Pharma Tips

Pharmaceutical Obesity

By: Pharma Tips | Views: 1714 | Date: 01-Jul-2010

Obesity is the most common and rapidly growing nutritional problem in Westernized countries. By dramatically raising mortality and the risk of morbidity from hypertension, dyslipidemia, diabetes mellitus, and cardiovascular diseases, this condition has become one of the major public health concerns for the 21st century.

Pharmaceutical Obesity

Pharmaceutical Obesity

1. INTRODUCTION
Obesity is the most common and rapidly growing nutritional problem in Westernized countries. By dramatically raising mortality and the risk of morbidity from hypertension, dyslipidemia, diabetes mellitus, and cardiovascular diseases, this condition has become one of the major public health concerns for the 21st century. Obesity is a complex multifactorial disease caused by the interaction of genetic and environmental factors. The potential implication of genetic factors in the development of human obesity is well demonstrated by the description of five monogenic forms of human obesity. The genes implicated in these forms of obesity encode proteins of the leptin axis and brain-expressed targets of leptin involved in the melanocortin pathway. They include leptin, the leptin receptor, proconvertase 1, pro-opiomelanocortin (POMC), and the melanocortin-4 receptor (MC4-R). Except for MC4-R, mutations in these genes cause rare, recessive, syndromic forms of obesity, associated with multiple endocrine abnormalities.
MC4-R is a 332-amino acid protein encoded by a single exon gene localized on chromosome 18q22. MC4-R belongs to the family of seven transmembrane G protein–coupled receptors (GPCR) and signals through activation of adenylate cyclase. MC4-R MC4-R belongs to the family of seven transmembrane G protein–coupled receptors (GPCR) and signals through activation of adenylate cyclase MC4-R belongs to the family of seven transmembrane G protein–coupled receptors (GPCR) and signals through activation of adenylate cyclase belongs to the family of seven transmembrane G protein–coupled receptors (GPCR) and signals through activation of adenylate cyclase MC4-R belongs to the family of seven transmembrane G protein–coupled receptors (GPCR) and signals through activation of adenylate cyclase The importance of MC4-R in body-weight regulation is clearly demonstrated by the obese phenotype of the homozygous MC4-R–deficient mice. Heterozygous MC4-R+/– mice present an intermediate average increase in weight, females being more severely affected than males.
We have reported a case of human obesity associated with a frameshift mutation in MC4-R. This case differed from the previously described monogenic forms of obesity by a dominant transmission of the morbidly obese phenotype and by the absence of associated endocrine symptoms. The description of a similar case and the report of several MC4-R missense and nonsense mutations in 1% of two cohorts of extremely obese children and adults suggest that such mutations could be a more frequent cause of obesity than the syndromic forms due to the other genes. Limited information on the function of most of the missense mutations as well as incomplete phenotypic characterization of the patients and their families have not yet allowed a case to be built for the overall importance of MC4-R mutations in human obesity.1

