G, Koutselini E, Louridas K, Liakopoulos V, Leivaditis K, Mantzavinos T, Sioutopoulou D, Vamvakopoulos N (April 2005). "Estradiol and leptin as conditional prognostic IVF markers". Reproduction 129 (4): 531–4. doi:10.1530/rep.1.00567. PMID 15798029.
- Zhao J, Townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP (2004). "Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus". Placenta 25 (8-9): 712–22. doi:10.1016/j.placenta.2004.01.017. PMID 15450389.
- Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ (2006). "Inhibitory effect of leptin on human uterine contractility in vitro". Am. J. Obstet. Gynecol. 195 (2): 504–9. doi:10.1016/j.ajog.2006.01.106. PMID 16647683.
- Aka N, Atalay S, Sayharman S, Kiliç D, Köse G, Küçüközkan T (2006). "Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum". The Australian & New Zealand journal of obstetrics & gynaecology 46 (4): 274–7. doi:10.1111/j.1479-828X.2006.00590.x. PMID 16866785.
- Cervero A, Domínguez F, Horcajadas JA, Quiñonero A, Pellicer A, Simón C (2006). "The role of the leptin in reproduction". Curr. Opin. Obstet. Gynecol. 18 (3): 297–303. doi:10.1097/01.gco.0000193004.35287.89. PMID 16735830.
- Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP (2007). "Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice". Peptides 28 (5): 1012. doi:10.1016/j.peptides.2007.02.001. PMID 17346852.
- Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (January 2000). "Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass". Cell 100 (2): 197–207. PMID 10660043.
- Hamrick MW, Ferrari SL (July 2008). "Leptin and the sympathetic connection of fat to bone". Osteoporos Int 19 (7): 905–12. doi:10.1007/s00198-007-0487-9. PMID 17924050.
- Allison SJ, Herzog H (2006). "NPY and bone". EXS (95): 171–82. PMID 16383006.
- Gordeladze JO, Reseland JE (March 2003). "A unified model for the action of leptin on bone turnover". J. Cell. Biochem. 88 (4): 706–12. doi:10.1002/jcb.10385. PMID 12577304.
- Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (November 2002). "Leptin regulates bone formation via the sympathetic nervous system". Cell 111 (3): 305–17. PMID 12419242.