An astonishing 57% of women and 67% of men are either overweight or obese in the UK based on a study done by the lancet medical journey. And since the 1980’s obesity has more than doubled around the world. The sum of the overall health problems linked with being overweight or obese cost the NHS and excess of 5 billion a year.
The problems that arise from being overweight or obese can significantly increase the likelihood of gaining various debilitating diseases such as colon cancer, arthritis, cardiovascular disease, high blood pressure and malignancies like pancreatic, breast and prostate cancer. A surplus amount of body weight also affects motion, disturbs the ability to sleep, exacerbates digestive disorders and further promotes to an overall lesser quality of life than that liked by lean people. Obesity leads to a shortening of the life span by mean of eight to ten years in comparison to people with a normal weight. For every 2.35 stone gained risk of premature death increases by around thirty percent.
For many older obese people, the struggle to attain a healthy body weight become a unlikely battle against biology to win, due to a several metabolic processes promoting weight gain despite sustained genuine efforts to lower food consumption and higher energy expenditure.
Scientific studies have opened the door on the biology of weight loss in recent times. It shows that that the battle against the bulge is very complex than the assumed overly simplistic ‘to lose weight you have to eat less’ a message generally endorsed by government health agencies.
Regulation of body weight
Our system of energy balance ever since our existence has evolved to make sure that a healthy person kept suitable reserves of body fat to sustain life through multiple times of food scarcity, for example famine. Food energy abundance is a somewhat new phenomenon, pretty much dissimilar to the vast majority of time over the past 100,000 years. In fact, maintenance of body is achieved by the extremely complex and interrelated interaction of hormonal and neurological factors, with the aim of raising appetite and reserving body fat when energy stores are diminishing. Inside the brain, a portion named the hypothalamus observes and integrates neural signals and modulates appetite fittingly. Sensory cells situated inside the stomach walls that perceive stretching of stomach tissue can directly signal satiety to the brain through nerve impulses. Indirectly, blood levels of amino acids, fatty acids and glucose induce the perception of satiety in brain centres and decrease eating behaviour. Furthermore, a number of hormones released at different levels of gastrointestinal tract take on numerous functions in the equilibrium of energy intake and utilisation. Cholecystokinin (CCK) [secreted by the superior part of the small intestine and is vital for initiating the release of bile and digestive enzymes] and insulin [secreted by the pancreas and is critical in the cells uptake of glucose] are also potent satiety signals.
The body’s fat stores are able to transmit the total state of energy storage to the brain through the release of leptin an adipocyte hormone. Adipose [fat] cells release the hormone leptin into the blood in correlation to their levels of stored fats. It moves to the brain and acts upon the hypothalamus, thus stimulating the release of neurotransmitters that signal satiety, and depressing those that signal hunger. So, leptin secreted by adipose tissue offers the brain with data on long-term energy economy, and lets it to adjust food intake correspondingly. Nevertheless, this complex system of appetite regulation can become disturbed in obesity, as surplus amount of fat store contribute to chronically high leptin levels. This result in down regulation of cellular sensitivity to the performance of leptin, a known physiologic state called leptin resistance. Efforts put into weight loss for obese individuals seem to be undermined by the inability of the leptin system to decrease their appetite, leading to disproportionate hunger.
The resting energy expenditure similarly influences weight gain and progression to obesity. The rate at which metabolic activity burns calories during times of rest is called Resting energy expenditure. If an individual has low resting energy expenditure this could contribute to a difficulty in losing weight or weight gain. Studies have proven that resting energy expenditure is directly related to serum adiponectin levels, and that increased leptin levels are linked with lower resting energy expenditure. Aging is also linked with lower Resting energy expenditure. The research in to resting energy expenditure implies that boosting it could be valued approach to mitigate age related weight gain.
