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How growth hormone(GH) relates to feeding and fasting
When the nutrient flow from intestine diminishes (fasting), GH can enhance the oxidation of fatty acids relative to glucose or amino acids by increasing adipose tissue lipolysis and/or reducing triglyceride storage so that adipose tissue can be redistributed from intra-abdominal to peripheral depots and decrease body fat mass. Besides, GH can enhance endogenous glucose production eg. Hepatic output of glucose and inhibit cellular glucose uptake to increase plasma glucose concentrations and prevent hypoglycemia. However, prolonged excess GH can lead to pancreatic-cell failure such that insulin secretion cannot overcome the insulin resistance, resulting in hyperglycemia and eventually diabetes.
The graph1 on the right shows the role of GH on the metabolic alterations in fasting and feeding states. Fasting for about 2 days was associated with a significant increase in GH secretion.
serum GH levels in the fed state (A) and during the last 24 h of a 2-d fast (B) . Only the mean data are shown, and the SE bars are omitted for clarity.
As seen from the graph1 on the left, although selective GH blockade did not significantly influence lipolysis, proteolysis and hepatic glucose ouput after a physiological overnight fast, fasting-associated increase in the lipolytic rate is greatly reduced after 2 days. These results indicate that endogenous GH does not play an important role in the regulation of metabolic processes after a very short-term fast (i.e.; overnight fast) but assumes a major role as a stimulator of the lipolytic rate during prolonged fasting.
Food and dieting control of body weight with knowledge of growth hormone
Fasting increases growth hormone production which can induce weight loss with lipolytic properties. Hence, decreasing frequency of feeding eg. plan 3 well balanced meals a day and allow at least 5 to 6 hours in between, avoid snacks etc may help control body weight. Growth hormone can also be experimental administered in visceral obesity subjects with low growth hormone concentrations. Its lipolytic effects may induce weight loss, and it may also protect against the negative nitrogen balance in hypocaloric diets because of its protein anabolic effects. Besides, growth hormone can redistribute fat, this may reduce visceral fat and improve metabolic health
Ghrelin is produced mainly by cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger.
Action of gherlin
promoting intestinal cell proliferation and inhibiting its apoptosis during inflammatory states and oxidative stress
inhibiting the pro-inflammatory mechanisms and stimulating anti-inflammatory mechanisms
stimulating growth hormone secretion from the anterior pituitary gland
enhancing the motility of gastrointestinal tract
promoting growth in fetuses
defending against symptoms of stress-induced depression and anxiety
contributing to the short sleep duration and obesity
altering nerve-cell connections by entering the hippocampus from bloodstream to enhance learning and memory. It may be best to learn when ghrelin levels are high during the day and when the stomach is empty
How ghrelin relates to feeding and fasting
Ghrelin is the first identified circulating hunger hormone. It is secreted primarily by the stomach and duodenum and is responsible for both meal-time hunger and the long-term regulation of body weight. In humans, plasma ghrelin levels rise shortly before (fasting) and fall shortly after every meal (feeding), with a role in urging eating. Increase level of ghrelin increases hunger feeling, slows metabolism, increases production of growth hormone and decreases breakdown of fat. As a result, it increases food intake and fat mass. It has a role in both mealtime hunger and the long-term regulation of body weight. According to research findings2, the levels of circulating ghrelin over a 24-hour period increased after diet-induced weight loss, suggesting that increased levels of circulating ghrelin may be an adaptive response to weight loss. Several observations from studies in rodents support that 1. continuous administration of ghrelin durably increases body weight 2. decreases the metabolic rate and the catabolism of fat and increase body weight 3. blockade of ghrelin in the brain leads to a reduction in food intake, implying endogenous ghrelin signaling is necessary for maintaining normal appetite.
Ghrelin exerts action at hypothalamus. Orexigenic neuropeptide Y (NPY) neurons that are also leptin- and insulin-sensitive in arcuate nucleus are activated.
Ghrelin is thought to be a counterpart of leptin that induces satiation when it is at higher levels. In some bariatric procedures, the drug for treatment of obesity is used, the ghrelin level reduced in patients and they have satiation earlier than normal condition. It is also suggested that ghrelin has a peripheral appetite modulatory effect on satiety by decreasing the mechanosensitivity of gastric vagal afferents to distension and this leads to over eating.
