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 Table of Contents  
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 99-116

Recent advances and current trend in the pharmacotherapy of obesity

Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria

Date of Web Publication11-Jun-2018

Correspondence Address:
Dr. Olumuyiwa John Fasipe
Medical Lecturer and Senior Physician, Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_30_18

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Nonpharmacological approach to the prevention and treatment of obesity includes considerable lifestyle changes such as adequate physical exercise, smoking cessation, limiting alcohol intake, avoiding sedentary lifestyles, intensive behavioral counseling (psychotherapy), proper nutritional (dietary) programs, and bariatric surgery. For a pharmacotherapeutic substance to be regarded as an anti-obesity drug, it has to demonstrate a reduction of at least 5%–10% in the baseline body weight within a year of commencing treatment. Pharmacotherapeutic agents used to treat obesity include sympathomimetic appetite suppressant drugs, pancreatic lipase inhibitors, antidiabetic drugs, serotonin 5-HT2Cagonists, anticonvulsant drugs, atypical antidepressants, hormones, selective β3adrenoceptor agonists, and various combination preparations. The choice of agent should be individualized and dictated by patient comorbidities, relative contraindications, available clinical trial evidence, and clinical expertise. In addition to pharmacological therapy, all anti-obesity drugs should be prescribed with the premise of dietary caloric restriction and exercise. Bariatric surgery is the most effective treatment for obesity when the other forms of intervention have failed to produce a clinically significant weight loss in individuals with a body mass index of ≥35 kg/m2. Finally, concerning the prospective future research directions on the pharmacotherapy of obesity, a number of initiatives have been put forward to develop a peripherally restricted CB1receptor antagonist (such as TM38837 compound) that targets only the peripheral CB1receptors by restricting their ability to cross the blood–brain barrier in order to avoid the serious and severe psychiatric adverse effects found to be associated with the unrestricted CB1receptor antagonists such as rimonabant.

Keywords: Current trend, obesity, pharmacotherapy, recent advances

How to cite this article:
Fasipe OJ. Recent advances and current trend in the pharmacotherapy of obesity. Arch Med Health Sci 2018;6:99-116

How to cite this URL:
Fasipe OJ. Recent advances and current trend in the pharmacotherapy of obesity. Arch Med Health Sci [serial online] 2018 [cited 2023 Mar 29];6:99-116. Available from: https://www.amhsjournal.org/text.asp?2018/6/1/99/234100

  Introduction Top

Obesity is a medical condition in which excess body fat has accumulated to the extent that it could produce an adverse health effect.[1] It is usually defined by body mass index (BMI) and further evaluated in terms of body fat distribution.[1],[2] BMI is closely related to both body fat percentage (BFP) and total body fat composition.[2] In children and adults, a healthy weight varies with age and sex. Obesity in children and adolescents is defined not by an absolute number but in relation to a historical normal group – match for age and sex, such that obesity is a BMI greater than the 95th percentile.[2],[3] The reference data on which these percentiles were based date from 1963 to 1994 and thus have not been affected by the recent increases in weight.[4]

  Epidemiology Top

Obesity is a leading preventable cause of death worldwide, with increasing rates in adults and children.[1],[5] The global prevalence of overweight and obesity has dramatically increased since 1980 when the average proportion of adults with a BMI of 25 kg/m 2 was estimated at 28%.[2] The latest WHO statistics indicate that approximately 39% (1.9 billion) of adults above the age of 18 years are overweight and 13% (603.7 million) are classified as obese.[1] Supporting the trend in increase, it has been estimated that by 2025, this figure will have risen to three billion people being overweight and nearly 700 million being obese. The incidence of obesity in children is also on the increase, with estimated new cases of about 42 million children worldwide being affected. Many studies have shown the increase in risk for obese and overweight individuals to develop diabetes mellitus (DM),[3] cardiovascular disease,[4] cancer,[6] musculoskeletal disorders,[7] endocrine disorders,[8] and psychiatric disorders.[9] Obesity is responsible for 3.4 million global deaths annually and accounts for about 4% of life lost per year. It can therefore be classified as a pandemic.[2] At the international level, in 2015, among the 20 most populous countries, the highest level of age-standardized adult obesity was observed in Egypt (35.3%; 95% uncertainty interval, 33.6–37.1), and the highest level of age-standardized childhood obesity was observed in the United States (12.7%; 95% uncertainty interval, 12.2–13.2). The prevalence was lowest among adults in Vietnam (1.6%; 95% uncertainty interval, 1.4–2.0) and among children in Bangladesh (1.2%; 95% uncertainty interval, 0.9–1.7). Between 1980 and 2015, the age-standardized prevalence of obesity increased by a factor of 2 or more in 13 of the 20 topmost countries affected by obesity; with only the Democratic Republic of Congo had no increase. In 2015, China and India had the highest numbers of obese children, whereas the United States and China had the highest numbers of obese adults.[2],[10] In 2013, the American Medical Association classified obesity as a disease.[11],[12] Obesity is associated with increased risk of many physical and mental disease conditions, particularly cardiovascular diseases, type 2 DM, obstructive sleep apnea, certain types of cancer, osteoarthritis,[2] asthma, and depression disorders.[2],[13] As a result, obesity has been found to reduce life expectancy significantly.[2] Obesity predisposes affected individuals to metabolic syndrome; a combination of medical disorders which includes type 2 DM, hypertension, and hyperlipidemias. Once considered a problem only of high-income countries, obesity rates are increasing worldwide and affecting both the developed and developing world.[7],[8],[9] These increases have been felt most dramatically in urban settings.[14] The only remaining region of the world where obesity is not common is Sub-Saharan Africa, but gradually, the reverse is coming into play as sedentary lifestyle is on the increase.[15]

  Pathophysiology of Obesity Top

There are many pathophysiological mechanisms involved in the development and maintenance of obesity. At an individual level, a combination of excessive food energy intake and inadequate physical activity is thought to explain most cases of obesity.[9] A limited number of cases are due primarily to genetic predisposition, medical reasons, or psychiatric illness.[14] Obesity is, therefore, the result of interplay between genetic and environmental factors. Not all people exposed to prevailing urban and rural environments become obese, which suggests the existence of underlying genetic mechanisms operating at the individual level. Rare monogenic forms of obesity are now recognized including a deficiency of the leptin and melanocortin-4 receptors, which are expressed mainly in the hypothalamus and are involved in neural circuits regulating energy homeostasis.[5] Heterozygous mutations in the melanocortin-4 receptor gene are currently the most common cause of monogenic obesity, appearing in 2%–5% of children with severe obesity.[5],[16] People with two copies of the FTO gene (fat mass and obesity associated gene) have been found on average to weigh 3–4 kg more and have a 1.67-fold greater risk of obesity compared with those without the risk allele. Obesity is a major feature in several inherited syndromes such as Prader–Willi syndrome, Bardet–Biedl syndrome, Cohen syndrome, and MOMO syndrome. In people with early-onset severe obesity (defined by an onset before 10 years of age and BMI over three standard deviations above the value for normal individual age-and sex-match), 7% harbor a single point DNA mutation.[5]

Currently looking at the molecular basis of obesity, in addition to other chemical substances (such as insulin, glucagon, cortisol, somatostatin, growth hormone, thyroxin, gastric inhibitory polypeptide/glucose-dependent insulinotropic peptide [GIP], adiponectin, chemerin, perilipin-1, apelin, glucagon-like peptide-1 [GLP-1], cholecystokinin-pancreozymin, and catecholamines), there are mainly five important endogenously produced chemical substances that seem to tightly regulate the feeding (appetite and satiety), energy storage, balance, metabolism, and expenditure pathways in humans. These endogenous chemical substances are as follows:

  • Leptin
  • Ghrelin
  • Obestatin
  • Nesfatin-1
  • Endocannabinoids.

In addition to genetic factors that predispose to obesity, these endogenous chemical substances act on varieties of pathway cascades within the central nervous system (CNS) and the periphery to promote or attenuate the development of obesity disorder. It is also worth mentioning here that leptin, obestatin, nesfatin-1, gastric inhibitory polypeptide/glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide-1 [GLP-1], adiponectin and chemerin are anti-obesogenic and anti-diabetogenic in activity, while ghrelin, endocannabinoids and perilipin-1 are pro-obesogenic and pro-diabetogenic in activity.