Adipose tissue (fat cells)
Adipose tissue is loose connective in which cells called adipocytes are specialised for storage of triglycerides. Adipocytes are derived from fibroblasts. Because the cells fill up with a single, large triglyceride droplet, the cytoplasm and nucleus are pushed to the periphery of the cell. Adipose tissue is found wherever areolar connective tissue is located. Adipose tissue is a good insulator and can therefore reduce heat loss through the skin. It is a major energy reserve and generally supports and protects energy various organs. As a person gains weight, the amount of adipose tissue increases and new blood vessels form. As adipocytes carry on storing lipids, they are able to adapt and change in size several folds; this mechanism of growth is commonly known as hypertrophy. In addition, adipose tissue is able to regenerate fat cells by de novo adipogenesis from adipocyte precursor cells. Adipogenesis is a method in which fibroblast like preadipocytes developed into mature adipocytes. Adipogenesis is a multistep method that needs the successive activation several gene families, including the PPAR-?? peroxisome proliferator activates receptor- ?? and C/EBP (CCAAt/enhancer-binding protein) transcription factors. In order to attain maturity, these ??ells must go through two vital steps: adipocyte determination and adipocyte differentiation. Even though several of the molecular specifics of adipogensis are still relatively too unknown, numerous factors involved in this processes have been recognized. Various stimulators include PPAR-??, IGF-1 (insulin like growth factor 1), MCSF (macrophage colony stimulating factor, glucocorticoids, FA (fatty acids) and prostaglandins. The surplus of intra-abdominal adipose tissue gathering often termed visceral obesity, due to higher energy intake this leads to saturation of expansion capacity of adipose tissue, which increases visceral adiposity. Intra-abdominal adipose tissue is found within the peritoneal cavity compressed in amongst the internal organs and the torso. Adipogenesis is a method during which
Brown adipose tissue (BAT)
BAT is generally used in thermogenic activity; it is distinctively able to produce big quantities of heat by activation of uncoupling proteins. Through maturity it keeps the capability to have an important role in energy balance, and is currently a main target organ in obesity prevention strategies. BAT is then lost or replaced with white adipose tissue (WAT,) due to age but could still possibly contain minor depots of beige adipocytes that have the capabilities to be reactivated. BAT are equipped with copious mitochondria, the so called ‘powerhouses’ of the cell, and distinctively express uncoupling protein-1(UCP). Uncoupling protein -1 dissipates the protein gradient of the inner mitochondrial membrane that is formed as a result of oxidative phosphorylation of nutrients. This produces heat instead of ATP this process is known as thermogenesis.
In healthy men who are not overweight WAT composes as much as twenty percent of the body weight and about twenty five percent of body weight in females. WAT is the chief source of energy reserves and the most common type of adipose tissue in adults. White adipose tissue constitutes the main source of fatty acids (FA) in the body, used as an energy substrate for the creation of ATP via oxidative phosphorylation. White adipose tissue has a few important functions including the maintenance of metabolism via energy homeostasis, insulin sensitivity and adipocyte differentiation. WAT initial function is to store TG (triacylglycerol) in times of energy surplus and to release energy in the form of free FA during energy deprivation.
There is an obese gene in humans known as the OB gene; it was located on chromosome 7. In humans leptin is produce in tiny amounts in other human tissues not just adipose tissue, like mammary epithelium and heart. Leptin acts via the leptin receptor (OBR /LEPR). The leptin receptor is expressed in other tissues like placenta and stomach. In addition leptin has influence on numerous biological systems, including angiogenesis, wound healing and bone formation. Leptin functions as a feedback mechanism that signals to key regulatory centres in the brain to inhibit food intake and to regulate body weight and energy maintenance. This has been demonstrated in rat studies.
Rodent studies have shown that the hypothalamus is the main centre for regulation of body weight and food intake. When leptin is released from the adipose tissue into the blood stream, it passes the blood brain barrier and binds to the hypothalamic leptin receptors, giving data about the status of the body energy supplies. Leptin binding to its receptors affects the activity of numerous anorexigenic and orexigenic neuropeptides. In addition, regulation of the effects of ghrelin on hypothalamic neurones (leptins actions are blocked by ghrelin via the activation of hypothalamic neuropeptide Y(NPY)/ Y1 receptor pathway) has been implies to be the most vital mechanisms by which body weight and food intake is controlled by leptin.
