1) INTRODUCTION:
Obesity is the most common metabolic disease in developed nations. Despite public health education and initiatives, its prevalence continues to increase, with >30% of adults in the United States being obese and >60% of adults being overweight or obese1. The World Health Organization has estimated that worldwide, over one billion adults are overweight, with at least 300 million of them being obese. The increasing prevalence of obesity among children and adolescents is also of great concern2 and suggests a likelihood of worsening obesity trends in future adults. Obesity leads to, or significantly increases the risk of, comorbidities involving various body systems including 1) cardiovascular [hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease (CHD)1], 2) neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica), 3) respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma), 4) musculoskeletal (immobility, degenerative osteoarthritis, low back pain),
5) skin (striae distensae or “stretch marks,” venous stasis of the lower extremities, lymphedema, cellulitis, intertrigo, carbuncles, acanthosis nigricans, skin tags), 6) gastrointestinal (GI; gastro-esophageal reflux disorder, nonalcoholic fatty liver/steatohepatitis, cholelithiasis, hernias, colon cancer), 7) genitourinary (stress incontinence, obesity-related glomerulopathy, breast and uterine cancer), 8) psychological (depression and low self-esteem, impaired quality of life), and 9) endocrine (metabolic syndrome, type 2 diabetes, dyslipidemia, hyperandrogenemia in women, polycystic ovarian syndrome, dysmenorrhea, infertility, pregnancy complications, male hypogonadism)3.Therefore, it has been a therapeutic and research goal to develop strategies to reduce the worldwide obesity epidemic4 and a research goal to develop safe and effective antiobesity drugs, analogous to what has occurred with hypertension, dyslipidemia, and diabetes5 .
2) HISTORY:
n Hippocrates stated in his writings “sudden deaths being more common among obese men than lean ones”
n In 1900’s obesity was tagged as “unfashionable" by Paul Poiret.
n In 1950’s drugs acting on biogenic amines were discovered to curb obesity
n In 1953, Kennedy proposed that there exist some homeostatic mechanism involving a hormone from the adipose tissue acting on the hypothalamus.
n In 1994, Friedman and his colleagues cloned the ob gene and identified its protein product-leptin
n Super Size Me” – a film by Martin Spurlock was released in 2004 in an exploration of the prevalence of obesity in the USA.
n Led to a few changes in the McDonald’s menu.
DEFINITION:
Obesity is a multifactorial disorder of energy balance in which calorie intake over the long term has been greater than energy output, resulting in an excessively large BMI.
Body mass (kg)
BMI (body mass index)=
square of the height (m)
n BMI of
20-25 = healthy
25-30= overweight
>30 = obese
>40 = morbidly obese
BMI is highly correlated with body fat
3) TYPES OF OBESITY:
The concept of fat distribution (android and gynoid) was first introduced in obese subjects with diabetes mellitus or cardiovascular disease by Vague6. Later, Kiessebah et al., proposed a classification of obesity - upper body segment and lower body segment using waist-to-hip circumference ratio7. There are two types of obesity- the central adiposity (upper body segment, android obesity), and the peripheral adiposity (lower body segment, gynoid obesity).
Central adiposity:
“Apple-shaped” people have excess fat in subcutaneous abdominal and visceral depots. This condition is associated with an increased morbidity and risk of a number of metabolic complications such as coronary heart disease, NIDDM, hormone-related cancers and several abnormalities in endocrine secretions including increased activity of CRF-ACTHadrenal axis, an elevated cortisol secretion as well as hyperandrogenicity in women, and a relative hypogonadism in men. There is also pronounced insulin resistance. Upper body obesity resembles Cushing’s disease in fat distribution. Such individuals have increased cortisol production and also increased expression of glucocorticoid receptors and PPAR-gene in the visceral region.
Peripheral adiposity:
“Pear shaped” people with peripheral adiposity have excessive fat distributed subcutaneously around the gluteofemoral region and in the lower abdomen (on the hips and thighs). They are less prone to metabolic disorders but more prone to mechanical disorders such as varicose veins and disorders of joints. With the availability of computer assisted tomography (CAT) accurate analysis (surface area and volume) of subcutaneous fat and intra-abdominal visceral fat could be done and a novel classification of obesity was proposed - visceral fat obesity (VFO) and subcutaneous fat obesity (SFO) based on the ratio of visceral fat area and subcutaneous fat area (V/S ratio) at the level of umbilicus. Significant positive correlations were demonstrated between V/S ratio and plasma glucose area, serum TG level, and total cholesterol level as well as systolic and diastolic blood pressure8. A new clinical entity called visceral fat syndrome has been reported as a multiple risk factor syndrome in which visceral fat accumulation, glucose intolerance, hyperlipidemia and hypertension cluster to induce the occurrence of atherosclerosis. This syndrome resembles syndrome X or the deadly quartet9.