The leptin gene was discovered in 1994.[12] While leptin is produced peripherally, it controls appetite through its actions at the hypothalamic feeding (appetite and satiety) centers in the CNS. The type I cytokine leptin is mainly produced by adipocytes to signal the energy state of the body and exerts its function as a satiety signal in the hypothalamus. In particular, leptin, ghrelin, and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite and satiety, the melanocortin pathway being the most well understood.[17] The circuit begins with an area of the hypothalamus, the arcuate nucleus that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's appetite and satiety centers, respectively.[18] The arcuate nucleus contains two distinct groups of neurons.[19] The first group coexpresses neuropeptide Y (NPY) and agouti-related protein (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocorticotropin and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus, a deficiency in leptin signaling, either via leptin deficiency or leptin receptor resistance (loss-of-function mutation), leads to overfeeding and may account for some genetic and acquired forms of obesity. Loss-of-function mutations in the gene encoding leptin (LEP) typically lead to the circulation of physiologically inactive form of leptin and to extreme obesity. The early onset of extreme obesity due to a novel homozygous transversion frameshift mutation (c.298G→T) in exon 3 of LEP gene leads to a change from aspartic acid to tyrosine at amino acid position 100 (p. D100Y) and has high immunoreactive levels of leptin. Overexpression studies confirmed that the mutant protein is secreted but neither binds to nor activates the leptin receptor. The mutant leptin protein failed to reduce food intake and body weight in leptin-deficient experimental models. Treatment of the affected leptin-deficient patient with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss. To date, reported cases of congenital leptin deficiency have been characterized by circulating leptin levels that are undetectable or very low as a result of defects in either synthesis or secretion of leptin. Clinical hallmarks of congenital leptin deficiency include early-onset extreme obesity, marked hyperphagia, and hormonal as well as metabolic disturbances.[2],[3],[15],[20],[21] Some patients may also have immunologic alterations.[5],[20] [Figure 1]a shows brief illustrations regarding the leptin–ghrelin pathway in the human body.
Figure 1: (a) Brief illustrations regarding the leptin-ghrelin pathway in the human body. (b) Brief illustrations regarding the various types of adipocytes

Click here to view


Ghrelin, the “hunger hormone,” also known as lenomorelin, is a peptide hormone produced mainly by ghrelinergic cells not only in the stomach (found in oxyntic glands) and duodenum (found in pyloric glands) but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, and kidney. It has recently been shown that ghrelin is produced locally in the brain which functions as a neuropeptide in the CNS. Besides regulating appetite, ghrelin also plays a significant role in regulating the distribution and rate of energy expenditure. Ghrelin is absorbed when the stomach is empty. Furthermore, when the stomach is stretched, its secretion stops. It acts on hypothalamic brain cells both to increase hunger and to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake. The receptor for ghrelin, known as the ghrelin/growth hormone secretagogue type 1A receptor (GHS-R1A), is found on the same cells in the brain as the receptor for leptin (the satiety hormone) that has opposite effects from ghrelin. Ghrelin also plays an important role in regulating reward perception in dopaminergic neurons that link the ventral tegmental area to the nucleus accumbens (a site that plays an important role in processing sexual desire, reward, and reinforcement and in developing addictions) through its colocalized receptors and interaction with dopaminergic and cholinergic neurons in the CNS. Ghrelin is encoded by the GHRL gene and is presumably produced from the cleavage of the ghrelin/obestatin preprohormone. Full-length preproghrelin is homologous to promotilin and both are the members of motilin family. Ghrelin is able to cross the blood–brain barrier, giving exogenously administered ghrelin unique clinical potential use. The GHRL gene produces the ghrelin mRNA (which has four exons) and gives rise to five products which are as follows. The first is the 117-amino acid ghrelin/obestatin preprohormone, also known as preproghrelin (a homolog to promotilin; both are the members of motilin family). This is further cleaved to produce proghrelin which is cleaved to produce a 28-amino acid unacylated ghrelin and the acylated C-ghrelin. Obestatin is presumed to be cleaved from the acylated C-ghrelin. In addition, ghrelin only becomes physiologically active when caprylic (octanoic) acid is linked post-translationally to the serine at its third position by the enzyme ghrelin O-acyltransferase (GOAT). GOAT is located on the cell membrane of ghrelin cells in the stomach and pancreas. The nonoctanoylated form is desacyl ghrelin. It does not activate the GHS-R1A but may also have some other effects that are not yet full known. Ghrelin has been linked to induce appetite and feeding behaviors. Ghrelin and synthetic ghrelin mimetics (i.e., GHS) increase body weight and fat mass by triggering receptors in the arcuate nucleus that include the orexigenic NPY and agouti-related protein (AgRP) neurons. Ghrelin responsiveness of these neurons is both leptin and insulin sensitive. Ghrelin reduces the mechanical sensitivity of the gastric vagal afferents, so they are less sensitive to gastric distension. Circulating ghrelin levels are highest before a meal and the lowest after. Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner. Hence, the more the ghrelin that is injected, the more the food that is consumed. However, ghrelin does not increase meal size, but only meal number. Ghrelin injections also increase animal's motivation to seek out food and behaviors including increased sniffing, foraging for food, and hoarding food. Body weight is regulated through energy balance, the amount of energy taken in versus the amount of energy expended over an extended period of time. Studies have shown that ghrelin levels are negatively correlated with weight. Data suggest that ghrelin functions as an adiposity signal, a messenger between the body's energy stores and the brain. In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link inputs to the ventral tegmental area and in the mesolimbic–mesocortical pathway, a circuit that communicates the hedonic (pleasure) and reinforcing (rewarding) aspects of natural rewards, such as food, sex, and addictive drugs, such as ethanol and psychostimulants. Ghrelin receptors are located on the neurons in this circuit. Hypothalamic ghrelin signaling is required for reward from alcohol and palatable/rewarding foods.[2],[3],[15],[20],[21]


Obestatin is a hormone that is produced in specialized epithelial cells of the stomach and small intestine of several mammals including humans. Obestatin was originally identified as an anorectic peptide, but its effect on food intake remains controversial. Obestatin is encoded by the same GHRL gene that encodes the ghrelin hormone. As earlier mentioned, obestatin is cleaved from the acylated C-ghrelin product of preproghrelin hormone. It was originally proposed that GPR39 functioned as an obestatin receptor; however, more recent findings suggest that this is unlikely. In functional similarity and activity to leptin hormone, obestatin opposes the actions of ghrelin which are growth hormone secretion and increased appetite, that is, obestatin has opposite action to ghrelin on food intake and role in energy balance/expenditure.[2],[3],[15],[20],[21]


Nesfatin-1 is a neuropeptide produced not only in the hypothalamus but also in the pancreatic islets, gastric endocrine cells, and adipocytes of mammals. Nesfatin-1 is a polypeptide encoded in the N-terminal region of the protein precursor, nucleobindin-2 (NUCB-2). It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a “sense of fullness and satiety,” and a potential loss of body fat and weight. A study of metabolic effects of nesfatin-1 in experimental animal models have been done, in which subjects administered nesfatin-1 ate less, used more stored fat, and became more active. Central nesfatin-1-induced inhibition of feeding is mediated through the inhibition of orexigenic NPY/AgRP neurons and stimulation of satiety POMC/CART neurons in the feeding center of hypothalamus. In addition, it stimulates insulin secretion from the pancreatic beta cells. Nesfatin-1/NUCB-2 is expressed in the appetite-control hypothalamic nuclei such as paraventricular nucleus, arcuate nucleus (ARC), supraoptic nucleus of hypothalamus, lateral hypothalamic area, and zona incerta in rats. Nesfatin-1 immunoreactivity was also found in the brainstem nuclei such as nucleus of tractus solitarius (NTS) and dorsal nucleus of vagus nerve. Nesfatin-1 can cross the blood–brain barrier without saturation. Recently, it has been reported that intracerebroventricular nesfatin-1 injection produced a dose-dependent delay of gastric emptying and resulted in a stimulation of liver insulin signaling that could account for the increased insulin sensitivity and improved glucose metabolism. Furthermore, central nesfatin-1 decreases glucose production mainly via decreasing gluconeogenesis by inhibiting the phosphoenolpyruvate carboxykinase (PEPCK) activity through the repression and downregulation of the PEPCK mRNA expression.[2],[3],[15],[20],[21]


Anandamide and 2-arachidonoylglycerol (2-AG) are the endogenous cannabinoid neurotransmitters that bind to the cannabinoid CB1 and CB2 receptors in the CNS and periphery. It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate feeding and hunger, nutrient transport, and energy storage/balance/metabolism/expenditure. The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood. For example, experimental animal models without leptin not only become massively obese but also express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism. Similarly, when these experimental animal models were treated with unrestricted endocannabinoid inverse agonists such as rimonabant, food intake was reduced. When the CB1 receptor is knocked out in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of tetrahydrocannabinol (THC) on the hedonic (pleasure) value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution. A related study found that endocannabinoids affect taste perception in the taste bud cells. In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to pleasure and appetitive, food-seeking behavior. The endocannabinoid system has also been shown to have a homeostatic role by controlling several metabolic functions by acting on the peripheral tissues such as adipocytes, hepatocytes, gastrointestinal tract, skeletal muscles, and endocrine pancreas. It has also been implied in modulating insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity, diabetes, and atherosclerosis, which may also give it a cardiovascular role.[2],[3],[15],[20],[21]

In contrast to the BMI cut-off point of 30 kg/m 2 set by the WHO to define obesity, the Asian populations develop negative health consequences at a lower BMI than the Caucasians, thereby making some nations to have redefined their own cut-off point for obesity. Furthermore, Japan has defined obesity as any BMI >25 kg/m 2, while China uses a BMI of >28 kg/m 2. It is also worth mentioning here that some obese patients, especially women, can seldom present with atypical clinical features or characteristics of lipodystrophy such as loss of subcutaneous body fat, occurring around or shortly after puberty in the extremities and/or gluteal region with sparing of fat loss, or accumulation of excess fat in the face, neck, and/or intra-abdominal regions.