1.1 PHARMACOLOGY
The melanocortin-4 receptor (MC4R) as a molecular target for both  indications because it plays an important role in the regulation of appetite and autonomic function (for  details see Figure 1). Our pharmacological approach consisted in the generation and characterization of  functionally active antibodies against extracellular sequences of the MC4R. Our initial studies in rats  evealed an obese phenotype after immunization against the N-terminal domain of the MC4R. These experiments are described in more detail in our previous biennial report and have been published in 2007. In subsequent experiments we attempted to generate monoclonal anti-MC4R antibodies since such molecules can be produced in unlimited amounts. Immunization of mice against the N-terminal domain resulted in a monoclonal antibody which blocked the activity of the MC4R. In further in vitro studies it was characterised as an inverse agonist with non-competitive antagonistic activity. A priority claim has been filed in collaboration with the Technology Transfer Unit of the University of Basel. The monoclonal antibody is currently being produced in larger amounts for acute and chronic studies on its blood-brain penetration after peripheral administration. Thereafter it will be used as a pharmacological tool to explore the therapeutic potential of MC4R blockade in various disease models. A simple model for cachexia-induced anorexia, i.e. the loss of appetite in association with inflammatory diseases, has been established and validated in our laboratory. It consists of the continuous monitoring of food intake in rats after the acute administration of lipopolysaccharide Our immunization studies on the MC4R in rats are being complemented with several series of immunizations against extracellular sequences of the MC3R. These experiments were initiated because presynaptic MC3Rs appears to modulate the release of the MC4R agonist alpha-melanocyte stimulating hormone (alpha-MSH) from nerve terminals. However, the precise function of the MC3R is not known because of the lack of suitable experimental tools. Based on preliminary results with two antigens from the first and the third extracellular loop a long-term immunization study has been started in rats which are chronically instrumented with telemetry transmitters. This makes it possible to monitor not only endocrine and metabolic parameters but also blood pressure, heart rate, body temperature and locomotor activity. Our observation that immunization against the MC4R resulted in an obese phenotype in rats prompted us to explore whether comparable findings can be obtained in obese patients. We therefore initiated a clinical study in collaboration with the University Clinic in Strasbourg, France, and the communal hospital in Baden-Baden, Germany. These institutions provided more than 200 plasma samples from patients with a wide range of body mass indices (BMI). The plasma samples were screened in our laboratory with an ELISA assay using the N-terminal peptide sequence of the MC4R. Positive samples were further assessed by flow cytometry (FACS) and cAMP measurements in HEK293 cells which overexpressed the human MC4R. The presence of auto-antibodies against the MC4R in humans and the increased prevalence of such autoantibodies in patients with increased BMI would suggest that they might play a pathogenetic role in the development of obesity. By using such a test in the clinic a subgroup of obese patients with a common pathophysiology could be identified and possibly causally treated. Several options for further clinical studies are currently being explored and experimental studies on possible therapeutic approaches have been initiated in our group. Our studies on the role of brain derived neurotrophic factor (BDNF) as a downstream mediator of the MC4R have been completed and are subject of a recent publication. In this paper we reported for the first time that MC4R stimulation in isolated hypothalami in vitro induced a release of BDNF into the incubation medium. In experiments in vivo we have shown that BDNF and a MC4R agonist have comparable effects on food intake. Moreover, the effects of MC4R stimulation could be prevented by the prior administration of a selective anti-BDNF antibody. In an additional series of experiments in rats with telemetry transmitters we could demonstrate that BDNF and a MC4R agonist also showed comparable cardiovascular effects, i.e. both agents induced an increase in blood pressure and heart rate which was associated with a rise in body temperature. These effects of MC4R stimulation could also be prevented by the anti-BDNF antibody. Thus BDNF appears to mediate not only the anorectic but also the autonomic effects of MC4R stimulation. This project was performed in collaboration with Prof. Yves Barde who also supplied the monoclonal antibody against BDNF. Karl G. Hofbauer contributed to pharmacology teaching in the Medical Faculty and the Faculty for Natural Sciences at the University of Basel. He took on responsibility for the planning and coordination of pharmacology teaching for medical students in the new Bologna system up to the Bachelor level. He contributed to a newly established course for a Master of Advanced Studies in Pharmacology degree at the University of Basel. Karl G. Hofbauer gave also lectures on drug discovery and development at the University of Zuerich. Karl Hofbauer was involved in several continuing education activities including the co-organization of and the active contribution to the annual “Cardiovascular Pharmacology Seminar” in Luzern. Together with several clinical colleagues Karl G. Hofbauer continued to co-organize a lecture series at the University of Basel with focus on obesity, metabolism and nutrition (OMeN). Karl G. Hofbauer and members of his  group presented their findings at several national and international scientific meetings including an invited lecture at the Joint Meeting of the Swiss and Canadian Pharmacological Societies in Banff, Canada, in early 2007. In addition to original papers and book chapters two reviews from our group covered the recent developments in the field of anti-obesity drugs.

 Figure 1: In the upper panel a schematic illustration of the structure of the MC4R is given.

The activation of the MC4R mediates a decrease in food intake and an increase in energy expenditure. Thus MC4R agonists could be useful drugs for the treatment of obesity. However, the MC4R has not only effects on energy balance but also influences autonomic function. MC4R activation results for instance in an increase in blood pressure and heart rate. In order to generate agonists with a selective effect on energy balance it is essential to identify downstream mechanisms which may mediate the MC4R induced effects separately. BDNF appears to be such a downstream mechanism of the MC4R but it shows no selectivity for the metabolic and autonomic effects. The subsequent steps in the MC4R downstream pathway are still unknown.2-8

1.2. LOCATION
The melanocortin-4 receptor (MC4R) is expressed in the hypothalamus and regulates energy intake and body weight. In silico screening of the canine chromosome 1 sequence and a comparison with the porcine MC4R sequence by BLAST were performed. The nucleotide sequence of the whole coding region and 3′- and 5′-flanking regions of the dog (1214 bp) and red fox (1177 bp) MC4R gene was established and high conservation of the nucleotide sequences was revealed (99%). Five sets of PCR primers were designed and a search for polymorphism was performed by the SSCP technique in a group of 31 dogs representing nineteen breeds and 35 farm red foxes. Sequencing of DNA fragments, representing the identified SSCP patterns, revealed three single nucleotide polymorphisms (including a missense one) in dogs and four silent SNPs in red foxes. An average SNP frequency was approx. 1/400 bp in the dog and 1/300 bp in the red fox. We mapped the MC4R gene by FISH to the canine chromosome 1 (CFA1q1.1) and to the red fox chromosome 5 (VVU5p1.2). 
1.2.1.Chromosome Location9
Location-MC4R is located on chromosome 18q22
Position-chr18:56190562-56189564
 
Figure shows the location of MC4R in context on chromosome 18.

1.2.2.Protein Location
MC4R mRNA has been found in multiple sites in virtually every region of the brain. Its major expression sites are thought to be the cortex, thalamus, hypothalamus, brainstem and spinal cord.