4) PATHOPHYSIOLOGICAL FACTORS UNDERLYING
OBESITY
In order to develop new treatments for obesity, it is very important to understand the physiological pathways that regulate the energy balance (both intake and expenditure) and to identify factors causing obesity.
ENERGY BALANCE EQUATION
ENERGY INTAKE = ENERGY EXPENDITURE+ ENERGY STORAGE
ADIPOSE TISSUE (TRIACYLGLYCEROL)
As illustrated above energy intake and energy expenditure play a pivotal role in controlling body fat stores10. The energy intake depends on appetite which is mainly controlled by glucostatic and lipostatic feedback systems. The energy expenditure depends mon heat production (diet induced thermogenesis, DIT, 10 - 12%), metabolism (basal metabolic rate, BMR 65%) and physical exercise (variable). Any imbalance between these two is translated into a change in fat stores and obesity. This balancing act also involves various neural and endocrine signals acting peripherally as well as centrally which cause disturbance and derangement of various other physiological functions as well.
Energy intake regulation in obesity:
The nerve centre for the regulation of energy balance is the hypothalamus, which integrates neural, hormonal, nutrient messages from elsewhere in the body and sends signals to the higher centers leading to feeling of hunger or satiety. The hypothalamus also controls energy expenditure via the autonomic nervous system and pituitary hormones. The neuroendocrine axis involved in energy balance regulation may be the hypothalamic links with the adrenals, gonads and the sympathetic nervous system. The hypothalamic arousal by physical and mental stressors result in fight or flight (defeat) reaction which leads to changes in these links11. The fight reaction occurs via the sympathetic pathways to help gain control by increasing the readiness of circulatory factors and to mobilize substrates needed to meet the challenges. When the individual loses control and ends up in a defeated, submissive, helpless situation, there is hyperactivity of CRF-ACTH-cortisol axis, hypercortisolism, and decreased secretion of sex-hormones. This type of reaction has been shown to be followed by abdominal fat accumulation and metabolic aberrations, including signs of insulin resistance. The reaction patterns may also shift from one type to another due to perceived stimulus, varying between and among individuals. It has been shown that long-term stress, in addition to being responsible for over-eating through neural mechanisms, results in elevated plasma levels of glucocorticoids. Glucocorticoid excess results in increased hepatic gluconeogenesis and diminished arteial glucose transport and utilization10. A large number of hypothalamic neurotransmitters have also been implicated in the control of energy balance. Those that increase food intake generally suppress sympathetic nervous system activity and thus thermogenesis, whereas the reverse is true for neurotransmitters that decrease the appetite12.
β 3 Adrenoceptors (β 3 AR):
β 3 - adrenergic receptor (formerly known as an ‘atypical adrenoceptor’) is mainly expressed in adipocytes. It is the principal mediator of catecholamine–mediated thermogenesis and fatty acid β -oxidation in BAT and an important stimulator of lipolysis in WAT. In contrast to other adrenoceptors, it is activated by high concentrations of catecholamines found in noradrenergic synapses (e.g., after a meal or during cold exposure) but not by lower levels present in the blood stream. Also, the β 3 adrenoceptors (β 3 AR) subtype is refractory to desensitisation by exposure to its ligands41. Considerable evidence is available for their physiological role. A study on rodents has established that β 3 AR is the predominant receptor type expressed in BAT and WAT and that β 3 agonists considerably reduce diet-induced obesity13. There is modest increase of body fat in the β 3 AR - deficient mice and reduction of β 3 AR mRNA levels in genetically obese ob/ ob mice57 and fa/fa Zucker rats14. Treatment of dogs for two months with ICID7114 (β 3 agonist) reduced weight and induced the reappearance of BAT, which is the tissue most responsible for thermogenesis and is undetectable in adult mammals (except rodents). In humans, functional expression of the β 3 AR has now been well documented in isolated mammary white and immortalised differentiated brown adipocytes where it regulates lipolysis15. Some studies have reported a polymorphism in the β 3 AR gene to be associated with increased prevalence of obesity. Over 50% of Pima Indians from Arizona who display hereditary obesity express mutation in α 3 AR gene in which tryptophan at position 64 is replaced by arginine. This mutation is also found in 25% of African-Americans and in 8-10 % of the general population of the U.S. and Europe16.The development of various selective α3 agonists like BRL-37344, CL-316243, CGP-12177A, LY-10419, SB-200464, bucindolol, carazolol, oxprenolol, pindolol, cyano-pindolol, alprenolol, nadolol have opened new doors for the treatment of obesity17.The selective β 3 agonist with mild β 1 or β 2 antagonistic activity will be especially beneficial in obese patients with stressed cardiovascular system. Many of these compounds are excellent lipolytic agents in rodents but perform poorly in humans which may be due to 1) differences in rodents and human β 3- adrenoceptors, 2) differences in metabolism and pharmacokinetics in the rodent and humans, 3) because the human has fewer β 3-adrenoceptors, or 4) because these receptors are less well coupled to thermogenesis18