Maternal malnutrition in early in utero life is also believed to play an important role in the rising rates of offspring obesity in the developing world. The maternal and fetal endocrine changes that occur during periods of undernutrition may promote the storage of fat once more food energy becomes available and this can predispose the affected offspring to obesity during later extrauterine life while growing up. In addition, maternal overnutrition or gestational DM can also lead to fetal macrosomia in utero with high birth weight. Furthermore, studies that have focused on inheritance patterns of obesity have found that 80% of the offspring of two obese parents were also obese, in contrast to <10% of the offspring of two parents who were of normal weight. This means that different people exposed to the same environmental conditions have different risks of obesity due to their underlying genetic compositions. This has led to the postulation of the “thrifty gene hypothesis” which states that, due to dietary food (energy) scarcity during human evolution, people are prone to obesity because of their ability to take advantage of rare periods of food energy abundance by storing energy as fat which would be advantageous during times of varying food scarcity, and individuals with greater adipose reserves would be more likely to survive famine. However, at the same time, this tendency to store fat, however, would be maladaptive and detrimental in the ecosystem with stable and constant food supplies.[2],[3],[15],[20],[21],[22],[23],[24],[25],[26],[27]

  Determining the Total Body Fat Composition and Body Fat Percentage Top

BFP is the total weight of estimated body fat divided by total body weight expressed as percentage. Body fat includes essential body fat and storage body fat. Essential body fat is necessary to maintain life and reproductive functions. The percentage of essential body fat for women is greater than that for men, due to the demands of childbearing and other hormonal functions. The percentage of essential fat is 2%–5% in men and 10%–13% in women.[6],[7],[8],[15] Storage body fat consists of fat accumulation in the adipose tissue, part of which protects internal organs in the chest and abdomen. The minimum recommended total BFP exceeds the essential fat percentage value reported above. For women, BFP value within the range of 26%–31%, 32%–39%, and ≥40% is regarded as normal, overweight, and obese, respectively. However, for men, BFP values within the range of 18%–22%, 23%–29%, and ≥30% are regarded as normal, overweight, and obese, respectively. The BFP is a measure of the fitness level of an individual since it is the only body measurement which directly calculates a person's relative body composition without regard to height or weight. [Figure 1]b shows brief illustrations regarding the various types of adipocytes. The various emerging and current investigational methods or techniques for the analysis and determination of total body fat composition and BFP in obesity are enumerated as follows:[5],[10],[11],[12],[16],[17],[18],[19],[20],[21],[38],[39]

  • The theoretical golden standard method of underwater weighing which has its foundation on Archimedes' principle
  • Bioelectrical impedance analysis
  • Whole-body air displacement plethysmography
  • Dual-energy X-ray absorptiometry
  • Near-infrared interactance
  • Body average density measurement
  • Ultrasound sonography technique
  • Anthropometric measurements such as triceps skinfold thickness, mid-upper arm circumference, BMI, waist circumference, waist-to-hip ratio, waist-to-stature ratio, and/or waist-to-thigh ratio.

Gold-Standard Method of Underwater Weighing

There are several methods of determining the body's fat composition. The most accurate determination method is still the “theoretical golden standard method of underwater weighing”, has its foundation on Archimedes' principle dating back to 250BC: “The buoyant force which water exerts on an immersed object is equal to the weight of water that the object displaces”[11]. Total body fat can therefore be calculated by completely submerging a person in water and measuring the weight (volume) of displacement. Fat-free mass has a density of 1.1kg per litre (consisting of 72% water (density = 0.993), 21% protein (density = 1.340), and 7% minerals (density = 3.000) by weight), where fatty tissues in humans body are composed almost entirely of pure triglycerides with an average density of about 0.9kg per litre. Ignoring the presence of air and contents in the lungs and gastrointestinal tract, it can then be calculated that if a person weighs 100kg, he will displace 95 litres of water if he has a fat percentage of 50%. This is obviously impractical to perform in the clinical setup, thus a lack of an acceptable golden standard has led to various methods attempting to measure and calculate body fat. Each method has limitations, and therefore practitioners need to have adequate knowledge of these measuring techniques in order to make an accurate assessment.

Bioelectrical Impedance Analysis (BIA)

BIA employs the principle of electrical impedance or resistance to the flow of an electric current through the different body tissues. An algorithm is used to calculate total body water and fat free body mass, which is subtracted from the total body mass to give an estimated of total body fat.[12] BIA devices are commercially available and frequently used due to the low cost, portability and non-invasiveness of this procedure. Several factors may affect the accuracy of the reading, such as hydration status, exercise, ambient temperature, position of electrode placement and equipment calibration. The over- and underestimation of body fat by using BIA ranges between 7-14%.[13]

Whole-Body Air Displacement Plethysmography (ADP)

Whole-body air displacement plethysmography (ADP) is a recognised and scientifically validated densitometric method to measure human body fat percentage.[5] ADP uses the same principles as the gold-standard method of underwater weighing, but representing a densitometric method that is based on air displacement rather than on water immersion. Air-displacement plethysmography offers several advantages over established reference methods, including a quick, comfortable, automated, noninvasive, and safe measurement process, and accommodation of various subject types (e.g., children, obese, elderly, and disabled persons).[6] However, its accuracy declines at the extremes of body fat percentages, tending to slightly understate the percent body fat in overweight and obese persons (by 1.68-2.94% depending on the method of calculation), and to overstate to a much larger degree the percent body fat in very lean subjects (by an average of 6.8%, with up to a 13% overstatement of the reported body percentage of one individual — i.e. 2% body fat by DEXA but 15% by ADP).[7]

Dual-Energy X-ray Absorptiometry (DEXA)

The use of DEXA has recently been advocated as a possible golden standard in determining body composition. Here an energy source produces photons at different energy levels, which are measured and used to differentiate between non-identical elemental profiles such as fat, bone and muscle. Body fat can accurately be calculated but the high costs involved make it an unlikely tool to be used in everyday practice. The instruments also have maximum capacity of approximately 180kg, thus morbidly obese patients would not enjoy any benefit.[14]

Near-Infrared Interactance (NIR)

Near infrared interactance (NIR) is a relatively new technique used to measure body composition. It is based on the varying degrees of infra-red light absorption by different tissues. It employs computerized spectrophotometer with a single, rapid scanning monochromatic and fibre optic probe. A beam of infra-red light is transmitted into a biceps. The light is reflected from the underlying muscle and absorbed by the fat. The method is safe, simple, non-invasive, rapid and easy to carry out within a few seconds. It is not affected by body fluid status.[8]

Body Average Density Measurement

Prior to the adoption of DEXA, the most accurate method of estimating body fat percentage was to measure that person's average density (total mass divided by total volume) and apply a formula to convert that to body fat percentage. Since fat tissue has a lower density than muscles and bones, it is possible to estimate the fat content. This estimate is distorted by the fact that muscles and bones have different densities: for a person with a more-than-average amount of bone mass, the estimate will be too low. However, this method gives highly reproducible results for individual persons (± 1%). The body fat percentage is commonly calculated from one of two formulas (ρ represents body average density in g/cm3):

  • Brozek formula: BFP = (4.57/ρ − 4.142) × 100
  • Siri formula is: BFP = (4.95/ρ − 4.50) × 100

Ultrasound Sonography

Ultrasound sonography is used extensively to measure tissue structure and has proven to be an accurate technique to measure subcutaneous fat thickness.[16] A-mode and B-mode ultrasound systems are now used and both rely on using tabulated values of tissue sound speed and automated signal analysis to determine fat thickness. By making thickness measurements at multiple sites on the body you can calculate the estimated body fat percentage.[17],[18] Ultrasound techniques can also be used to directly measure muscle thickness and quantify intramuscular fat. Ultrasound equipment is expensive, and not cost-effective solely for body fat measurement, but where equipment is available, as in hospitals, the extra cost for the capability to measure body fat is minimal.[12]