 
Figure shows the predicted structure of the MC4R protein. This protein also has the synonym MC4-R

1.2.3.Melanocortin 4 receptor, also known as MC4R, is a human gene.10 it encodes the MC4 protein, a G-protein coupled receptor that binds α-melanocyte stimulating hormone (α-MSH). In murine models MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function 11-13 In 1998, it was reported that MC4R mutations were associated with inherited human obesity. They were found in heterozygotes, suggesting an autosomal dominant inheritance pattern. However, based off other research and observations, these mutations seem to have an incomplete penetrance and some degree of codominance. It has a prevalence of 1-2.5% in people with BMIs of greater than 30, making it the most commonly known genetic defect predisposing people to obesity.14
1.3. BODY FUNCTION
Defects in signaling by leptin, a hormone produced primarily by adipose tissue that informs the brain of the body's energy reserves, result in obesity in mice and humans. However, the majority of obese humans do not have abnormalities in leptin or its receptor but instead exhibit leptin resistance that could result from defects in downstream mediators of leptin action. Recently, two potential downstream mediators, agouti-related protein (Agrp) and its receptor, the melanocortin-4 receptor (Mc4r), have been identified. Agrp and Mc4r are excellent candidates for human disorders of body weight regulation and represent promising targets for pharmacological intervention in the treatment of these disorders.15
The peptide products of the pro-opiomelanocortin (POMC) gene have established roles in the control of physiological processes as diverse as adrenal steroidogenesis, skin pigmentation, analgesia and inflammation. In the last 5 years, evidence accumulated from murine and human genetic models of disrupted melanocortin signalling has firmly established a central role for a population of hypothalamic neurons expressing POMC in the control of appetite and body weight. Of the five known melanocortin receptors, the MC4R has been most closely linked to body weight regulation. While a-MSH is active at this receptor and suppresses appetite after central injection, important roles for other POMC-derived products have not been excluded. The development of pharmacological agonists acting on, or mimicking, the hypothalamic melanocortinergic pathway may provide exciting opportunities for the therapy of human obesity.16

1.4. CLASSIFICATION 17-20
Table no 1.  classification of melanocortin receptor 
Currently accepted nameMc1-r Mc2-r Mc3-r Mc4-r Mc5-r Mc6-r
Alternate names Msh-r Acth-r Pressor receptor
Structural information 317 aa (human) 297 aa (human) 360 aa (human) 332 aa (human) 325 aa (human) Not determined
Selective antagonists Agouti Shu9119 (m 4603) Shu9119 (m 4603) 
Agrp agouti
Agrp
Ro 27-3225
Hs028 (h 4402)
Hs014 (h 2396)
Signal transduction mechanisms Gs (increase camp) Gs (increase camp) Gs (increase camp) Gs (increase camp), gaba releaseGs (increase camp)
Selective agonists Shu9119 (m 4603) Acth) (a 0423 (h), a 6303 (p), α2-msh (m 9638) (in rodents) [d-trp8]-α-msh
A 7075 (r))Ro 27-4680 Shu9119(m 4603)α-msh(6-12
Radioligands of choice [125i]-[nle4-d-phe7]- 
α-msh [125i]-[tyr23]-acth [125i]-[nle4-d-phe7]-α-msh[125i]-[nle4-d-phe7]- α-msh [125i]-[nle4-d-phe7]-α-msh