Studies have shown that two children who were severely obese had congenital leptin deficiency, because a homozygous frameshift mutation in the OB gene, was discovered to be linked with normal birthweight, then a quick progression of severe obesity linked with over eating (hyperphagia) and compromised satiety. Individuals examined with a heterozygous for the identical frameshift mutation. Had serum leptin levels lower compared with controls and were associated with an increased prevalence of obesity. Reduced weight loss, a change in metabolism and endocrine function and higher physical activity resulted with leptin treatment. In normal humans who followed a 12 week dietary fat restriction leptin seem to influence the ongoing weight loss after the 12 weeks. But there is also a strong correlation between serum leptin levels and resting metabolic rate. There has been evidence that numerous intestinal peptides induce gastric leptin secretion. Consequently gastric leptin release is induced by the administration of insulin, a hormone released after food intake. Also, mixed meals and high in fat meals decrease twenty four hour circulating leptin levels. It is, still, probable that gastric leptin functions as a local stimulus.
The human prepro-ghrelin is composed of one hundred and seventeen amino acids (AA), while mature ghrelin peptide consists of twenty eight amino acids with a FA chain modification on the 3rd AA. The ghrelin protein has been found in the peripheral tissues, like GIT and pancreas. Ghrelin binds to the GHS-R (growth hormone secretagogue receptor). The nutritional state of the body controls whether or not ghrelin is secreted. There has been a hypothesis that ghrelin release is supressed by leptin’s satiety inducing effect. Undeniably, the results of leptin on energy maintenance are opposite to those of ghrelin; ghrelin acts as an appetite inducing signal while leptin stimulates weight loss by depression of food intake.
The hypothalamus mediates the effects on ghrelin on energy balance. The pathways for appetite-stimulating effects of ghrelin are; after secretion into the bloodstream via the stomach, ghrelin goers through the blood brain barrier and binds to receptors in the hypothalamus. Then ghrelin reaches the brain via vagal nerve and then the nucleus tractus solitaries. Finally ghrelin is generated locally in the hypothalamus, where it can directly affect numerous hypothalamic nuclei.
Ghrelin is shown to control the release of growth hormone by the pituitary gland. Subsequently, ghrelin has effect on the G.I.T, inflammation and immune cell activation. It has been shown that that pre-prandial increase in ghrelin concentrations connects with hunger scores in healthy humans, starting meals on their own accord in the absence of time and food associated cues. In addition infusion of ghrelin stimulates food intake and hunger amongst obese and healthy humans. Overall, this implies that ghrelin seems to acts as a meal initiation indicator in the system for short term control of energy balance.
Administration of ghrelin stimulates adiposity in rats by decreasing fat utilisation, whilst circulating ghrelin levels are negatively linked with body mass index in humans and these concentrations increases when obese people lose weight, and reduce when anorexia nervosa individuals gain weight. This has shown that ghrelin can play a long term role in regulation of energy balance and also implies that ghrelin concentrations deviate in response to dieting to retain body weight.
Types of obesity
Obesity which is a type-1 is not caused by a disease per say, in a lot of circumstances it is caused by unnecessary eating behaviours and absence of exercise
Obesity which is a type-2 accounts for less than one percent of obesity cases, this is generally caused by a disease which causes the individual to gain weight rapidly even when very little is eaten.