Mid-Upper Arm Anthropometric Measurements

Measuring triceps skinfold thickness (TSF) and mid-upper arm circumference (MAC) are non-invasive, inexpensive and easy to perform. From these two measurements the mid-upper arm muscle circumference (MAMC) can be calculated: [MAMC= MAC-(3.1416TSF)]. The determined value is then compared to standardized age and gender reference ranges. A value below the fifth percentile demonstrates underweight, whereas a value above the 95th percentile implies obesity.[15] The mid-upper arm muscle area (MAMA) = { [MAMC]2/9.425}. Anthropometric measurement arithmetic is more useful in monitoring long-term nutritional therapy in malnourished children than assessing obesity in adults. Using this method may under-or overestimate body composition by up to 10% in severely obese individuals.[16]

Body Mass Index (BMI)

BMI also known as Quetelet index is calculated by dividing the body weight by the square of the body height (kg/m2). It is easy to perform and is the most widely used clinical tool in the indirect assessment of obesity. A typical BMI representing a normal weight range is between 18.5kg/m2 and 24.9kg/m2. Values less than 18.5 are considered underweight whereas a value above 30 is classified as obese. Overweight represents values between 25 and 29.9.[1] Although the definition and classification of obesity by the WHO make use of the BMI scale, it has serious limitations. Omitted variables such as age (body fat physiologically increases with age), sex (females inevitably have a higher body fat composition), fat distribution, muscle mass and bone structure (athletes or body builders with high muscle mass and lower body fat), may result in an individual being misclassified due to either overestimation or underestimation of body fat.[4],[17] Some studies suggest that if the calculated BMI has to be compared to BIA, the overestimation of obesity could be as high as 30-60%.[18]

Body fat may be estimated from the body mass index by formulae derived by Deurenberg and co-workers. When making calculations, the relationship between densitometrically determined body fat percentage (BFP) and BMI must take age and sex into account. Internal and external cross-validation of the prediction formulas showed that they gave valid estimates of body fat in males and females at all ages. In obese subjects, however, the prediction formulas slightly overestimated the BFP. The prediction error is comparable to the prediction error obtained with other methods of estimating BFP, such as skinfold thickness measurements and bioelectrical impedance. The formula for children is different; the relationship between BMI and BFP in children was found to differ from that in adults due to the height-related increase in BMI in children.[11]

  • Child BFP = (1.51 × BMI) − (0.70 × Age) − (3.6 × sex value) + 1.4
  • Adult BFP = (1.20 × BMI) + (0.23 × Age) − (10.8 × sex value) − 5.4

Where, the Sex value substitute is One (1) for males; and Zero (0) for females in the above stated equations.

Waist Circumference (WC)

Determining the waist circumference is another tool for classifying obesity with regards to the cardiovascular risk profile. Waist circumference measurement is useful in patients who are categorised as normal or overweight on the BMI scale (30kg/m2). Men are classified as “high risk” if the horizontally measured circumference at the midpoint of the distance between the lower margin of the last palpable rib and the top of the iliac crest exceeds 102cm using a stretch-resistant tape that provides a constant 100 g tension. For nonpregnant women, the threshold should not exceed 88cm. A higher than these threshold values for the specified sex is considered to imply a high risk for type 2 diabetes, dyslipidemia, hypertension, and CVD. Measuring circumference at the level of umbilicus may underestimate the true waist circumference.[19] Measuring the WC only alludes to the location of fat, but not the absolute percentage of body fat. Using this method has an error rate of approximately 3%. Waist-to-hip circumference ratio has also been used, but has been found to be no better than waist circumference alone, but more complicated to measure.[18],[20] Waist circumference can be a better indicator of obesity-related disease risk than BMI; for example, this is the case in populations of Asian descent and older people.

Hip Circumference (HC)

The Hip circumference should be horizontally measured around the widest portion of the buttocks taking into consideration both the left and right lateral iliac crests (or anterio-superior iliac spines) as landmark, with the stretch-resistant tape parallel to the floor. For either HC or WC measurements, the individual should stand with feet close together, arms at the side and body weight evenly distributed, and should wear little clothing. The subject should be relaxed, and the measurements should be taken at the end of a normal respiration. Each measurement should be repeated twice; if the measurements are within 1 cm of one another, the average should be calculated. If the difference between the two measurements exceeds 1 cm, the two measurements should be repeated.[2]

Waist-Hip Ratio (WHR)

Waist–hip ratio or waist-to-hip ratio (WHR) is the dimensionless ratio of the circumference of the waist to that of the hips. This is calculated as waist measurement divided by hip measurement (WC/HC). WHR is used as a measurement of obesity, which in turn is a possible indicator of other more serious health conditions. The WHO states that abdominal obesity is defined as a waist-hip ratio above 0.90 for males and above 0.85 for females. Men or women with WHR values more than these specified thresholds are at increased health risk because of their fat distribution. WHR has been found to be a more efficient predictor of mortality in older people (>75 years of age) than waist circumference or BMI.[8] If obesity is redefined using WHR instead of BMI, the proportion of people categorized as at risk of heart attack worldwide increases threefold.[9] The body fat percentage (BFP) is considered to be an even more accurate measure of relative weight. Of these three measurements, only the waist-hip ratio takes account of the differences in body structure. Hence, it is possible for two women to have vastly different body mass indices but the same waist-hip ratio, or to have the same body mass index but vastly different waist-hip ratios. WHR has been shown to be a better predictor of cardiovascular disease than waist circumference or body-mass index alone.[10] However, other studies have found waist circumference, not WHR, to be a good indicator of cardiovascular risk factors, body fat distribution, and hypertension in type 2 diabetes.[11],[12],[13] In fact it is more pragmatic to say that “Hip size indicates pelvic size and the amount of additional fat storage that can be used as a source of energy while the waist size conveys information such as current reproductive status or health status. In westernized societies with no risk of seasonal lack of food, the waist size, conveying information about fecundity and health status, and will be more important than hip size for assessing a female's attractiveness.”

Waist-to-Height Ratio (WHtR) or Waist-to-Stature Ratio (WSR)

Waist-to-height ratio (WHtR), also called waist-to-stature ratio (WSR) is estimated by using the body waist circumference divided by the body height. The values indicating increased risk are: greater than 0.5 for people under 40 year of age, 0.5 to 0.6 for people aged 40–50, and greater than 0.6 for people over 50 years of age. A 2010 study that followed 11,000 subjects for up to eight years concluded that WHtR is a much better measure of the risk of heart attack, stroke or death than the more widely used body mass index.[2] However, a 2011 study that followed 60,000 participants for up to 13 years found that waist-hip ratio (when adjusted for BMI) was a better predictor of ischaemic heart disease mortality than WHtR.[3]

Waist-Thigh Ratio (WTR)

Waist-thigh ratio (WTR) is another recently discovered new anthropometric measurement and tool that is being used as one of the important marker for diagnosing obesity and to predict high risk of developing type 2 DM. It is defined as the ratio of the waist circumference (WC) to the thigh circumference (TC); that means WC/TC. Thigh circumference (TC) has been recognized recently as a relevant anthropometric measure that identifies individuals with increased risk of premature morbidity and mortality from cardiovascular diseases early in the disease. Strong relationships with obesity, fasting, random and 2 hours-postprandial plasma glucose level have been demonstrated. Insulin resistance syndrome and obesity are associated with excessive visceral abdominal fat. Recent evidence links low subcutaneous fat, especially in the thighs, with adverse glucose and lipid metabolism. Insulin resistance also depends on muscle mass. Less muscle mass, especially in the lower extremity, is inversely related to the development of type 2 DM and obesity. A thin thigh with low TC and low muscle mass and a greater waist-thigh ratio (WTR) predicts obesity and increase risk for type 2 DM.