Melanin concentrating hormone (MCH):19,20
MCH is a cyclic 19 amino-acid neuropeptide identified initially in the intermediate lobe of the teleost fish pituitary from which it is released into circulation and causes aggregation of melanophores. MCH receptors are found exclusively in the zona incerta and the lateral hypothalamus. It is reported to stimulate food intake after central administration and expression of gene encoding MCH is upregulated in ob/ob mice and through fasting in wild type of mice. Leptin decreases expression of this gene in the hypothalamus via co-existing leptin receptors. The exact mechanism of action of MCH in the hypothalamus is not known. MCH has been reported to both mimic and antagonise the actions of α-MSH.
Cholecystokinin (CCK):21
Cholecystokinin is released from the gut after ingestion of lipids and other nutrients and may be one of many peripheral satiety signals. Interestingly, it also acts as a central inhibitor of appetite and its peripheral release may mediate its release in the CNS. CCK levels are normal in obese persons but infusion of CCK-8 peptide has been shown to decrease the meal size in humans. Two pathways have been suggested for inhibitory effect of CCK on food intake: the action of CCK at peripheral sites, mediated by CCKA-type receptors, and the action at central sites mediated by CCKB-type receptors. The pretreatment of rats or pigs with selective CCKA antagonists - devazepide, lorglumide prior to administration of fats decreases the satiating potency of specific fats. But pretreatment with CCKB antagonists did not alter fat-induced satiety in the rat. Thus, CCKA agonists could be useful in the treatment of obesity. But no CCKA agonist with acceptable bioavailability is available and therefore, compound which prevented the breakdown of CCK- 8 could prove useful. Butabindide is a new drug in the pipeline that acts by inhibiting the action of CCK- 8 inactivating peptidase. The studies have shown butabindide to potentiate the delay of gastric emptying by CCK-8 at a dose of 10mg/kg and reduce food intake.
Neuropeptide Y (NPY):22
Of the few neurotransmitters that stimulate feeding, neuropeptide Y has attracted the most interest. It is a linear 36 amino acid peptide which was first isolated from the porcine brain. It is a member of the pancreatic polypeptide (PP) family of regulatory peptides that includes the endocrine peptides, peptide YY (PYY) and PP. It has been shown to have powerful and complex effects on feeding, anxiety, circadian rhythms, reproduction, pituitary-adrenocortical axis function, memory retention, seizures, thermoregulation, and cardiovascular and gastro-intestinal functions. One of the most striking actions of NPY is the induction of feeding. Further, NPY activates a heterogenous population of at least six receptor subtypes, Y1-Y6, of which Y1 and Y5 receptors are required for appetite regulation by NPY. It is the most abundant neuropeptide in the central and peripheral nervous systems especially in the hypothalamus of rodents and humans. Its cell bodies are cited in the arcuate nucleus (ARC) and project to the paraventricular nucleus (PVN) and dorsomedial nucleus (DMN) and there are binding sites (probably the Y5 receptors) in the lateral hypothalamus. By acting on Y5-receptors, it increases the food intake, reduces thermogenesis in brown fat, increases insulin levels (by stimulating vagal outflow to the pancreas) and reduces muscle sensitivity to insulin. Neuropeptide Y is the most powerful appetite stimulant known in the rodents. It has been reported to increase the triglyceride content in white fat and after 5 days of intracerebral administration it doubled the fat stores in both lean and ob/ob mice. Its expression is also reported to be increased in ARC, PVN and DMN in the ob/ob mouse and Zucker rat. But the genetic studies have not shown any association with the genes for neuropeptide Y1 or Y5 receptors in human obesity. The NPY neurons in the ARN possess glucocorticoid, insulin and leptin receptors and leptin has an inhibitory effect on the NPY neurons via the Rb receptors and reduces NPY mRNA, NPY protein and NPY release. The prototype NPY5 antagonists have been shown to inhibit feeding in genetically obese rats and in food deprivation. But their effects in rodents with diet-induced obesity (the nearest model to human obesity) have not yet been reported. It is speculated that NPY5 antagonists could be effective antiobesity drugs.