Hypothroidsism is a disorder where the thyroid gland, is unable to produce sufficient amount of thyroid hormone (TH). TH is supposed to regulate our metabolism. So small amounts of hormone slows the down our metabolism and often cause again in weight. Blood tests are taken and if a professional suspects that the thyroid disease is the cause of the individual obesity. This could cause weight gain as a result of little calorie consumption. Polycystic ovary syndrome, depression and Cushing syndromes which leads to a surplus amount of steroid hormone named cortisol produced by the adrenal glands found in the kidneys. This results in an accumulation of fat in specific sites such as abdomen, face and upper back. These are handful of internal secretion disease that leads to obesity type 2. Cushing syndrome is distinguished by thinning legs, abdominal obesity and thinning arms, whereby fat accumulates in the body, in some cases, the hypodermis cracks from abrupt change in weight resulting in line marks on the underarm, abdomen, back and groin.
Obesity in child is based on where the numbers of fat cells have proliferated in comparison to adults with obesity they are judged on where only the size of fat cells is greater than before. The after we have been birthed is when the most fat cells proliferate. Individual who have been obese since childhood; have three to four times more adipose tissue than individuals who became obese as adults. With adult type obesity, the number of adipose tissue is close to normal, but the size gets bigger. This occurs mostly around middle age.
Obesity can be separated depending on where the fat is stored on the body, it can be divided into abdominal or limb obesity. Limb obesity generally happens to women, where the fat is stored in the thighs arms and legs. While abdominal obesity the fat is distributed over the abdomen and back.
The importance of where the fat is distributed is substantial because depending on where it’s focused the risk level for adult diseases changes. Abdominal obesity increases the chance of ischemic heart diseases, hyperlipidaemia and diabetes. This is due to low levels of protein steatolytic protein enzymes which break down nutrients into triglycerides and store them in adipose tissue, are extremely active inside the abdominal fat.
Causes of obesity
The gain of weight and the development to obesity tend to be cause by energy imbalances.
The older you get can have an adverse effect on the balance of energy input and expenditure in numerous ways. The normal aging process is linked with changes in hormones, specifically a reduction in TH and sex hormones, this leads to a reduction in energy expenditure and metabolism. Advancing age is linked with a decrease in insulin sensitivity; this could possibly interfere with the control of appetite. With an increase in age there is also reduction in activities which requires physical strength; this in turn results in a decrease in energy expenditure (EE). In England only 19% of adults between the ages of 65 to 74 say they meet the minimum level of physical activeness to produce the benefits. This drop seems to drop over the age of seventy five years old. In the elderly decreased mobility and obesity has a mutual effect on one another; age related increases in weight and decrease in muscle mass results to reduced movement and EE. A study was done on 28 populations this review showed that the older obese individuals, showed major links between reduced mobility and obesity, apart from one.
Sex hormones and TH imbalances
A decrease in age in male and females causes concentration of dehydroepiandrosterone and testosterone (sex hormones) to decline also. Equally, a decreasing TH concentration is linked with declining metabolic rate and thus obesity.
In males, between the ages of forty and eighty there is a sharp decline in the levels of free testosterone. Free testosterone and total testosterone concentrations are both much lower in overweight and obese males compared to males who have a normal weight range across all ages. Males with hypogonadism (low testosterone) develop increased fat mass, and the replacement therapy of testosterone for male with hypogonadism decreased fat mass by six percent in a study.
Decreased testosterone and obesity have a complex relationship; having low levels of testosterone is thought of to be equally a consequence and a cause of obesity. For males an increase in fat mass could possibly increase the conversion of t??stosterone to estrogen by the enzyme aromatase. Even though this conversion is a usual occurrence, aromatisation happens more frequently in adipose tissue, and is increased by stress, insulin and age. Thus, elderly men with surplus amounts of abdominal fat, the ratios of estrogen to testosterone are lesser in younger men. Higher levels of estrogen, similar to low levels of testosterone are linked with increased abdominal fat. If blood vtest are taken and high levels of estradiol are detected, anastrozole (aromatase-inhibiting drug) may be prescribed.
For women, menopause initiates a decrease in estrogen. The use of hormone replacement therapy has shown to decreased waist circumference and increase lean body mass in some, but not all studies of post-menopausal women.