Those suffering from the anorexia nervosa have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls. This suggests that ghrelin is inversely related to calorie intake.
Leptin is a hormone that is produced by fat cells and secreted into the blood stream.
Action of leptin
acting on receptors in the hypothalamus and inhibiting appetite by counteracting the effects of neuropeptide Y(a potent feeding stimulant secreted by cells in the gut and hypothalamus) and anandamide(a potent feeding stimulant)
promoting the synthesis of Î±-MSH, an appetite suppressant. The inhibition is long-term, different to cholecystokinin (CCK) that inhibits eating rapidly and PYY3-36 that slowly suppress hunger between meals. The absence of a leptin (or its receptor) leads to uncontrolled food intake and leads to obesity
modulating T cell activity in immune system experimentation with mice. It modulates the immune response to atherosclerosis, a predisposing factor in patients with obesity
promoting angiogenesis by increasing vascular endothelial growth factor (VEGF) levels.
How leptin relates to feeding and fasting
According to the graph3 on the right, leptin levels decrease after fasting or a very-low-calorie diet (VLCD) and increase after refeeding. 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. Leptin can respond to an acute change in energy balance and it's related to appetite and eventually to food intake. Leptin signals to the brain satiety by inhibiting the activity of neurons that contain neuropeptide Y (NPY)(NPY stimulates feeding) in the arcuate nucleus and agouti-related peptide (AgRP), and by increasing the activity of neurons expressing Î±-melanocyte-stimulating hormone (Î±-MSH) that suppress appetite. Serum leptin concentrations are positively correlated with the amount of fat mass in the body. However, during short-term severe energy restriction(fasting), serum leptin concentrations rapidly fall. Hence, it's thought that leptin can restore negative energy balances.
Leptin may regulate energy balance by affecting energy intake ie. appetite and food intake. It is found that after exogenous leptin has been administered, there is a decrease in appetite ratings during energy restriction. There is also a strong inverse relationship between leptin concentrations and appetite ratings during energy restriction (fasting). Stronger inverse association between proportional fasting leptin concentrations and appetite response is found when fasting period increases. This suggest that leptin play a role in restoring energy balance through controlling the expression of appetite4.
Food and dieting control of body weight with knowledge of gherlin and leptin
There is a complex interaction between insulin, leptin, and ghrelin; leptin regulates ghrelin levels as they counterpart with each other. Leptin also affects changes in body weight, while insulin and ghrelin are involved in the physiological response to food intake and are reciprocally regulated.
From animal studies it is known that leptin has an inhibiting effect on food intake. Transgenic mice that lack the gene to produce leptin, are leptin deficient and extremely obese. Also some obese humans are leptin deficiency due to rare mutations in the leptin gene. Injecting these humans or ob/ob mice with leptin reduces their food intake and brings them back to lower body weight.
Appetite hormones leptin and ghrelin become resistant to the effects of excess food because of years of dietary abuse and poor lifestyle, and this affects proper signal transmission to the brain. Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin. They are resistant to the effects of leptin, the high sustained concentrations of leptin from the enlarged adipose stores result in leptin desensitization. Their bodies do not adequately receive the satiety feeling subsequent to eating. It is known that supplementing in pill form has no effect on weight loss or blood levels of the hormones.
In order to maintain healthy body weight, one should control leptin and ghrelin with healthy natural diet and lifestyle:
Decrease sugar and processed carbohydrates content in meals
Refined carbohydrates and sugar can lead to metabolic dysfunction. Eventually this also disrupts the normal function of leptin and ghrelin as the hormones become less responsive to food intake and results in fat storage and obesity. A study published recently suggests that the consumption of high amounts of fructose causes leptin resistance in rats. The high-fructose diet rats subsequently ate more and gained more weight than controls when fed a high fat, high calorie diet.
Calories restriction at different meals
Plan nutritionally balanced meals of 400 to 500 calories each, depending on individual's activity level. One should not digest large amounts of food at one time as this leads to malfunction of leptin and ghrelin signaling mechanism. One should eat slowly and chew each bite for 30 seconds so that leptin can send the satiety signal to your brain and not over consume food.