1.5. EXPRESSION
Regulation of endogenous melanocortin-4 receptor expression and signaling by gluco corticoids21, the melanocortin-4 (MC4) receptor plays a pivotal role in regulating food intake and energy expenditure, and obesity results from mutations that interfere with the MC4 receptor pathway. We investigated the effect of gluco corticoids on endogenous MC4 receptors expressed in GT1-1 cells, an immortalized hypothalamic neuronal cell line. Dexamethasone (Dex) caused a 5- to 10-fold increase in the cAMP response to the MC4 receptor agonist, NDP-alpha MSH. The stimulatory effect of Dex reached a maximum within 24 h and was blocked by the gluco corticoid antagonist RU486. This gluco corticoid effect was specific for the MC4 receptor and not a result of up-regulation of another component of the cAMP cascade, because the response to endogenous beta-adrenergic receptor stimulation was not altered by Dex. Dex also potentiated NDP-alpha MSH-mediated ERK1/2 activation. After 12 h, Dex caused a 3- to 5-fold increase in [125I]NDP-alpha MSH binding, which was maintained for at least 48 h and prevented by RU486. Dex withdrawal caused a rapid return of MC4 receptor concentration to the basal level. Dex-mediated increases in MC4 receptor concentration resulted from a rapid but transient increase in MC4 receptor mRNA. This regulation apparently requires genomic regulatory sequences because Dex did not increase MC4 receptor expression or signaling in CHO cells expressing the MC4 receptor under the control of a cytomegalovirus promoter. We conclude that in GT1-1 hypothalamic neurons, gluco corticoids increase the amplitude of MC4 receptor signaling. This regulation may serve as a control to limit the effects of gluco corticoids on food intake. Expression of the human melanocortin-4 receptor gene is controlled by several members of the Sp transcription factor family 22,the melanocortin-4 receptor (MC4-R) plays a key role in the hypothalamic control of food intake, lending importance to the understanding of the mechanisms that regulate its expression. To identify factors controlling the expression of the human (h) MC4-R gene, a fragment containing 1253 bp of the 5'-flanking region of the hMC4-R gene was isolated. A series of hMC4-R luciferase constructs were developed and used to transiently transfect HEK293 and GT1–7 cell lines, both expressing endogenous MC4-R mRNA, Deletion analysis of the 1253 bp fragment showed that the basal promoter activity is mainly restricted to the 179 bp upstream of the transcription start site in both cell types. Mutation of a putative Sp1-binding site located at position –76 bp resulted in a dramatic reduction of the luciferase activity in HEK293 and GT1–7 cells by 87 and 80% respectively. Both in vitro and in vivo studies (gel shift and chromatin immunoprecipitation analyses) revealed binding of both Sp1 and Sp3 to this site in HEK293 cells, cotransfection with an Sp1 expression vector in Drosophila cells that do not express Sp1, in conjunction with treatment of HEK293 cells with mithramycin A, a specific inhibitor of Sp1, confirmed the role of Sp1. For the first time, we have demonstrated that the constitutive activity of the hMC4-R promoter is dependent upon Sp transcription factors. Expression of Mc-4 Receptor In Hypothalamuic Gt1-1 Cell Line, mutations in the melanocortin-4 receptor (MC4-R) cause obesity in both mice and humans, and the receptor is presumed to have an important role in the regulation of energy homeostasis. The MC4-R is expressed in discrete sets of neurons in the central nervous system, and thus it has been technically difficult to study the regulation of expression and the signaling mechanisms of this receptor. We report here a neuronal cell line that exhibits endogenous functional expression for the MC4-R. Initially, RT-PCR analysis showed the presence of MC4-R RNA in the hypothalamic GT1-1 and GT1-7 cells.23-25 In addition, GT1-7 cells expressed melanocortin-3 receptor while the GT1-1 subclone specifically expressed predominantly the MC4-R RNA. High-affinity binding sites were demonstrated in the GT1-1 and GT1-7 cells for NDP-  melanocyte-stimulating hormone (MSH; Ki = 1.1 × 10-10 and 1.8 × 10-10M) and agouti-related protein (AGRP; Ki = 1.548 × 10-9 and 1.663-9M).  -MSH-stimulated cAMP production in GT1-1 cells with an EC50 of 2.2 × 10-8M, and cAMP production was inhibited in the presence of AGRP, an endogenous antagonist of the MC4-R. Stimulation of gonadotropin-releasing hormone (GnRH) secretion was achieved with 1 nM to 1µM concentrations of NDP- -MSH while no GnRH secretion was observed when the GT1-1 cells were treated with AGRP. The data presented here show that GT1-1 cells specifically express a functional MC4-R that couples to GnRH release.
1.6. RECEPTOR
Acetylcholine, Angiotensin, Apelin , Bombesin, Bradykinin, Calcitonin, amylin, CGRP and adrenomedullin, Calcium-sensing, Cannabinoid, Chemokine, Chemotactic peptide, Cholecystokini, Dopamine, Endothelin, GABAB, Ghrelin, Glutamate, metabotropic, Glutamate, Gonadotrophin-releasing Hormone (GnRH), Histamine, 5-HT (5-Hydroxytryptamine), Leukotriene, Lipoxin, Lysophosphatidic acid, Melanin-concentrating hormone, Melanocortin, Melatonin, Neuropeptide Y, Neurotensin, Opioid and opioid-like, Orexin, P2Y, Platelet-activating factor (PAF), Prostanoid, Prostanoid, Proteinase-activated, Relaxin family peptide, Somatostatin, Sphingosine-1-phosphate, Tachykinin, Thyrotropin-releasing hormone, Vasopressin and oxytocin. Among these melanocortin receptors are as under. 

Melanocortin receptor
Melanocortin receptors (provisional nomenclature) are activated by members of the melanocortin family (MSH – a, b, and g forms – d form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein (AGRP).
Table no 2.  Melanocortin Receptor
NomenclatureMC1MC2MC3MC4MC5
Other names_ACTH receptor___
Ensembl IDENSG00000141037ENSG00000185231ENSG00000124089ENSG00000166603ENSG00000176136
Principal transductionGsGsGsGsGs
Rank order of potency α-MSH>β-MSH>
ACTH, γ-MSHACTH 
γ-MSH, β-MSH>
ACTH, α-MSHβ –MSH> α-MSH,
ACTH>γ
MSHα-MSH> β –MSH> ACTH>γ-MSH
Selective agonists__D-Trp8-γMSH (Grieco
et al., 2000)THIQ (Van der Ploeg et al., 2002)_
Selective antagonists___HS014 (8.5, Schio¨ th
et al., 1998), MBP10
(Bednarek et al.,
2001)_
Radioligands 
[125I]-NDP-MSH  [125I]-ACTH-(1 – 24)[125I]-NDP-MSH,
[125I]-SHU9119
[125I]-NDP-MSH,
[125I]-SHU9119
[125I]- NDP-MSH
Polymorphisms of the MC1 receptor have been linked to variations in skin pigmentation. Defects of the MC2 receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC4 and MC5 receptors have been linked to obesity (Chagnon et al., 1997).