For metabolism the thyroid is the central regulator, it mixes signals from the brain and releases thyroxine or T4 (TH) to affect metabolism in a range of tissues. Dysfunction of the thyroid can affect body composition and weight, EE independent of physical activity and body temperature. Hyperthyroidism (supressed thyroid function) has been linked with reduced thermogenesis (which is the conversion of stored energy in to heat) and gain of weight and metabolic rate.
Clinical studies have revealed that use of thyroxine to treat hypothyroidism may result to loss of weight and population studies imply that high TSH and low T4 levels are both linked to individuals with higher BMI. Supressed activity of the thyroid is more likely to be the norm as people age; in the general population hyperthyroidism accounts for 3.7%, but is five time more likely in persons over the age of eighty or older when compared to twelve and forty nine year olds.
A large number of patients that have morbid obesity often displayed high levels of TSH (thyroid stimulating hormone). A thyroid stimulating hormone generated in the brain by the pituitary gland, then moves to the thyroid and induces the production of TH, Higher blood levels of thyroid stimulating hormones may imply dysfunction of the thyroid and is linked with development of obesity. A study done in Norway showed more than 27,000 individuals older than forty, thyroid stimulating hormone correlated with BMI (body mass index): for each unit that thyroid stimulating hormone increased, BMI increased in men by 0.48 and in women 0.41.
In addition to being a consequence of obesity, high concentrations of the hormone insulin and leptin in obese people may be symptomatic of a r??sistance to their activities. The hormone insulin helps assist cellular up take of glucose, mainly in the adipose tissue and muscles and liver. After insulin resistance develops, the levels of glucose are not proficiently regulated by the action of insulin and blood levels increase, pr??disposing the insulin-resistant individual to numerous long-term diseased linked with aging. Furthermore, while elevated levels of insulin and leptin are generally supressed the desire to eat and induce EE, they’re incapable of performing these duties in resistant people.
Insulin resistance is result of continued hyperinsulinemia (high levels of insulin) and is an aggravated by obesity and chronic inflammation. Strategies aimed to improve insulin sensitivity include use of the drug metformin, which assists in the reduction of body fat.
Leptin resistance is a consequence of sustained times of elevated leptin release linked with high fat store. In obese people the ability for leptin to be moved to the brain may be lost.
Lipids are hydrophobic heterogeneous group pf organic molecules which are nonpolar, with the use of solvents they can be removed from tissue. Due to lipids insolubility in solutions that are aqueous, lipids in the body are usually found compartmentalised. Lipids provide an essential source of energy which is used for the body. Lipids have several roles in the body, for e.g. coenzyme roles, steroid and prostaglandins hormones play a major role in the regulation of homeostats is for the body. Problems in lipid metabolism results in significant problems witnessed by physicians like obesity and atherosclerosis.
Digestion of lipids
Lipids are digested by type stomach first, and then catalysed by lingual lipase (acid stable lipase) that is located in the glands, which is at the back of the tongue. Triacylglycerol molecules (TGA), specifically those which have fatty acids of small to medium chain lengths(less than twelve carbons, like milk fat), are the main target of the lingual lipase enzyme. These same triacylglycerol’s are also degraded by a different gastric lipase, release by the gastric mucos??. Together these enzymes are moderately acid stable, with pH optimums of pH4 to pH6. These ac??d l??pases play a specific major role in lipid digestion in neonates, in which milk fat is a main source of energy. Additionally, they play an important role in for an individual with pancreatic insufficiency acting as digestive enzymes.
Emulsification of lipids
The crucial process off emuls??f??cation of lipids happens in the duodenum. The reason why emuls??f??cation happens is to ??ncrease the surface area of the hydrophobic lipid drop’ets and the surrounding aqueous solution, can perform efficiently. The machine-like mixing because of peristalsis and the detergent like attributes of the bile salts are the two processes that allow emulsification to happen. The liver makes bile salts which are kept in the gall bladder, is a derivative of cholesterol. The emulsifying agents combine with lipid particles and the aqueous duodenal contents, thereby stabilising the particles as they become smaller, and preventing them from coalescing.