According to the WHO standard, the thigh circumferences (TC) should be measured when the individual patient is standing upright with both feet close together, both arms at the side and body weight evenly distributed, and should be wearing little clothing. The patient right thigh clothing is minimally exposed to the hip region when about to take the TC measurement. TC is measured horizontally at the level of the midpoint located on the lateral surface of the right thigh, midway between the greater trochanter of the right femur and the upper lateral border of the head of the right tibia using a standard flexible inelastic measuring tape and the patient should also be relaxed. Each measurement should be repeated twice; if the measurements are within 1 cm of one another, the average should be calculated. If the difference between the two measurements exceeds 1 cm, the two measurements should be repeated. In a research done by Kumar et al. (2018);[39] WTR correlates significantly and positively with obesity and to all the three measures of type 2 DM namely fasting plasma glucose (FPG), random plasma glucose (RPG), and 2 hours-postprandial plasma glucose (2 hours-PPG) [P < 0.0001]. While TC has a strong negative correlations with obesity and to all the three measures of type 2 DM namely FPG, RPG, and 2 hours-PPG (P < 0.0001). Compared to WHR; WTR has a higher correlations with obesity and to all the three measures of type 2 DM (FPG, RPG and 2 hours-PPG), suggesting that it is a statistically more powerful and better predictor of obesity and type 2 DM. Furthermore in the Kumar et al.[39] study, a WTR value of 2.3 was found to identify 98.7% of the true negatives (degree of specificity) and this WTR value of 2.3 was proposed to be used as the cut-off point for obesity diagnosis and better predictor of increased risk for type 2 DM.[39] However, there is need to carry out a much larger and varied sample research in order to develop a more robust and stable standard reference range that would make this measurement more reliable across age- and sex-match groups in addition to well define separate criteria for males and females.[39]

  Nonpharmacological Therapy for Obesity Top

Prevention is an important part of dealing with any disease including obesity. Nonpharmacological approach to the prevention and treatment of obesity includes considerable lifestyle changes such as adequate physical exercise, smoking cessation, limiting alcohol intake, avoiding sedentary lifestyles, intensive behavioral counseling (psychotherapy), proper nutritional (dietary) programs, and bariatric surgery. Dietary programs may produce weight loss over the short term,[14],[16] but maintaining this weight loss is frequently difficult and often requires making exercise and a lower food energy diet, a permanent part of affected person's lifestyle. In the short term, low carbohydrate diets appear better than low-fat diets for weight loss;[11] however, in the long term, all types of low-carbohydrate and low-fat diets appear to be equally beneficial and effective.[12],[17],[18],[19],[20] Promotion of the Mediterranean diets among the obese may lower the risk of cardiovascular diseases. Furthermore, intensive behavioral counseling is recommended in those who are both obese and have other significant risk factors for severe cardiovascular disorders.[15],[20],[21] [Table 1] shows the recommended components of a high-intensity comprehensive lifestyle intervention to achieve and maintain a 5%–10% reduction in body weight within a year of commencing treatment.
Table 1: Recommended components of a high-intensity comprehensive lifestyle intervention to achieve and maintain a 5%–10% reduction in body weight within a year of commencing treatment.

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Bariatric surgery is the most effective treatment for obesity when the other forms of intervention have failed to produce a clinically significant weight loss in individuals with a BMI of ≥35 kg/m 2. The types of procedures include laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and biliopancreatic diversion.[4] Surgery for severe obesity is associated with long-term weight loss, improvement in obesity-related conditions,[5],[6],[10],[11],[16],[21] and decreased overall mortality. One study found a weight loss of between 14% and 25% (depending on the type of procedure performed) at 10 years and a 29% reduction in all causes of mortality when compared to standard weight loss measures.[7] Complications occur in about 17% of cases and reoperation is needed in 7% of cases.[8],[10],[11],[12],[17],[18] Due to its high cost and risks, researchers are searching for other effective, yet less invasive treatments including devices that can occupy space in the stomach.[9],[19]

  Current Pharmacological Therapy for Obesity Top

Pharmacological therapy is indicated for obese persons (BMI ≥30 kg/m 2) or overweight individuals with a BMI ≥27 kg/m 2 with associated complicating risk factors, such as DM, hypertension, hyperlipidemia, sleep apnea, and/or symptomatic osteoarthritis.[38] Potentially serious side effects limit its use to short term duration although chronic therapy is indicated in resistant cases and where the benefit outweighs the risk. To date, no clinical trials on any anti-obesity drugs have been conducted for longer than 4 years. Patients should be extensively counseled before initiating drug treatment and the unrealistic expectations explained. During the 1st month, weight loss should exceed 2 kg and thereafter 5% within the next 3–6 months. Pharmacotherapy is considered to be effective if a patient achieves a weight loss of 10%–15% in combination with lifestyle modifications in a period of 1–2 years.[40] To maintain the achieved weight loss, patients should furthermore reduce their energy intake by at least 8 kcal/kg (34 kJ/kg).[41] For a pharmacotherapeutic substance to be regarded as an anti-obesity drug, it has to demonstrate a reduction of at least 5%–10% in the baseline body weight within a year of commencing treatment. Pharmacotherapeutic agents used to treat obesity include sympathomimetic appetite suppressant drugs, pancreatic lipase inhibitors, antidiabetic drugs, serotonin 5-HT2C agonists, anticonvulsant drugs, atypical antidepressants, hormones, selective β3 adrenoceptor agonists, and various combination preparations. The choice of agent should be individualized and dictated by patient comorbidities, relative contraindications, available clinical trial evidence, and clinical expertise. In addition to pharmacological therapy, all anti-obesity drugs should be prescribed with the premise of dietary caloric restriction and exercise. [Table 2] shows the pharmacotherapeutic agents currently approved for the treatment of obesity. [Figure 2] reveals the weight loss at 1 year with high-intensity lifestyle interventions or pharmacotherapy combined with low-to-moderate-intensity lifestyle counseling. Finally, [Figure 3] describes briefly the mechanisms of action and common adverse effects for the anti-obesity agents approved for clinical use.
Table 2: Pharmacotherapeutic agents currently approved for the treatment of obesity

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Figure 2: Weight loss at 1 year with High-Intensity Lifestyle Inventions or Pharmacotheraphy combined with Low to-Moderate-Intensity Lifestyle Counseling. Shown are the percentages of participants in randomized, controlled trials who had weight loss of at least 5% or at least 10% of their initial weight at 1 year after a high-intensity lifestyle intervention or pharmacotheraphy that typically was combined with low-to-moderate-intensity lifestyle counseling (≤1 session per month). Percentages shown are cumulative; the percentage of the participants who lost at least 5% of their initial weight includes the percentage who lost at least 10%. For example, 68% of participants in the Look AHEAD study lost at least 5% of their initial weight and 37% of the participants lost at least 10%. The lifestyle intervention trials (Look AHEAD,[22] the Diabetes Prevention Program trial,[24] and the trial reported by Teixeria et al.[62]) were selected because they were judged to be of fair or good quality by the Guidelines (2013) for the Management of Overweight and Obesity in Adults[56] and because the trial data are reported as categorical weight losses. Additional categorical weight-loss data from the Diabetes Prevention Program trial[24] were provided by the Diabetes Prevention Program Research Group. The median percentages of participants who had a weight loss of at least 5% or 10% with each of five medications approved for long-term weight management are form a meta-analysis by Khera et al.[63] Data on the percentage of participants with weight loss at 1 year of at least 15% of their initial weight were available for the Look AHEAD study[22],[23] (16%), the Diabetes Prevention Program trial[24] (11%), liraglutide[64] (14%), Phentermine-topiramate[65] (32%), and naltrexone-bupropion[66] (14%)

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Figure 3: Describing briefly the mechanisms of action and common adverse effects for the anti-obesity agents approved for clinical use

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Sympathomimetic appetite suppressant agents

All of the currently available sympathomimetic appetite suppressants are β-phenylamine derivatives, which are structurally related to noradrenaline, dopamine, or amphetamine. They increase the synaptic concentrations of noradrenaline and dopamine by:

  1. Displacing these transmitters from their storage vesicles (amphetamine)
  2. Stimulating the release and inhibiting reuptake into presynaptic vesicles (phentermine, diethylpropion, phendimetrazine, d-norpseudoephedrine, and sibutramine)
  3. Directly agonizing adrenergic receptors (phenylpropanolamine). Appetite is resultantly suppressed by the stimulation of the hypothalamic satiety center in the brain.[42] Sympathomimetic drugs therefore reduce food intake by causing early satiety. All of these drugs have a rapid onset of action but relatively short half-lives. They have been associated with numerous systemic side effects including hypertension, palpitations, insomnia, cardiovascular toxicity and valvular heart disease, stroke, depression, and high potential for abuse. This has made them highly scheduled substances, with some being discontinued worldwide (sibutramine and phenylpropanolamine).[43] It is generally accepted that these agents should not be used for a period exceeding 12 weeks. Calculating or predicting a dose–response relationship is difficult, and the initial degree of obesity has a considerable effect on the rate of absolute weight loss. Clinical data sheet reviews for the periods of 12 weeks have shown the following average weight loss per substance: phendimetrazine 140 mg (3.6 kg),[44] phentermine 30 mg (8.1 kg),[45] and diethylpropion 75 mg (7.2 kg).[46]

Pancreatic lipase inhibitors

The pancreatic lipase is a digestive enzyme secreted into the lumen of the small intestine (duodenum) by the exocrine pancreatic acinar cells. It is responsible for breaking down triglycerides into monoglycerides and absorbable free fatty acids.[47] When pancreatic lipase activity is blocked, triglycerides are excreted undigested, thereby reducing fat absorption from the diet and reduction in caloric intake. Achieved weight loss with orlistat is dose dependent. A maximum dose of 120 mg three times per day reduces intestinal fat absorption by almost 30% after which a peak effect is reached.[13] The ordinary expected weight loss in 12 weeks is 4% of the initial body weight but could increase to >10% if treatment is continued beyond 6 months.[48] Orlistat is a preferred option for obese patients with diabetes, dyslipidemia, and hypertension, considering its efficacy and favorable safety profile. Adverse gastrointestinal side effects are frequent, whereby 15%–30% of patients will experience gastroesophageal reflux disease, flatus, fecal incontinence, frequent bowel movements, and steatorrhea.[49] Drug interactions with orlistat are uncommon, except with cyclosporine, but it may inhibit the absorption of fat-soluble drugs and fat-soluble Vitamins A, D, E, and K.