1.7.PHYSIOLOGY                                                                          
Obesity is caused by a dysregulation in energy homeostasis that promotes an increase in body fat stores. The neuroendocrine system regulates energy balance by controlling appetite, as well as food intake and utilization. Leptin, a cytokine-like peptide produced by adipose tissue in proportion to adipose mass, acts on the melanocortin system, inducing proopio melanocortin (POMC)1 synthesis in the hypothalamic arcuate nucleus. The action of POMC-derived peptides,  -, ß-, and  -melanocyte–stimulating hormone (MSH), and adrenocorticotropic hormone (ACTH), is mediated by a family of guanosine triphosphate–binding protein receptors, one of which, melanocortin receptor 4 (MC4R), is produced at high concentrations within the central nervous system and plays an important role in the control of food intake and energy balance. The first compelling evidence that the POMC gene is involved in the control of human appetite came from a report of 2 defects in ACTH synthesis and in POMC gene translation in 2 children affected by hyperphagia and uncontrolled obesity . Investigation of other POMC mutations confirmed the link between this gene and obesity in humans and mice. Increased food intake, obesity, and hyperinsulinemia are features of MC4R knock-out mice, and various MC4R missense and nonsense mutations have been reported in patients with severe early-onset obesity. These findings prompted us to study the POMC and MC4R genes in relation to serum leptin concentrations and to anthropometric measurements in a large group of severely obese adults from southern Italy. Our aims were to identify mutations in susceptibility genes in relation to obesity and to identify subgroups in whom major genes exert greater phenotypic effects. 31
This application discloses novel piperazinyl amino acid derivatives as ligands for melanocortin (MC) receptors. The examples in the filing are built around a key, core fragment from which there are three points of diversity. In the absence of biology data in the application, an analysis of the moieties within each point of diversity may suggest that some compounds are more preferred as MC ligands than others.32 
The natural melanocortin agonists, α-, β-, γ-melanocyte-stimulating hormones (MSHs), 
and adrenocorticotropin have been receiving great attention in the recent years because of their involvement in a large number of multifaceted biological actions, including skin pigmentation, control of the immune system, erectile function, blood pressure and heart rate, control of feeding behavior and energy homeostasis, modulation of aggressive/defensive behavior, and mediation of pain. These endogenous neuropeptides are ligands for the five known subtypes of human melanocortin receptors, which are expressed in various tissues, including skin [human melanocortin-1 receptor (hMC1R)], adrenal cortex (hMC2R), and throughout the central nervous system (hMC3R, hMC4R, and hMC5R). 
Previous reports from our laboratories had focused on finding potent and selective agonists and antagonists for the hMC3R and hMC4R, which have been implicated to play complementary roles in weight control. 
Kavarana et al. and Bednarek et al. have reported that replacing the Ac-Nle4-Asp33 part of the non-selective superagonist MT-II (Ac-Nle4-c[Asp5, D-Phe7, Lys10]α-MSH-NH2)with a variety of dicarboxylic acid linkers yielded several potent and selective hMC3R and hMC4R agonists and antagonists. Extending these studies, a series of novel cyclic α-MSH analogs possessing a variety of flexible aliphatic and constrained aromatic and heterocyclic dicarboxylic acid linkers (c[CO-R-CO-His-D-Phe/D-Nal(2′)-Arg-Trp-Lys]-NH2) have been designed and synthesized by solid-phase methods to further investigate the effects of macrocycle size and flexibility on melanocortin receptor selectivity34

2.OBESITY 
Obesity means having too much body fat. It is different from being overweight, which means weighing too much. The weight may come from muscle, bone, fat and/or body water. Both terms mean that a person's weight is greater than what's considered healthy for his or her height. 
Obesity occurs over time when you eat more calories than you use. The balance between calories-in and calories-out differs for each person. Factors that might tip the balance include your genetic makeup, overeating, eating high-fat foods and not being physically active. 
Being obese increases your risk of diabetes, heart disease, stroke, arthritis and some cancers. If you are obese, losing even 5 to 10 percent of your weight can delay or prevent some of these diseases.
The English word ‘Obesity’ derives from the Latin Obesus meaning ‘fat’ or ‘plump’. The first English use of the word was made in 1651 in Noah Bigg’s medical book Mataeotechnia Medicinae Praxeos.
In medical studies, obesity is defined as a person having more than 20 per cent of ideal weight. Ideal weight takes into account height, age, sex and build of a person. According to National Health Institute, USA, the Body Mass Index of a person is the key factor to define obesity. As per NHI standard, a person with 30 pounds of more fat content in his or her body is considered obese.
Body Mass Index, or BMI, is a health indicator of the diseases associated with obese men and women. These health factors include “silent-killers” such as: diabetes, heart disease and cancer. Many obese individuals do not even realize they have one or more of these diseases.
By waist measurement and BMI, body fat can be measured. Obesity is defined as a waistline of 35 inches or higher for woman and for men a waistline of 40 inches or higher. The BMI formula calculates body weight and height.  The formula works by dividing an individual’s weight (Kg) by their height (meters squared). It can also be worked out by multiplying weight in pounds by 703, and dividing height in inches. Again a division is necessary by height (inches).
Obesity can also be defined as a BMI of 30 pounds over a person considered normal weight. Weight standards are calculated according to a person’s height. Excessive obesity is defined as a BMI of 40 or higher. There is another way of defining obesity. It is overweight, with a BMI of 25 to less than 30. A person’s BMI of about 25 kg/m (squared) corresponds to about 10 per cent over a normal weight.
Body mass index (BMI), developed by Belgian anthropometrist Adolphe Quetelet, is a widely accepted scale to measure obesity. Its formula is division of the weight of an obese in kilograms by his height in square metres. Another formula is BMI = weight (lbs.) * 703 / height (inches)35