Degradation of lipids
The dietary triacylglycerol, phospholipids (PPL) and cholesteryl esters are degraded by enzymes from the pancreas, which is released due to hormonal control. Triacylglycerol molecules are very big so they cannot be taken up effectively by the mucosal cell of the intestinal villi. So that means they have to be dealt with by the enzyme esterase which is a pancreatic lipase, which favours the elimination of FA at carbons one and three. Hydrolysis produces free FA and two-monoacylglycerol which are the main products. The 2nd protein which is colipase, is secreted via the pancreas and binds the lipase at a one to one ratio, this attaches it to the aqueous- lipid interface. If the lipase is inactive, colipase is able to activate it whilst, being surrounded by an inhibitory substance.
The majority of cholesterol is in its free form, while ten to fifteen percent of cholestetol is in its esterified form. The pancreatic cholesteryl ester hydrolase hydrolyses cholesteryl esters, which generates cholesterol and free FA’s. Bile salts help to optimise the activity of cholesteryl ester hydrolyse.
The juice of the pancreas is abundant in the pro-enzyme of PPL-A2 that, similar to procolipase, needs trypsin to activate it, and similarly to cholesteryl ester hydrolase, need to use bile salts for increased activity. PPL-A2 eliminates one FA from carbon two of PPL, leaving a lysophospholipid. The leftover FA at carbon one can be eliminated by lysophospholipid, which means a glycerylphophoryl base is left, this could result in it being released in the feces to be absorbed.
Hydrolytic enzymes that are released via the pancreas degrade lipids in the small intestine which is hormonally controlled. The mucosa cell of the inferior duodenum and jejunum generate tiny peptide hormone, cholecystokinin, in response to be surrounded by lipids and moderately digested proteins which enters these segments of the superior small intestine. Cholecystokinin functions on the gall bladder, and on the exocrine cells of the pancreas. There is also a decline in gastric motility, this leads to a slower secretion of gastric contents into the small intestine. The hormone secretin is produced in other intestinal cell, it is a tiny peptide. When low pH chime enters the intestine the hormone is produce as a response mechanism. The hormone triggers the pancreas and the liver to secrete a solution rich in hydrogen carbonate that aids in the neutralisation of pH intestinal contents, returning them to regular pH levels for digestive activity by pancreatic enzymes.
Absorption of lipids
Free FA, two-monoacylglycerol and free cholesterol are main products of lipid digestion in the jejunum. Additionally, fat soluble vitamins and bile salts; make mixed micelles-disc shaped clusters of amphipathic lipids that coalesce with their hydrophobic and hydrophilic groups. Mixed micelles remain soluble in the aqueous setting of the intestinal lumen. The particles go to the main area of lipid absorption, the brush border membrane of the mucosal cell (enterocyte). The membrane is divided from the fluid contents of the intestinal lumen by unstirred water film that combines weakly with the bulk fluid. The hydrophilic part of the micelle aids the movement of hydrophobic lipids via the unstirred water section to the brush border membrane where they are absorbed in the ileum.
The lipids absorbed by mucosal cells moves to the ER (endoplasmic reticulum) where biosynthesis of complex lipids takes place. Firstly, FA is converted to their activated state by thiokinase. Using the thiokinase derivative, the two-monoacylglycerols absorbed by the mucosal cell are changed to triacylglycerol by the triacylglycerol synthase enzyme. This enzyme manufactures triacylglycerol by consecutive actions of two enzyme activities: mono and dia-glycerol acyltransferase. Whilst, acyl CoA: cholestereol acyltransferase esterifies cholesterol into FA and acyltransferase reacylates the lysophospholipids to make phospholipids.
There is an increase in lipids due to malabsorption in the feces, this can result to problems in absorption of lipids. Such problems can stem from numerous disorders. Like cystic fibrosis.