Antidiabetic drugs

Antidiabetic drugs commonly used to achieve weight loss include biguanides (such as metformin) and GLP-1 receptor agonists (such as liraglutide, albiglutide, dulaglutide, and semaglutide). Although the precise mechanisms of action for these agents in weight reduction are not fully understood, several hypotheses have been proposed.


Metformin is a biguanide antidiabetic agent that has been found to possess anti-obesity effect in addition to its euglycemic action. NPY is a neurotransmitter present in the sympathoadrenomedullary nervous system. The NPY pathway is stimulated by exercise, fasting, and energy loss, which results in suppression of sympathetic activity and increased appetite.[50] Recent studies suggest that unlike its anti-diabetogenic effects, metformin's anorectic properties are unrelated to its peripheral suppression of hepatic gluconeogenesis, increased insulin sensitivity, or enhanced peripheral glucose uptake, but that a central mechanism is responsible. In similarity to leptin, metformin inhibits NPY expression, thereby reducing food intake and decreasing body weight.[51] Metformin is not primarily indicated as a weight loss drug, seeing that it does not achieve the required reduction of 5% or more loss in baseline weight. It is nonetheless useful in overweight individuals with elevated insulin levels at risk for type 2 diabetes. A customary weight loss of approximately 3 kg in 8 weeks can be expected on a dose of 1000 mg per day.[52] If adherence to treatment is continued, metformin can sustain weight loss for at least 10 years. Side effects are uncommon and mainly include gastrointestinal upset (4%), which usually resolves spontaneously. Patients with renal or hepatic insufficiency are at risk for developing lactic acidosis, and it is therefore relatively contraindicated in these individuals.

Glucagon-like peptide-1 receptor agonists

GLP-1 is an incretin hormone which is secreted by the ileal L-cells in the presence of nutrients in the lumen of the small intestines. It stimulates the release of insulin from the pancreatic beta islet cells and inhibits glucagon release from the alpha islet cells, thereby causing a decrease in blood glucose levels. In addition, it reduces the rate of gastric emptying, thereby slowing the rate of nutrient absorption and reducing food intake.[53] Liraglutide, albiglutide, dulaglutide, and semaglutide are the agonists at GLP-1 receptors used to diminish weight in obese diabetic and nondiabetic patients. The mean weight loss on daily subcutaneous dosages of liraglutide between 1.2 mg and 3 mg during a 20-week period ranges from 4.8 to 7.2 kg.[54] Nausea and vomiting is the most common side effect (45%) and is experienced by about 5% of patients. Other adverse effects include hypoglycemia, diarrhea, constipation, headache, fatigue, dizziness, abdominal pain, and increased lipase levels. Treatment should not exceed 12 months as there is an increased risk for developing pancreatitis. These drugs are contraindicated during pregnancy, gallbladder disease, and thyroid abnormalities.

Serotonin 5-HT2c receptor agonists

Pro-opiomelanocorticotropin (POMC) is a protein present in the CNS. It is cleaved into several smaller peptides, each controlling important metabolic and physiological functions in the brain. One of these peptides, β-melanocyte-stimulating hormone, interacts with the melanocortin-4 receptor in the hypothalamus, which regulates the balance between energy from food taken into the body and energy spent by the body. Eating and weight are thus maintained through this mechanism.[55] Stimulation of 5-HT2C receptors in the hypothalamus enhances pro-opiomelanocorticotropin production, resulting in weight loss through satiety.[56] Lorcaserin is a selective serotonin 5-HT2c receptor agonist, which is available in the United States (but not approved in the European Union) for the treatment of obesity with comorbid conditions. Its efficacy is comparable to orlistat, with an average weight loss of 3.6 kg in 12 weeks on a dose of 20 mg/day.[57] Side effects are dose dependent and include headache (18%), nausea, dizziness, fatigue, dry mouth, and constipation.[22] There is also increased risk of valvular heart disease with lorcaserin. It should not be taken by patients with renal/hepatic dysfunction or those on serotonergic agents such as SSRI or TCA or SNRI or unselective MAOI due to the risk of developing serotonin syndrome.

Anticonvulsant drugs

Topiramate's mechanism of action as an anticonvulsant involves the enhancement of gamma-aminobutyric acid and modification of the excitatory voltage-gated activated sodium and calcium channels in the brain. Its mechanism as an anti-obesity drug is not fully known, but studies indicate that it may increase the brain noradrenaline/dopamine expression. Enhanced noradrenaline/dopamine in the CNS resultantly suppresses appetite.[23] Average weight loss on a dose between 96 and 200 mg/day for 28 weeks is approximately 6.5 kg.[24] The most common side effects include paresthesia, psychomotor disturbances, memory impairment, diarrhea, and changes in vision. Topiramate is not recommended as a single use agent in the management of obesity.

Atypical antidepressants

Bupropion is a dopamine and noradrenaline reuptake inhibitor. Its mechanism is similar to other sympathomimetic agents and is structurally related to diethylpropion. The additional effect of raising the dopamine concentration in the brain's reward/pleasure center (nucleus accumbens and ventral tegmental area) makes it useful in treating depression, sexual dysfunction, smoking cessation, substance of abuse-dependent disorders, attention-deficit hyperactive disorder, and suppression of appetite. Published literature reports an average weight loss of 4.4 kg in 6 months on a daily dose of 300 mg.[25] Bupropion is ordinarily well tolerated with few side effects but may cause agitation, headache, nausea, sweating, and abdominal discomfort in rare instances.

Hormonal agents

Various hormones acting on the hypothalamus play a role in appetite and energy metabolism homeostasis, some of which have been previously mentioned. One of such hormones is leptin. It is secreted by the adipose tissue, gastric epithelium, and placenta. Hypothalamic stimulation by leptin suppresses appetite and increases thermogenesis and metabolic rate in the long term.[26] Obese individuals typically have high plasma leptin levels but display insensitivity and resistance toward its hypothalamic stimulation. Early research done recommended the injection of 125 iU human α-chorionic gonadotropin (hCG) daily to restore hypothalamic–leptin sensitivity. The weight loss achieved by this method in combination with a calorie-restricted diet was between 9 and 14 kg in 6 weeks.[27] This observation has been refuted by many researchers, yet the act of injecting hCG is still widely practiced. Similarly, the administration of exogenous thyroxin in euthyroid obese patients is considered inappropriate since the weight loss achieved is the result of a loss in lean muscle mass and not adipose tissue. Congenital leptin deficiency is treated with recombinant human leptin (metreleptin).[28],[29]

Selective β3-adrenergic receptor agonists – mirabegron and solabegron

The β3-adrenoceptors are found in the gallbladder, urinary bladder, and brown adipose tissue (BAT). Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat. In the urinary bladder, it is thought to cause relaxation of the bladder and prevention of urination.

The β3-adrenergic receptor (ADRB3) belongs to the Gs protein-coupled receptor superfamily that activates adenylyl cyclase with subsequent increase in the production of cAMP. It plays an important role in energy metabolism, which includes enhancing lipolysis, mobilization of free fatty acids into the circulation in white adipose tissue (WAT), and thermogenesis in BAT. ADRB3 is a potential target for anti-obesity and antidiabetes therapy. Some β3-agonists have also demonstrated anti-stress effects in experimental animal model studies, suggesting that it also has a role in the CNS. BAT in humans is an exquisitely designed tissue/organ system evolved for the maintenance of body temperature. It is characterized by smaller cells with large amounts of mitochondria and small-lipid droplets providing a potential for high cellular metabolism. At the metabolic, protein, and transcription levels, the BAT is upregulated principally by the sympathetic nervous system when production of heat is needed to maintain body temperature. The mechanism for heat production was based on a specific highly abundant protein (uncoupling protein 1 [thermogenin] [Ucp1]) in the inner mitochondria of the brown adipocytes, which uncouples the production of chemical energy as adenosine triphosphate (ATP) from oxidative phosphorylation and instead produces heat. Although the normal function of brown fat thermogenesis may be specific for the regulation of body temperature, many genetic and pharmacologic studies in the experimental model rodents have shown that constitutive overexpression of Ucp1 in the white fat and skeletal muscle can drastically reduce both genetic and diet-induced obesity, offering therefore a new safe molecular target for the treatment of obesity. This potential for brown fat adaptive thermogenesis as a drug target for obesity has been thoroughly explored by the pharmaceutical industry. Mirabegron and solabegron are selective agonists for the ADRB3.