Eat 3 Properly Spaced Meals Each Day
Plan 3 well balanced meals a day and allow at least 5 to 6 hours in between. Enough timing between meals allows digestion to complete and blood sugar and lipid levels to return to normal. Avoid snacks as this inhibits the release of stored fat, causes leptin to malfunction and encourages weight gain. It is important to create times during the day when triglycerides, are cleared from your blood. If triglycerides build up during the day they physically clog leptin entry into your brain, causing leptin resistance and results in you eating much more than you really need. When you clear your circulatory highways of extra fat during the day then leptin works better.
Stop Eating 3 Hours before Bed
Allow 11-12 hours between dinner and breakfast. Never go to bed on a full stomach. Finish eating dinner at least three hours before bed. One of leptin's main rhythms follows a 24-hour pattern. Leptin levels are highest in the evening hours. This is because leptin sets the timing for nighttime repair. It coordinates the timing and release of melatonin, thyroid hormone, growth hormone, sex hormones, and immune system function to carry out rejuvenating sleep. It does this while burning fat at the maximum rate compared to any other time of the day. And it does this only if you will allow it, by not eating after dinner.
Melatonin is a naturally occurring compound found in animals, plants, and microbes. There are variations of circulating levels of melatonin in animals in a daily cycle. In this essay, biological functions of melatonin, contribution of melatonin to cancer prevention and methodologies of studying melatonin functions are discussed.
Biological Functions of Melatonin
synchronizing the body's hormone secretions, setting the brain's internal clock and generating circadian rhythms (daily biorhythms)
regulating sleep-wake or circadian rhythms. Production of melatonin by the pineal gland is stimulated by darkness and inhibited by light.
Suppressing libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland.
melatonin pulse regulates many neuroendocrine functions. When the timing or intensity of the melatonin peak is disrupted (as in aging, stress, jet-lag, or artificial jet-lag syndromes), many physiological and mental functions are adversely affected. The ability to think clearly, remember key facts, and make sound decisions can be profoundly hampered by these upsets in the biological clock.
controlling the timing and release of female reproductive hormones and determining when menstruation begins, the frequency and duration of menstrual cycles, and when menopause.
Its antioxidant properties suggests that it may help strengthen the immune system, hunting down and eliminating cell-damaging free radicals, possibly helping to prevent or delay the development of heart disease, cancer and other conditions.
When combined with certain cancer drugs, melatonin may destroy malignant cells. It is twice as effective at protecting cell membranes from lipid peroxidation as vitamin E and five times more effective than glutathione for neutralizing hydroxyl radicals.
neutralizing superoxide, singlet oxygen, hydrogen peroxide and hypochlorous acid
inhibiting peroxynitrite formation by inhibition of the enzyme nitric oxide synthetase in some brain tissues
increasing gene expression and activity of the anti-oxidant enzymes glutathione peroxidase, superoxide dismutase and catalase.
Inhibiting aging and prolong survival in rodents
Comment on "Melatonin is a safe natural hormone from our body for cancer prevention"
Melatonin is a natural hormone mostly produced by pineal gland and intestines. Its levels increase during sleep but the increase is lessened by presence of light.
It is believed that the anti-cancer actions of melatonin are mediated through immuno-stimulatory, free radical scavenger and direct anti-proliferative effects of the hormone5. Direct anti-proliferative action
of melatonin has been tested and confirmed in a diverse range of human cancer cell lines derived
The lowest effective concentration of melatonin which caused significant inhibition of JEG-3 cell proliferation was 5.3X 10-10 M and the EC50 for the anti-proliferative action of melatonin was 5.5X10-8 M.from different malignant tissues such as breast cancer, ovarian cancer, melanoma, sarcoma, choriocarcinoma and prostate cancer. The direct anti-proliferative action of melatonin, has been demonstrated in vitro and also in vivo for many of these tumors. Using a human choriocarcinoma cell line JEG-3 as an example5 (shown in following graphs), concentration-dependent inhibition of the proliferation JEG-3 at both physiological and pharmacological concentrations of melatonin was demonstrated.
Volume changes of JEG-3 tumors in nude mice given daily melatonin or saline injection initiated 10 days
before (A) or after (B) inoculation of tumor cells.
At and beyond 20 days post-inoculation of JEG-3 cells, there is significant decreases in tumor volume
in melatonin-treated animals versus saline-treated animals, no matter whether
melatonin was given before or after tumor cell transplantation.