Mucosal cell lipid secretion
The recently synthesised cholestryl esters and triacylglycerol are extremely hydrophobic and combined together in an aqueous setting. This means that they have to form particles of lipid droplets enclosed by a fine sheet made out of apoliproprotein ??-48 and phospholipids. This thin sheet stabilises the particle and raises its solubility, thus stopping several particles from coalescing. The particles are secreted by exocytosis from mucosal cells into the lacteals. The milky look of the particles is due to it being in the presence of the lymph after a meal rich in lipids. The lymph is named chyle, and the particles are named chylomicrons. Through the lymphatic system and towards the thoracic duct, is where chylomicrons have to travel. Additionally, they travel through the left subclavian vein, ??nto the blood.
Use of lipids
TGA that are in chylomicrons is degraded mainly in the capillaries of fat cell and skeletal muscle, liver and heart. TGA in chylomicrons is broken down by enzyme lipoprotein lipase into glycerol and free FA.
Triacylglycerol is sent to fat cells in the form of chylomicrons and very low-density lipoprotein, the triaglycerol is hydrolysed into free FA and monoacylglycerol and enters adipose tissue. The FA and monoacylglycerol are re-esterified to reform triacylglycerol. The triacylglycerol coalesce into the cytoplasm of adipose cells to create a big globule.
The drugs used for anti-obesity should only be used as an addition to the primary treatment for obesity treatment, which is a change in lifestyle, improved diet and exercise. Recently, there have been no main acting drugs which are on the available for the treatment of overweight and obese individuals in Europe. In the United States of America, the one main CNS drugs that is used to deal with overweight to obese people is sympathomimetic, which is drug that supresses appetite. The drug is not long-term is made to be used for less than twelve weeks. Drugs like didrex, tenuate, adipost and zantryl have been marketed for years. Drugs like dextroamphetamine and N-methylamphetamine were being used fifty years ago and were even prescribed to supress appetite, but due to numerous cases of abuse resulted in them becoming highly regulated drugs. In the nineties, the 5-hydroxytryptamine agents, Ponderax (Fenfluramine) and dexfen- fluramine, were taken away from the market due to their extended use was related to life threatening cardiac valvulopathy.
Synthetic anti-obesity drugs
The CB-1 receptors antagonist:
The CB-1 receptor has been identified as a target for anti-obesity due to its ability to cause an orexigenic effect on the receptor. Rimonbant was able to selectively inhibit the CB-1 receptor in the cannaboids system. A Study which includes six thousand overweight to obese individuals, weighing an average of ninety four to one hundred an eight kilograms. It showed that there was a major decline in weight and waist circumference over a two year period, with the use of rimonabant. It enhanced cardio metabolic risk factors such as, HDL cholesterol levels in diabetic type-2 to non-diabetic obese individuals, blood pressure and resistance to insulin. Unfortunately, it had side effects which included such as anxiety, suicidal thoughts and depression. This caused rimonabant to be withdrawn from the markets in Europe and America.
Is an effective and reversible G.I.T lipase inhibitor stopping lipid absorption by thirty percent stopping gastric and pancreatic lipase and also increasing fat excretion. It was approved in 1998 and is presently the one accessible drug for the long term controlling of obesity.
Orlistat Mechanism of action
Orlistat has a distinctive molecular structure which allows it to form a stable complex by binding to the active site on the pancreatic lipase covalently. The catalytic binding site is showing on the lipase due to there being a conformational change in the enzyme which is initiated by the complex. The lipase is made inactive as an enzyme because of acylation of a -OH group on serine blocking the active site. The hydrolysis of fats into FA is unable to happen because of the inactive lipase, this leads to their passage with faeces.
Insignificant amount of orlistat is able circulates due of a lack of absorption because of its lipophilic nature. One percent of urine and more than ninety six percent recovered from stool culture over a four day of administration, after 360 milligram radioactive orlistat is ingested. It has a fourteen to nineteen hour half-life. It implies that orlistat is significantly excreted unchanged.