Mirabegron is a drug for the treatment of overactive bladder. It was developed by Astellas Pharma and was approved in the United States in July 2012. Mirabegron activates the ADRB3 in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Its primary Food and Drug Administration approval use and indication is in the treatment of overactive bladder but has recently been found to be also effective for treating obesity and type 2 DM. Mirabegron was recently shown to activate BAT and increase metabolism. In a small study of 15 healthy, lean men, mirabegron at a dose range between 50 and 100 mg was shown to significantly increase basal metabolic rate with clinically insignificant slight increase in the basal heart rate and blood pressure, which are the signs of cardiovascular stimulation. Recently, mirabegron was also shown to relax in vitro human and rabbit prostatic smooth muscle through activation of β3 adrenoceptor and blockade of α1 adrenergic receptor. The same group also showed that mirabegron promotes smooth muscle relaxation by α1 adrenergic receptor blockade.

Solabegron (code name GW-427,353) is a new drug which acts as a selective agonist for the ADRB3. It is a novel agent being developed for the treatment of overactive bladder, irritable bowel syndrome, obesity, and type 2 DM. It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes. Currently, solabegron is still in clinical trial (phase-II studies recently completed) for these above-mentioned indications.[58],[59],[60]

Combination preparations

As a result of the complex regulation of food intake and the multitude of mechanisms and pathways involved in energy homeostasis, it is suggested that combining two drugs with different mechanisms of action could improve efficacy and tolerability and enhance pharmacodynamics synergism and the need for lower doses of individual drugs.

Combination preparation of phentermine (immediate release) and topiramate (extended release) capsules are only currently available in the USA. This combination should not be used in patients with cardiovascular diseases such as hypertension, diabetes, or dyslipidemia, rendering it an inappropriate choice for the majority of obese patients. It carries a risk of increased congenital malformations, especially orofacial clefts when taken during the first trimester of pregnancy. It is considered as the second-line therapy for obese postmenopausal women or men without complicating risk factors not responding or unable to tolerate orlistat or lorcaserin. This formulation, however, appears to produce the target mean weight loss (>10%) after years of treatment.[28]

Naltrexone and bupropion sustained-release formation has been available in Europe since 2012 and the USA since 2014. Both drugs have anorectic properties, and their combination proves favorable in the reduction of visceral fat. The propose mechanism involves the increase firing rate of POMC neurons, leading to appetite suppression.[29] This combination shows an increased risk of suicidal thoughts and behavior, may precipitate seizures, and shows adverse cardiovascular events in patients with epilepsy and uncontrolled hypertension. Expected weight loss is roughly 9 kg during a 24-week period.

  Prospective Future Research Directions Concerning the Pharmacotherapy of Obesity Top

Cannabinoid-1 receptor antagonist/Inverse agonist

The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the Gi/o protein-coupled family receptors.[30],[31] The terminal presynaptic CB1 autoreceptor (mediating presynaptic inhibition) plays an important role in the regulation of appetitive behavior and energy metabolism both centrally and peripherally.[32],[33],[34],[35] Exogenously administered CB1 receptor agonists such as delta-9-THC stimulate food consumption in animals and humans. Endogenous CB1 receptor agonists such as anandamide are present in the brain, and the brain level of anandamide increases with greater demand of food.[36],[37] Specific CB1 receptor antagonist compounds have been discovered which display high affinity and selectivity for the CB1 receptor. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food.[61],[62],[63],[64] At CNS level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to the modulation of release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell.[65],[66] Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism.[67] Experimental models have provided that solid evidence that genetically induced obesity leads to a long-lasting overstimulation of the endocannabinoid system, resulting in permanent overactivation of CB1 receptors, which may then contribute to the maintenance of this disease.[68],[69] Importantly, at the peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 receptor blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance.[69],[70],[71],[72] Moreover, CB1 has been shown to be upregulated in adipocytes derived from obese experimental models. These results support the role of endocannabinoids in the development and maintenance of obesity.[68] The CB1 receptor antagonist rimonabant (SR-141716) was an anorectic anti-obesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious and severe psychiatric adverse effects, including anxiety, depressive disorders, or mood alterations in up to 10% of subjects and suicidal ideation in around 1%. It was never approved in the United States.[71],[72],[73],[74] Rimonabant is a selective antagonist (inverse agonist) for the cannabinoid receptor CB1 and was the first drug to be approved in that class. Rimonabant inhibits both acute and long-term food intake in experimental models. Chronic treatment with CB1 receptor antagonists results in a sustained reduction in body weight in rodents (at 5 weeks)[69],[74] and weight loss in humans (at 16 weeks).[74] This means that the pharmacodynamics action of CB1 receptor is of important therapeutic relevance: as cannabinoid receptor CB1 agonists are currently used to alleviate anorexia and nausea/vomiting in AIDS and cancer patients, while the cannabinoid receptor CB1 antagonist – rimonabant (SR-141716) – was found to be effective in the treatment of obesity as it decreases appetite and body weight in humans.[23],[29]

Due to the serious and severe psychiatric adverse effects associated with the unrestricted CB1 receptor antagonists such as rimonabant, a number of initiatives have been published to develop CB1 antagonists that target only peripheral CB1 receptors by restricting their ability to cross the blood–brain barrier.[26],[71],[72],[73],[74] Among these initiatives, 7TM Pharmaceutical Company has reported the recent development of TM38837 compound. This compound is now being pursued as a peripherally restricted CB1 receptor blocker for the treatment of obesity.[73],[74]

The CB2 receptors are found predominantly in the peripheral tissues and cells of the immune system, such as the spleen, tonsil, payers' patches, monocytes, macrophages, B-cells, and T-cells, and also found throughout the gastrointestinal system where they modulate and inhibit intestinal pro-inflammatory response when activated by endogenous CB2 receptor agonist, such as 2-arachidonyl glycerol (2-AG). This made CB2 receptors a potential target in the pharmacotherapy of inflammatory bowel diseases.[13],[68],[69],[70],[71],[72]

  Other Novel Therapeutic Targets in Human Brown Adipose Tissue Top

The natriuretic peptides also stimulate the expansion and activation of human BAT. Natriuretic peptides are released during exercise, activate adipocyte lipolysis and therefore fat oxidation, and when infused into humans increase thermogenesis. This combined with the newly discovered capacity for BAT activation and interaction with the β3(beta-3) adrenoceptor, natriuretic peptides, therefore, provides an attractive target for reversing metabolic disturbances of obesity. Furthermore, the neuropeptide orexin-A has been shown in mice to expand and activate BAT and is necessary for BAT development. Irisin, metorin, and fibroblast growth factor-21 (FGF-21) are other key peptides in the regulation of BAT mass and activity, the latter in a paracrine and endocrine fashion involving the sympathetic nervous system. Together, these results raise the intriguing possibility that BAT might be activated pharmacologically through nonadrenergic peptides such as orexin-A, irisin, metorin, FGF-21, and the natriuretic peptides.

Another important active line of research showed that the effects of genetic, pharmaceutical or cold-induced upregulation of uncoupling protein 1 [Ucp1; thermogenin] in the mouse models result in the emergence of new brown adipocytes in white fat depots with levels of Ucp1 upregulated up to several hundred folds. But unfortunately, human white adipose tissue (WAT) does not appear to be able to mount such transient induction of brown adipocytes, at least not in subcutaneous adipose tissue. The failure of brown fat thermogenesis in humans appears to be based upon the lack of fundamental information on the mechanisms controlling the developmental origins of brown adipocytes in the discrete brown fat depots (e.g., interscapular brown fat) and in the small number of diffusely localized brown adipocytes in various white fat depots. PR domain containing 16 (PRDM16), is a protein which in humans is encoded by the PRDM16 gene. PRDM16 acts as a transcription coregulator that controls the development of brown adipocytes in brown adipose tissue. Previously, this coregulator was believed to be present only in brown adipose tissue, but more recent studies have shown that PRDM16 is highly expressed in subcutaneous white adipose tissue as well. The PRDM16 protein is a zinc finger transcription factor that controls the cell fate between muscle and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. However, the transcription factor PRDM16, whose presence can promote the differentiation of preadipocytes and myoblasts into brown adipocytes and whose absence promotes the myogenic differentiation program, plays a key role in the development of BAT. Importantly, the ability of PRDM16 to induce the brown adipocyte lineage is restricted to the discrete brown fat depots such as those found in the interscapular and supraclavicular region, but it does not participate in the induction of the diffuse brown adipocytes located in the white fat depots. The data support the concept that interscapular BAT and brown adipocytes in white fat have separate independent developmental origins. PRDM16 is clearly an important player in brown adipogenesis but may not be sufficient, since PRDM16 Knock Out mice have significant levels of interscapular fat with Ucp1 expression. Diffuse BAT adipogenesis is more closely related to increased thermogenesis and with reduced obesity. Enthusiasm for the promise of PRDM16 as a drug target needs to be tempered by the caveat that mice with an inactivated PRDM16 gene die at birth, suggesting that PRDM16 is a transcription factor with additional unknown functions in mammalian development. Researches to know whether the upregulation of PRDM16 in humans can induce increased discrete BAT and/or diffuse brown adipocytes are currently on-going. While the regulator PRDM16 has provided important insights into the developmental origins of discrete brown fat depots, the next important step will be to determine the origin(s) of diffusely localized brown adipocytes in white fat depots.