Whether melatonin is safe or not is still a controversial issue. There may be no harm when one try to increase melatonin levels by sleeping in a completely dark room or using a sleep mask. However, it's uncertain when melatonin level increases exogenously. According to an article6, the range of melatonin dosage involved in the adverse reactions is between 1 and 36 mg. The adverse reactions were not necessarily related to melatonin usage and were relatively rare. Cases of autoimmune hepatitis, confusion caused by melatonin overdose, optic neuropathy, fragmented sleep, psychotic episode, nystagmus, seizures, headache and skin eruptions were found. There is no long-term data on the safety of high levels of melatonin intake and some adverse effects may not be realized in the short term. In addition, melatonin has antigonadotropin effects. Hypothalamic hypogonadism have high plasma levels of melatonin. Parenchymal pinealomas with enlarged pinealocytes can cause delayed puberty. Hence, high dose of melatonin can be dangerous. It shouldn't be taken without medical supervision. Doctors also warn that people with kidney or liver disease shouldn't take melatonin, neither should those with a history of stroke, depression or a neurological disorder. Women who wish to become pregnant should also avoid the use of melatonin.
Methodologies of studying melatonin functions
In general, melatonin functions can be studied by:
Surgical methods: melatonin is mainly produced by pineal gland, removal of pineal gland leads to atrophy of melatonin, this result in physiological effects in the animal and its functions can be predicted.
hormone replacement therapy: melatonin replacement/related analog to animals surgically removed pineal gland to confirm biological roles of melatonin. Studies on other species of animals may also suggest additional or alternate roles of melatonin.
immunological (antibody) neutralization of activity of melatonin or adding antagonist of melatonin and observe if there is any physiological effects resulted
After exogenous administration of melatonin, in vivo and in vitro cellular changes in biochemical processes and products can be measured to indicate second messengers involved in hormone action
Compare the structure of melatonin with other molecules with similar structure and known biological functions, that may give us hints about melatonin functions
Some examples of studying specific function of melatonin are shown as follows:
Study the role of melatonin in release of LH and follicle stimulating hormone (FSH) from fetal pituitary cells7
Rats on day 14 of pregnancy are obtained from a commercial source and maintained on a 14-h light, 10-h dark schedule of illumination for 6 days. animals have free access to food and water. After decapitation of the mothers between 1000--1100 h, fetuses are removed immediately and decapitated and the entire pituitary gland is removed. The gland (from 52 or 53 fetuses) is minced and dissociated with 0.1% collagenase for 40 min at 37°C with gentle shaking and then dispersed by gentle pipetting. The cells are used at concentrations of 1.5 x 105 cells/well and cultured with 10% fetal bovine serum for 2 days at 37°C in an atmosphere of 95% air/5% CO2 before being used for experiments. Incubations are started by the addition of melatonin in the absence or presence of [D-Ala 6, des-Gly10] -LHRH ethylamide. After incubation for 2 hours, media are collected and stored as frozen stock at -70°C until assayed. Pituitary cells are removed from the wells and stored in phosphate-buffered saline (10 mM, pH 7.5) containing 1% bovine serum albumin at -70°C until extraction. The cells are sonicated for 30 s, and the supernatant assayed for LH and FSH. The LH and FSH concentrations in the media and cells are determined by radioimmunoassay.
Study the effect of melatonin on inhibition of malignant trophoblastic cell profiferation5
Cell proliferation assay
Malignant trophoblastic cells in exponential growth phase are seeded into culture plates and incubated in growth medium at 37°C. Cells are treated with vehicle control or melatonin with different concentrations in different wells of plates. After 40-hour incubation, radioactive [3H] thymidine is added. Incorporation of [3H] thymidine is quantified 8 hours later. The medium is aspirated and 10% trichloroacetic acid (TCA) is added to precipitate cellular DNA. After ~30 minutes, TCA is removed and the precipipate is dissolved in NaOH for 1 hour. Lysates are assayed for protein content by Lowry's method. Glancial acetic acid is added to neutralize alkalinity and radioactivity of content in each well added with scintillation cocktail is measured by scintillation counter. All measurements were triplicated and incorporation of [3H] thymidine is normalized for total protein per culture well. Cell viability can also be determined by trypan blue assay/lactate dehydrogenase leakage assay/MTT assay or neutral red assay before and after treatment with vehicle control and melatonin of different concentrations.
If the radioactivity decreases after treatment of melatonin compared with vehicle control, it implies melatonin inhibit malignant trophoblastic cell proliferation.