M1 and M3 are two metabolites detected to be excreted through the bile. In comparison to the parent compound it was found to have no pharm logical activity. They both have a half-life of two to three hours. The beta-lactone moiety in orlistat is opening leads to M1 while the opening of beta- lactone and N-formyl leucine side chain leads to M2.
It is a SSRI (selective serotonin reuptake inhibitor); it was approved in 1998 by the United States food and drug agency and was widely used. Before it was withdrawn from the market, a study was done it showing that the use of sibutramine had positive effects on inflammation in with obese individuals who were hypertensive diabetic, insulin resistance and body weight. It was shown to reduce weight loss by about 4.5%, especially if used long-term. It was generally well tolerated it didn’t show any glaring signs of any dangerous side effects just constipation and dry mouth. Nevertheless, in 2002 it was reviewed by EMA and concerns over raised blood pressure and heartrate, caused it to be momentarily removed from the European market on the understanding of forty seven adverse reports and two deaths. The CHMP determined that the risks outweighed the benefits and was subsequently removed from all the markets.
Natural obesity agents
The need to find to natural product to help treat and reduce obesity has amazing potential. This could be a brilliant way of creating upcoming successful, non-toxic anti-obesity drugs and a change in approach, compared to past drugs who had dangerous side effects. A number of different natural products, such as isolated uncontaminated natural mixtures and crude extracts to initiate loss of weight and to stop diets that promote obesity.
The use of dietary phytochemicals as preventative obesity measures is because they subdue the proliferation of the fat cells, stop differentiation of preadipocytes and induce the degradation of lipids through hydrolysis activity changing into free FA and triglycerides. Overall they decrease the mass of adipose tissue.
Natural products that inhibit lipase activity such as, flavonoids and caffeine are plant products, they’re also numerous carbohydrates that retain the same effect like chitosan which in inhibit the enzymes of the pancreas. Several M.O (microorganisms) like panclicins from Streptomyces have the same inhibitory effects on enzymes.
The control of bodyweight via appetite mechanisms is based on several different factors stemming from hormonal and neurological interdependence. Sense of fullness is achieved by the appetite supressing qualities of products such as hoodi gordoni thus acting on the control hunger centres in the hypothalamus. It controls hunger and considerably decreases calorie intake and enhance loss of weight.
The triggering of the expression of the uncoupling protein in brown adipose tissue and the liver is triggered by the extract of solanum tuberosum. This causes non shivering thermogenesis through dissipation of surplus energy as warmth. Thus energy expenditure.
Natural products that decrease lipogenesis by acting on polyunsaturated FA which acts as s??gnal transducing molecules in adipocyte differentiation. Therefore, polyunsaturated FA has the ability to prevent lipogenisis and control adipocyte differentiation. Capsaicin and esculetin have these apoptotic effects on developing pre-adipocytes.
The consumption of pineapples on a daily basis can reduce body weight by 7.14 stones on a strict pineapple regimen. Due to the enzyme bromelain it aids in the digestion of both lipids and protein. This can used as a treatment for obesity.
The activity of bulk producing activity can be used in the treatment of obesity, this aids the feeling of being full, thus decreasing hunger. These are found in roughage such as fibres, polysaccharides and synthetic resin policarbophil. Cascara have laxative effects which results in fast excretion of foods and loss of weight.
The use of natural products that contain iodine, helps reduce obesity by inducing the thyroid gland triggering weight loss. In fucus vesiculosus it is the main active component. The plasma and hepatic triglyceride levels and the activities of adipocytic FA creation is drastically decreased by fucoxanthin found in brown seaweed. Futhermore the combination fucoxanthin and fucoxanthinol which is also in brown seaweed stopped both the increasing levels of triglyceride in systemic circulation and triglyceride absorption in the lymph, possible due to G.I.T lumen lipase activity inhibited.
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