The following values are commonly accepted:
A BMI less than 18.5 is underweight 
A BMI of 18.5 - 24.9 is normal weight 
A BMI of 25.0 - 29.9 is overweight 
A BMI of 30.0 - 39.9 is obese 
A BMI of 40.0 or higher is severely (or morbidly) obese 
A BMI of 35.0 or higher in the presence of at least one other significant co morbidity is also classified by some bodies as morbid obesity. 
To interpret BMI, physicians take into account race, ethnicity, lean mass, age, sex and other similar factors. Although there is no dispute to accept BMI to measure obesity, but it is not accurate in judging body fact of a very muscular person, for example an athlete or the lost mass of an old person. It is also not correct in measuring waist circumference as it does not take into account differing ratios of adipose to lean tissues. BMI also cannot differentiate between separate types of adiposity, which on many occasions relates to cardiovascular danger.
Broadly speaking, obesity can be defined as a body’s extra fat that is stored in tissues as a result of excessive consumption of caloric food, which is not compatible with the routine manual labor undertaken. Simply put, what a person takes in they must put out. This involves the physical act of eating in comparison with the level of physical movement.
Obesity has become a growing epidemic that plaques people of different cultures worldwide. Obesity is such a major health concern because it leads to several fatal diseases. Obesity sufferers are prone to cardiovascular problems, diabetes, stroke and heart attack. Many of these health issues are called “silent-killers” because the victim does not even know they have these diseases. Obesity is not only negatively affecting adults but it affects the younger generation as well. Children and teenagers are becoming obese at alarming rates. It is said that if this trend continues our children’s generation will not live as long as their parents. This is a serious fact that is terrifying on every level. Obesity does not discriminate as it takes out so many in its path. Obesity is preventable.

3.RELATION WITH OBESITY
Early Onset Obesity (MC4R) 
Frequently Used Abbreviations: α-MSH: alpha-melanocyte stimulating hormone; MC4R: melanocortin 4 receptor. Obesity is associated with major causes of morbidity and mortality. It affects approximately 50% of the adult and 25% of the pediatric population in the United States, making it one of the country’s (and the industrialized world’s) major current health problems. In approximately 10% of affected children (2.5% of the pediatric population), obesity can be considered severe. In approximately 5% of severely obese children, the condition has been linked to autosomal dominant mutations in the gene for the melanocortin 4 receptor (MC4R)36
Early diagnosis of MC4R-related obesity is important, as this type of obesity is unlikely to resolve without aggressive treatment. Knowing that a child with MC4R-related obesity may not experience a sense of satiety can help parents to understand their child’s eating behavior and emphasize the necessity to work with the child on limiting his or her food intake. In addition, a diagnosis of MC4R-related obesity may relieve feelings of guilt and failure related to the child’s weight problems in both patient and parents.
Genetic testing provides the only method for definitive diagnosis of MC4R-linked obesity. Genetic testing can also identify carriers of obesity-associated mutations in MC4R, who may be at an increased risk for developing obesity.
Monogenic Causes of Early Onset Obesity
Several different monogenic causes of childhood obesity have been identified. In every case, the mutated gene product plays a role in a complex signaling pathway believed to be involved in controlling eating behavior. Within this pathway, binding of α-melanocyte stimulating hormone (α-MSH) to MC4R appears to form a central link.Affected Protein Normal Physiological Function Leptin37 Protein hormone produced by adipocytes; serves as one of inputs into signaling pathway believed to be involved in control of eating behavior Leptin receptor in hypothalamus. Binding of leptin to leptin receptor stimulates synthesis of pro-opiomelanocortin. Pro-opiomelano-cortin (POMC). Precursor protein for several peptide hormones, including α-melanocyte stimulating hormone (α-MSH) Prohormone convertase-1 Catalyzes post-translational cleavage of POMC into α-MSH Melanocortin 4 receptor (MC4R)  α MSH receptor expressed in the hypothalamus; binding of α-MSH to MC4R activates anorexigenic signals MC4R is expressed in the hypothalamus. Stimulation of MC4R by α-MSH binding triggers the activation of anorexigenic signals, which, through a series of further steps, are believed to reduce food intake by creating the perception of satiety. In cell culture studies, many of the obesity-linked MC4R mutations have been shown to render the receptor protein dys- or non-functional. Thus, mutations in MC4R appear to prevent the activation of anorexigenic signals in response to α-MSH binding, so that individuals with obesity-linked mutations in MC4R may not experience the feeling of satiety. 
Leptin is a protein hormone produced in adipose tissue. Its secretion is correlated to energy intake: While insulin and cortisol increase leptin secretion, catecholamines decrease leptin secretion. A long-term reduction in leptin levels due to a sustained shortage of food intake leads to a decrease in the metabolic rate and inhibition of the reproductive, growth hormone, and thyroid axes, allowing the body to conserve energy. It is not yet clear, what role short-term leptin fluctuations play in the normal physiology of weight regulation.
Clinical Presentation of Early Onset Obesity
Early onset obesity first occurs in children38 under ten years of age, and is characterized by hyperphagia and a body mass index (BMI) approximately four standard deviations higher than age appropriate. In children as in adults, severe obesity leads to insulin resistance and, consequently, hyperinsulinemia. Approximately 30% of hyperinsulinemic individuals eventually develop pancreatic β-cell failure and type 2 diabetes. As severely obese children reach adulthood, other common complications of obesity begin to manifest themselves, including the metabolic syndrome with its attendant atherosclerotic cardiovascular disease, type 2 diabetes, nephropathy, retinopathy, and neuropathy. In addition, obese individuals are prone to developing hepatic steatosis, obstructive sleep apnea, orthopedic complications, and acanthosis nigricans.
In contrast to several other known monogenic causes of obesity, defects in MC4R lead to non-syndromic obesity. Symptoms linked to MC4Rrelated early onset obesity include binge eating behavior, severe hyperinsulinemia, an increase in bone minerals, a higher linear growth velocity, and an earlier than normal onset of puberty. 