Measuring effects of melatonin on tumor growth in tumor-bearing nude mice
Nude mice are inoculated subcutaneously with carcinoma cells. Nude mice are injected with saline (control) or melatonin 10 days before inoculation. Daily treatment of saline or melatonin is continued after tumor cell inoculation. Volume of tumor is measured with calipers at 5-day intervals after tumor cell inoculation. The total tumor volume is calculated by a formula V= ½(4Ï€/3)(l/2)(w/2)(h)=0.5236lwh.8.
If the volume change of tumor after treatment of melatonin is less than control, it implies melatonin can slow down tumor growth.
Study the antioxidant protection exerted by melatonin9
Quinolinic acid (QUIN) is a metabolite of the tryptophan-kynurenine pathway present in the human and rat brain. It produces oxidative damage in neurons and glutamate-type excitotoxicity. Exposure to QUIN results in the generation of free radicals, which can ultimately cause neuronal degeneration and death.
In the experiment, thirty adult male rats are used. They are harvested under temperature controlled condition, with food and water ad libitum. They are killed by decapitation before experiment. After decapitation, their brains are removed and cut into explants, which are then immersed in the culture medium and incubated at.
5% CO2 at 37°C for 24 hours. Then the tissue is cultured with (1) control (CON), (2)melatonin, (3) quinolinic acid (QUIN) and (4) melatonin in combination with quinolinic acid (melatonin + QUIN). The samples are obtained at different time intervals and immediately frozen in liquid nitrogen, and stored at -20°C. After thawing, tissue is homogenized in 50 mm phosphate buffer, pH 7.5 with homogenizer.
Measure extent of lipid peroxidation by QUIN in treatment with or without melatonin
A lipid peroxidation kit can be used to measure oxidative destruction of lipids. Whether melatonin can protect lipid from oxidation by QUIN can be determined by comparing results with or without melatonin.
Measure extent of protein oxidative damage by QUIN in treatment with or without melatonin
Protein carbonyl, as an expression of oxidatively damaged protein, can be assayed by Protein carbonyl kit. Data are presented as nmol protein carbonyl/mg protein. Protein concentrations are determined by the method of Bradford using bovine albumin as standard. Whether melatonin can protect protein from oxidation by QUIN can be determined by comparing results with or without melatonin.
Measure the activity of antioxidant enzymes
After centrifugation for 6 min at 3000 g, supernatants were used for assaying catalase, superoxide dismutase, and glutathione reductase. Data are presented as lmol H2O2/mg protein min for CAT, units SOD/mg protein for SOD, and nmol NADPH/mg protein min for glutathione reducatase. Increase activity of antioxidant enzyme after treatment with melatonin indicates that melatonin may exert indirect antioxidant action by increasing activity of antioxidant enzyme.
Study the effect of exogenous melatonin on neuroendocrine-reproductive function of middle-aged female rats10
A total of 30 control female rats are used. Animals are housed under a 12- hour light and12- hour dark photoperiod at about 23°C. Food and water are available. Vaginal smears are taken from animals for 15 days to select rats showing irregular duration of the oestrous cycle. Blood samples at different stages of the oestrous cycle are randomly obtained from all female rats by jugular venepuncture under ether anaesthesia. At this stage, the rats are considered as the control group. Blood samples are then collected for different stages of oestrous cycle. Then, the animals are treated with melatonin and become the experimental group. Melatonin are dissolved in a small volume of absolute ethanol and diluted in 0.9% (w/v) NaCl. A dose of 150 pg melatonin per 100 g body weight is administered once a day at the end of the light phase for 2 months to 1-months-old female rats which show irregular duration of the oestrous cycle. After the melatonin treatment, blood samples are obtained at different stages of the oestrous cycle. Melatonin treatment is continued until completion of blood sample collections. Blood sampling is carried out. The blood samples are centrifuged to obtain plasma. Plasma LH, FSH and prolactin concentrations are then measured by specific radio immunoassays. All samples should be run in the same assay for each hormone to avoid interassay variations.
Plasma oestradiol can be measured using an 125I-labelled radioimmunoassay kit
Data from each age group should be adjusted to a normal distribution test before they are used in the statistical analysis. A 99% accuracy to normal distribution is required. The level of significance accepted is
P < 0.05.
In conclusion, there are many biological functions of melatonin and some evidences show that melatonin play roles in preventing cancer. Different methods are developed to study different melatonin functions.