Figure 1. Antagonists of the NPY receptors.
Mitochondrial uncoupling proteins (UCP):23
The uncoupling proteins play an important role in generating heat and burning calories. They uncouple oxidative phosphorylation process in mitochondria and oxidise the fatty acids released by lipolysis without forming ATP. These uncoupling proteins thus, form an important link between β 3-adrenoceptor and thermogenesis. They play an important role in regulating the body temperature, body composition and glucose metabolism. There are 3 forms of UCP. UCP1 expressed mainly in BAT and is induced by cold and β 3 agonists. This form of UCP is likely to be involved in weight regulation in adult large-size animals and humans living in thermoneutral environment as there is little BAT present. The studies in UCP1 knock out mice has shown them to be extremely sensitive to cold, unresponsive to β 3 agonists and not hyperphagic or obese. They also overexpress UCP2 in BAT which compensates for absence of UCP1. UCP2 is widely expressed in adult human tissues including the WAT and is up regulated in response to fat feeding. It is also expressed highly in spleen, macrophage, thymus and bone marrow which suggest that this gene may underlie thermogenic responses to inflammatory stimuli. In addition, UCP2 maps to region of human chromosome 11 and mouse chromosome 7 that has been linked to hyperinsulinemia and obesity. UCP3 is mostly expressed in skeletal muscle and in rodents in BAT. Other as yet undiscovered UCPs may exist. Agents that activate them or increase their expression offer a new therapeutic approach. In some people, age-associated increase in body fat has been related to UCP polymorphisms and in mice UCP 2 has been found to be up-regulated in response to high-fat diet. These findings suggest that uncoupled mitochondrial respiration may help dissipate excess energy in people.
Selective 5HT 2c receptor agonists:
The 5-HT2c receptor was identified in 1986 and widely expressed in CNS. 5-HT releasing compounds like d-fenfluramine, mCCP are reported for inhibiting food intake in human and rodent.
(1) (2)
(3) (4)
(5) (6)
Tricyclic analog- WAY163909 (1)
The non-selective tricyclic derivative hexahydro-pyrido[3’,2’4:,5] pyrrolo[1,2-a]pyrazine (2) was used as starting point for the discovery of selective 5HT2C receptor agonist.
Some (4), (5), (6) new 5HT2c receptor agonist have been recently disclosed in patent literature having good anti-obesity action.
5HT 6 receptor antagonists:
It is found in CNS. Historically, the first ligands for the 5-HT6 receptor were found in the late 1990's by high-throughput screening of compound libraries at Roche and GlaxoSmithKline, resulting in the antagonist tool compounds, (1) and (2), as well as in the first clinical development candidate, the phenyl–piperazine 5-HT6 receptor antagonist (3), EMDT (4) and the antagonist, (5)
Ro 04-6790 (1)
Ro 63-0563 (2)
SB-271046 (3)
EMDT(4)
MS-245 (5)
Several pharmacological studies and genetic models support a role for this receptor in obesity.
(1)
(2)
A patent application claims a series of benzoxazinone-derived piperidinesulfonamide (2)for treatment of food intake disorders
CB-1 receptor antagonists (Rimonabant):
Cannabinoid (CB) receptors may control neurotransmitters
1) glutamate
2) GABA and glycine
3) noradrenaline, 5-HT, dopamine, acetylcholine, neuropeptide
Rimonabant is an example of a CB antagonist that
§ blocks the CB-1 receptor that may be involved with appetite
§ It may increase satiety and cause weight reduction
Taranabant
The endocannabinoid system consist of endogenous ligands (anandamine and 2-arachidonoyl glycerol) that bind to and activate CB1R and CB2R that are distributed throughout the periphery and the CNS.
Rimonabant, a selective CBR1 antagonist, have been published which has significantly reduced waist circumference and plasma triglycerides and an increase HDL cholesterol and sustained reduction in body weight.