Diagnosis of MC4R-Related Obesity
Symptoms accompanying MC4R-related early onset obesity are also seen with other types of obesity and may become apparent only over extended periods of time. Thus, these symptoms do not permit the differential diagnosis of MC4R-related early onset obesity. In contrast, genetic testing allows a diagnosis of MC4R-related early onset obesity at any age. 39
Treatment of MC4R-Related Obesity
Traditionally, childhood obesity has been managed by dietary approaches combined with efforts to increase physical activity. However, dietary management in general is often ineffective, and more and more older children and young adults are undergoing bariatric surgeries. These procedures are highly effective in promoting weight loss in the short term, but have their own attendant complications. 
Several drugs for targeted therapy of MC4R-related obesity are presently undergoing clinical development. The therapeutic concept is based on the finding that most patients with MC4R-related obesity are heterozygous for the mutation in the MC4R gene. Studies in cell culture have indicated that the functionality of a normal MC4R protein is not affected by presence of a mutated receptor protein in the same cell. Therefore, increased stimulation of the remaining healthy MC4R protein with specific drugs may be able to compensate for the loss of function in the mutated receptor. 
Genetics of MC4R-Related Obesity
MC4R-related early onset obesity is inherited in an autosomal dominant manner. While individuals with mutations in only one of the two MC4R gene copies (heterozygotes) can express the obesity phenotype, patients with mutations in both copies of the MC4R gene (homozygotes) demonstrate more severe obesity. In heterozygotes, expression of the obesity phenotype appears to be due to haploinsufficiency, i.e., insufficient amounts of intact MC4R protein are expressed from the remaining normal gene copy. Penetrance of the mutation varies within and between families, i.e., not all heterozygous individuals carrying an obesityassociated MC4R mutation are obese. Within families, female carriers of obesity-linked MC4R mutations are often more severely affected than males with the same mutation.40

Genetic Testing for MC4R-Related Obesity
The Early Onset Obesity (MC4R) Evaluation detects mutations in the gene coding for MC4R, which represent the most common monogenic cause of early onset obesity known to date. 
DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of MC4R are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.41