Brown adipose tissue (BAT) oxidizes chemical energy to produce heat energy. This heat energy can act as a defense against hypothermia and obesity. PRDM16 is highly enriched in brown adipose cells as compared to white adipose cells, and plays a role in these thermogenic processes in brown adipose tissue. PRDM16 activates brown fat cell identity and can control the determination of brown adipose fate. A knock-out of PRDM16 in experimental mice model shows a loss of brown cell characteristics, showing that PRDM16 activity is important in determining brown adipose fate. Brown adipocytes consist of densely packed mitochondria that contain thermogenin (uncoupling protein 1 [UCP-1]). UCP-1 plays a key role in brown adipocyte thermogenesis. The presence of PRDM16 in adipose tissue causes a significant up-regulation of thermogenic genes, such as UCP-1 gene and CIDEA gene (that produces the cell death activator CIDE-A protein involved in the activation of apoptosis), resulting in thermogenic heat production. This activation of apoptosis by cell death activator CIDE-A protein is inhibited by the DNA fragmentation factor DFF45 but not by caspase inhibitors. Mice that lack functional CIDEA have higher metabolic rates, higher lipolysis in brown adipose tissue and higher core body temperatures when subjected to cold. These mice are also resistant to diet-induced obesity and diabetes. This suggests that in mice this gene product plays a role in thermogenesis and lipolysis. Understanding and stimulating the thermogenic processes in brown adipocytes provides possible therapeutic options for treating obesity.

Furthermore, white adipose tissue (WAT) primarily stores excess energy in the form of triglycerides. Recent research has shown that PRDM16 is present in subcutaneous white adipose tissue. The activity of PRDM16 in white adipose tissue leads to the production of brown fat-like adipocytes within white adipose tissue, called beige cells (also called brite cells). These beige cells have a brown adipose tissue-like phenotype and actions, including thermogenic processes seen in BAT. In experimental mice model, the levels of PRDM16 within WAT, specifically anterior subcutaneous WAT and inguinal subcutaneous WAT, is about 50% that of interscapular BAT, both in protein expression and in mRNA quantity. This expression takes place primarily within mature adipocytes. Transgenic aP2-PRDM16 experimental mice model were used in a study to observe the effects of PRDM16 expression in WAT. The study found that the presence of PRDM16 in subcutaneous WAT leads to a significant up-regulation of brown-fat selective genes UCP-1, CIDEA, and PPARGC1A. This up-regulation lead to the development of a BAT-like phenotype within the white adipose tissue. Expression of PRDM16 has also been shown to protect against high-fat diet induced weight gain. Seale et al experiment with aP2-PRDM16 transgenic mice and wild type mice showed that transgenic mice eating a 60% high-fat diet had significantly less weight gain than wild type mice on the same diet. Seale et al showed that the weight difference was not due to differences in food intake, as both transgenic and wild type mice were consuming the same amount of food on a daily basis. Rather, the weight difference stemmed from higher energy expenditure in the transgenic mice. Another of Seale et al.'s experiments showed that the transgenic mice consumed a greater volume of oxygen over a 72-hour period than the wild type mice, showing a greater amount of energy expenditure in the transgenic mice. This energy expenditure in turn is attributed to PRDM16 ability to up-regulate UCP-1, CIDEA and PPARGC1A genes expression, resulting in thermogenesis. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene (also known as human accelerated region 20 [HAR20]). PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism and is the master regulator of mitochondrial biogenesis. This protein interacts with the nuclear receptor PPAR-γ, which permits the interaction of this protein with multiple transcription factors and regulate the activities of cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs). If human WAT expresses PRDM16 as in mice, this WAT could be a potential target for stimulating energy expenditure and combating obesity. Since the re-emergence of BAT as a potential player in the regulation of energy homeostasis, there has been a lingering question regarding the absolute effects in terms of calories that can be burned by the small amount of BAT in humans. Recent studies using chronic cold to activate BAT, analogous to using physical exercise to train muscle, showed that BAT can be expanded and activated in vivo in humans. The overall thermogenic capacity appears to be between 100-300 kcal/day. The discovery of previously uncovered BAT in adult humans and its potential physiologic significance in cold- and dietary-induced thermogenesis should revamp our effort to target the molecular development of brown adipogenesis in the treatment of obesity.[58],[59],[60]

  Conclusion Top

The incidence and prevalence of obesity are on the increase worldwide. The cost burden and negative impacts on the healthcare system are tremendously alarming. Clinically significant weight loss attenuates the risk of cardiovascular disease morbidity and mortality. Prevention is an important part of dealing with any disease including obesity. Nonpharmacological approach to the prevention and treatment of obesity includes considerable lifestyle changes such as adequate physical exercise, smoking cessation, limiting alcohol intake, avoiding sedentary lifestyles, intensive behavioral counseling (psychotherapy), proper nutritional (dietary) programs, and bariatric surgery. For a pharmacotherapeutic substance to be regarded as an anti-obesity drug, it has to demonstrate a reduction of at least 5%–10% in the baseline body weight within a year of commencing treatment. Pharmacotherapeutic agents currently used to treat obesity include sympathomimetic appetite suppressant drugs, pancreatic lipase inhibitors, antidiabetic drugs, serotonin 5-HT2C agonists, anticonvulsant drugs, atypical antidepressants, hormones, selective β3 adrenoceptor agonists, and various combination preparations. The choice of agent should be individualized and dictated by patient comorbidities, relative contraindications, available clinical trial evidence, and clinical expertise. In addition to pharmacological therapy, all anti-obesity drugs should be prescribed with the premise of dietary caloric restriction and exercise. Bariatric surgery is the most effective treatment for obesity when the other forms of intervention have failed to produce a clinically significant weight loss in individuals with a BMI of ≥35 kg/m 2. Finally, concerning the prospective future research directions on the pharmacotherapy of obesity, a number of initiatives have been put forward to develop a peripherally restricted CB1 receptor antagonist (such as TM38837 compound) that target only the peripheral CB1 receptors by restricting their ability to cross the blood–brain barrier in order to avoid the serious and severe psychiatric adverse effects found to be associated with the unrestricted CB1 receptor antagonists such as rimonabant.

  What This Review? Top

  • Nonpharmacological approach to the prevention and treatment of obesity includes considerable lifestyle changes such as adequate physical exercise, smoking cessation, limiting alcohol intake, avoiding sedentary lifestyles, intensive behavioral counseling (psychotherapy), proper nutritional (dietary) programs, and bariatric surgery
  • Bariatric surgery is the most effective treatment for obesity when the other forms of intervention have failed to produce a clinically significant weight loss in individuals with a BMI of ≥35 kg/m 2
  • For a pharmacotherapeutic substance to be regarded as an anti-obesity drug, it has to demonstrate a reduction of at least 5%–10% in the baseline body weight within a year of commencing treatment. All anti-obesity drugs should be prescribed with the premise of dietary caloric restriction and exercise
  • Pharmacotherapeutic agents currently used to treat obesity include sympathomimetic appetite suppressant drugs, pancreatic lipase inhibitors, antidiabetic drugs, serotonin 5-HT2C agonists, anticonvulsant drugs, atypical antidepressants, hormones, selective β3-adrenoceptor agonists, and various combination preparations. The choice of anti-obesity agent(s) should be individualized and dictated by patient comorbidities, relative contraindications, available clinical trial evidence, and most importantly clinical expertise
  • Concerning the prospective future research directions on the pharmacotherapy of obesity, a number of initiatives have been put forward to develop a peripherally restricted CB1 receptor antagonist (such as TM38837 compound) that target only the peripheral CB1 receptors by restricting their ability to cross the blood–brain barrier in order to avoid the serious and severe psychiatric adverse effects found to be associated with the unrestricted CB1 receptor antagonists such as rimonabant
  • Finally, nonadrenergic peptides such as orexin-A, irisin, metorin, FGF-21, natriuretic peptides, and transcription factor PRDM16 are currently important novel targets in the pharmacotherapy of obesity.

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