Rimonabant Pyrazolyl derivative
Pyrrolyl derivative Pyrrolyl derivative
Bicyclic 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-ones
1,2,3,4-tetrahydroquinoline
Melanocortin-4 Receptor (MC4R) Agonists:
MC4R is widely distributed throughout the brain. MC4R agonists will cause sustained body weight loss by decreasing food intake without a compensatory reduction in energy expenditure.
Agonists for the MC4 receptor based on the peptidyl privileged structure design.
The majority of MC4R patent application and publications continue to be focused around two main structural classes- piperidyl amide derived from 4-halophenylalanine, and piperidyl amides derived from 3,4-disubstituted pyrrolidine
Opioid receptor antagonist:
The endogenous opioid system has been known to regulate the appetite behavior for last 30 years. In preclinical species, both endogenous peptidic and non peptidic opioid receptor agonists have exhibited orexigenic properties. The µ- opioid receptor plays a n important role in feeding behavior. A selective opioid receptor antagonist naltrexone reported to produce weight loss in human. So result observed with antagonist in clinic, the discovery of new selective or pan-selective opioid receptor antagonists have been occurred for use as weight loss.
(1)
(2) (3)
(4 )
· Structurally unrelated nicotinamide derivatives (2) shows good antagonistic
· Activity and cause weight loss in rodent model.
· 4,5-dihydro-1H-imidazolyl derivative (3) shows good antagonistic activity
· Also cause weight loss.
· Tricyclic dibenzo[b,f]oxepine compound (4) showed good functional
· Activities in different opioid receptor.
Serotonin: 24
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has an established role in decreasing appetite. The widely prescribed anorectic drugs like dexfenfluramine, fenfluramine, fluoxetine also cause hypophagia by increasing brain extracellular 5-HT levels. The main antagonistic system for this is noradrenergic. Besides regulating appetite serotonin is also responsible for the selection of foods of major constituents. The high local levels of serotonin result in preference for proteins and low levels the opposite. The high carbohydrate and low protein diet promotes uptake of serum tryptophan in the brain and promote its conversion to serotonin which decreases feeding. This forms a self regulatory mechanism for serotonergic system. But in patients with decreased insulin sensitivity, this system may be disturbed causing over-consumption of carbohydrates resulting in clinical picture of 'carbohydrate craving obesity.
α- Melanocyte stimulating hormone (α -MSH) and melanocortin (MC) Receptors: 25
α -MSH is produced from proopiomelanocortin (POMC) neurons which exist in the ARC and nucleus stria terminalis of hypothalamus. It acts on MC4 receptors to reduce feeding. In mice, α -MSH is a centrally acting appetite suppressant. The physiological significance of this is indicated by up-regulation of MC4 receptors in food deprivation, presumably resulting from inhibition of α -MSH release. Also targeted disruption of MC4 receptors results in mice that develop maturity onset obesity syndrome associated with hyperphagia, hyperinsulinaemia and hyperglycaemia. This resembles agouti mouse model (yellow yellow obese mouse) which over expresses agouti protein, a pigmentation factor normally expressed in the skin. This protein is antagonist at MC2 receptors expressed in skin (failure to produce melanin, yellow coat colour) and MC4 receptors expressed in hypothalamus (obese mouse).
Tumour necrosis factor- α (TNF- α):26
TNF- α has been recognized as an inflammatory cytokine produced not only by the classic inflammatory cells but also by adipocytes. Within adipocytes, TNF- α has been postulated to be a mediator of insulin resistance via alterations in the phosphorylation status of insulin receptor substrate -1 (IRS-1) and to alter insulin receptor activity . Because of the overexpression of TNF- α mRNA and protein in the adipose tissue of obese animals and humans, TNF- α is a potential mediator of insulin – resistance associated with obesity. It is also expressed at higher levels in muscle cells of insulin resistant subjects and may also inhibit lipoprotein lipase (LPL) expression. Thus, it is a candidate gene product for the genetic predisposition to obesity. Since TNF- α is normally present at very low concentration in the circulation, it must act as an autocrine or paracrine factor.
Peroxisome proliferator activated receptor (PPAR)-γ gene:
PPAR- γ is a member of the PPAR subfamily of nuclear hormone receptors. PPAR- γ exists as two isoforms (γ 1 and γ 2) formed by alternative splicing and differing in their N-termini. PPAR- γ 2 is expressed at high levels in adipose tissue, while low levels of PPAR- γ 1 can be found in many other tissues. This receptor is induced very early in adipose cell differentiation, and is present at higher levels in preadipocytes. PPAR- γ appears to function as both a direct regulator of many fat-specific genes and also as a ‘master regulator' that can trigger the entire program of adipogenesis. It is also implicated in the control of adipocyte differentiation. Recently, the gene expression (mRNA) of PPAR- γ was found to be higher in subcutaneous than in visceral adipocytes of nonobese people. However, the mRNA concentrations were similar in subcutaneous and visceral depots in obese people, mainly because of an obesity-linked increase in the expression of the gene in visceral region (Yamashita S., 1996).
Energy expenditure regulation in obesity:
The energy expenditure has three components – resting metabolic rate, physical activity and thermogenesis. Among these, thermogenesis plays an important role in regulating body’s fat stores. By definition, thermogenesis is a process which is used to generate heat from food energy and also in response to stress. It represents about 10% of energy expenditure. It mainly occurs in the brown adipose tissue. Catecholamines (adrenaline and noradrenaline) stimulate thermogenesis in BAT, as well as lipolysis in white adipose tissue (WAT) .Any drug which could increase thermogenesis might, therefore, be useful for the treatment of obesity. sintolerance.
Effect of increased lipolysis on glucose use and gluconeogenesis.
5) MANAGEMENT OF OBESITY:
TREATMENT STRATEGIES:
These include drug treatment and nondrug treatment strategies (behavioral, dietary and surgical).
Behavioral therapy:
Behavioral modification is a method for systematically changing eating, exercise or other behaviours that contribute to or maintain obesity . These include-
Self-monitoring: This involves systematic observation and recording of target behaviors e.g., using food and activity diaries to record caloric intake; how many fat grams and food groups are eaten; conditions or situations when eating is common and frequency, duration and/or intensity of exercise.
Stimulus control: Involves identifying and modifying environmental cues associated with overeating and activity and thereby, changing an individual’s microenvironment e.g., eliminating the availability of snack foods in the house or restricting eating to particular rooms.
Cognitive restructuring: Many obese patients hold unrealistic beliefs about themselves and their weight. This strategy teaches the patients to actively challenge and change aspects of their internal dialogue.
Stress management: Stress is a primary predictor of relapse and over-eating. Various stress management techniques like diaphragmatic breathing; progressive muscle relaxation or meditation helps to overcome various health related problems.
Social support: This gives patient greater self acceptance, develop new norms for interpersonal relationships and manage stressful work or family situations.
Physical activity: This helps to maintain the lost weight and produces various psychological benefits like coping better with stressful situations, reduces unhealthy reactions to stress such as over-eating and the resultant negative
emotions and certain social situations such as travel or parties to be associated with obesity.
Various drugs for treatment of obesity:
1. Appetite suppressants:
(a) Centrally acting adrenergic agents-
Benzphetamine, phentermine, diethylpropion,
mazindol, phendimetrazine, phenylpropanolamine
(b) Serotonergic agents-
Dexfenfluramine, fenfluramine, fluoxetine
(c) Adrenergic/serotonergic agents-
Sibutramine
2. Thermogenic agents:
(a) Adrenergic agents-
Ephedrine+caffeine
(b) β 3 –Agonists-
BRL 26830A, BRL 35135, RO 40-2148,
RO 16-8714, CL 316243
3. Digestion inhibitors:
(a) Lipase inhibitors-
Orlistat
(b) Carbohydrate-based fat substitutes-
Guar gum, polydextrose, sugar beet fiber.
(c) Protein-based fat substitutes-
Microparticulated egg white and milk protein.
(d) Fat-based fat substitutes-
Olestra, caprenin
4. Hormonal manipulation:
Leptin analogues and neuropeptide Y antagonists
5. Plant sources:
INDIAN: Garcinia cambogia, Commiphora mukul, Teucrium chamaedrys (germander), Paeonia suffruticosa
(tree-peony), hydrophilic mucilages, preparations from
plantago seeds and senna pods, noncarbohydrate sweeteners
Dietary therapy:
Dietary method remains the primary method for obesity treatment. Dietary intervention along with other treatment strategies remains a useful tool used continuously overtime to accelerate weight loss or to maintain a constant body weight. This involves restricting total energy intake with healthful food selections and exercising prudent control over eating habits. It can be implemented with the help of encouragement of a dietitian along with a primary health care physician.
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Received on 25.01.2010 Modified on 20.03.2010
Accepted on 17.04.2010 © AJRC All right reserved
Asian J. Research Chem. 3(2): April- June 2010; Page 278-287