4. SUMMARY
Masuzaki H et al. A variety of metabolic/molecular changes in obese adipose tissue considerably contribute to the pathophysiology of life style-related diseases. Fat cell-derived hormone leptin controls appetite and energy homeostasis, thereby enhancing whole body insulin sensitivity. However, clinical application of leptin for the treatment of obesity/metabolic syndrome has been hampered by the fact that leptin does not fully exert its beneficial metabolic impact on prevalent forms of obesity. In an attempt to elucidate underlying mechanism of leptin resistance in obesity, we found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) tightly parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Actually, intracerebroventricular administration of melanocortin agonist MT-II robustly overcomes high fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia in mice, with a concomitant recovery of AMPK activity in skeletal muscle, thereby highlighting the system as a therapeutic target for leptin resistance. In this context, type 4 melanocortin receptor is a promising drug target for the treatment of obesity/metabolic syndrome.42
Hofbauer KG et al. OBJECTIVE: Active immunization in rats may serve several purposes: the production of a disease-like phenotype, the generation of pharmacologic tools, and the development of clinically useful therapies. We selected the melanocortin-4 receptor (MC4R) as a target because its blockade could provide a treatment for anorexia and cachexia. METHODS: We used a sequence of the N-terminal (NT) domain of the MC4R as an antigen. Rats immunized against the NT peptide produced specific MC4R antibodies (Abs) that were purified and characterized in vitro and in vivo. RESULTS: The Abs acted as inverse agonists and reduced under basal conditions the production of cyclic adenosine monophosphate in HEK-293 cells expressing the human MC4R. Rats immunized against the NT peptide developed a phenotype consistent with hypothalamic MC4R blockade, i.e., increased food intake and body weight, liver and fat-pad weights, hepatic steatosis, and increased plasma triacylglycerols. With a high-fat diet, plasma insulin levels were significantly increased. In separate experiments an increase in food intake was observed after injection of purified MC4R Abs into the third ventricle. When lipopolysaccharide was administered in NT-immunized rats the reduction of food intake was partly prevented in this model of cytokine-induced anorexia. CONCLUSION: Our results show that active immunization of rats against the MC4R resulted in the generation of specific Abs that stimulated food intake by acting as inverse agonists of the hypothalamic MC4R. Pharmacologically active monoclonal MC4R Abs could be the starting point for the development of novel treatments for patients with anorexia or cachexia.43
Tian X et al. A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.44
Kawahara Y et al. RNA editing that converts adenosine to inosine replaces the gene-encoded Ile, Asn, and Ile (INI) of serotonin [5-hydroxytryptamine (5-HT)] receptor 2C (5-HT(2C)R) with Val, Gly, and Val (VGV). Up to 24 different 5-HT(2C)R isoforms are detected in different brain regions (Burns et al., 1997; Fitzgerald et al., 1999; Wang et al., 2000). To elucidate the physiological significance of 5-HT(2C)R mRNA editing, we derived mutant mouse lines harboring a knock-in INI or VGV allele, resulting in sole expression of one of two extremely different editing isoforms 5-HT(2C)R-INI (editing blocked) or -VGV (fully edited). Although INI mice grew normally, VGV mice had a severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized in VGV mice, most likely because of the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al., 2008), and Mc4r(-/-) mice are obese because of hyperphagia and reduced energy expenditure (Huszar et al., 1997). However, the elevated energy expenditure of VGV mice could not be rescued in the Mc4r(-/-) background, indicating the presence of a distinct signaling pathway mediated via 5-HT(2C)R-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated 5-HT(2C)R mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.45
Park TJ et al. It has been demonstrated that human melanocortin-4 receptor (hMC4R) plays an important role in the control of energy homeostasis, and heterozygous mutations in the hMC4R gene are the most frequent genetic cause of severe human obesity. In order to obtain additional insight into the structure and function, we cloned, expressed, and purified the second transmembrane domain of the wild-type hMC4R (wt-TM2) and D90N mutant hMC4R (m-TM2). To facilitate structural studies of these hMC4R by solid-state NMR, efficient methods for the production of milligram quantities of isotopically labeled protein are necessary. However, large-scale production of most transmembrane proteins has been limited by experimental adversities due to insufficient yields and low solubility of protein. Nevertheless, through the optimization of the expression and purification approach, we could obtain uniformly or selectively labeled fusion proteins in yields as high as 200-250 mg per liter M9 minimal medium. These proteins were overexpressed in inclusion bodies as a fusion protein with ketosteroid isomerase (KSI) in Escherichia coli, and the fusion protein was purified using immobilized metal affinity chromatography under denaturing conditions. wt-/m-TM2 peptides were released from the fusion by cyanogen bromide cleavage at the Met residue and separated from the carrier KSI by size exclusion chromatography. Initial structural data obtained by solution NMR measurements of wt-/m-TM2 is also presented. The successful application to the production of the second transmembrane domain of human MC4R indicates that the method can be applied to other transmembrane proteins as well and also enable its structural and functional studies using solid-state NMR spectroscopy.46
Gupta A et al. The offspring of high fat (HF) diet-fed rats display increased body weight during adulthood. However, it is not known whether the changes in appetite regulation in these animals occur in-utero or postnatally. We investigated effects of maternal obesity induced by a HF diet prior to and during pregnancy on leptin and insulin signaling and the expression of orexigenic and anorexigenic peptides in term fetal hypothalami. The consumption of a HF diet prior to and during pregnancy resulted in obesity in HF female rats; additionally, HF female rats exhibited hyperinsulinemia and hyperleptinemia which were exaggerated in late gestation compared with control female rats that were fed a standard rodent laboratory chow (LC). Term fetuses of HF female rats (FHF) also had significantly higher serum leptin and insulin levels compared with control fetuses (FLC) while there was no difference in average fetal weight between the two groups. FHF hypothalami showed elevated levels of mRNA and proteins for leptin long receptor and insulin receptor beta subunit. However, the protein levels of STAT-3 and insulin receptor substrate-2, the downstream signaling components of leptin and insulin signaling respectively, were decreased. Also, FHF hypothalami had increased mRNA levels of neuropeptide Y and agouti-related polypeptide indicating that orexigenic neuropeptides in HF progeny are already upregulated by term fetal stage. Additionally, the mRNA levels of pro-opiatemelanocortin and melanocortin receptor-4 were also increased in the HF fetal hypothalami. These findings indicate potential programming effects of an altered intrauterine environment induced by HF diet consumption on appetite-regulating neuropeptides and leptin and insulin signaling in the late fetal period.47
Hughes DA et al. The melanocortin 4 receptor (MC4R) is routinely investigated for the role it plays in human obesity, as mutations in MC4R are the most common dominantly inherited form of the disease. As little is known about the evolutionary history of this locus, we investigated patterns of variation at MC4R in a worldwide sample of 1,015 humans from 51 populations, and in 8 central chimpanzees. There is a significant paucity of diversity at MC4R in humans, but not in chimpanzees. The spectrum of mutations in humans, combined with the overall low level of diversity, suggests that most (if not all) of the observed non-synonymous polymorphisms are likely to be transient deleterious mutations. The MC4R coding region was resequenced in 12 primate species and sequences from an additional 29 vertebrates were included in molecular evolutionary analyses. MC4R is highly conserved throughout vertebrate evolution, and has apparently been subject to high levels of continuous purifying selection that increased approximately threefold during primate evolution. Furthermore, the strong selection extends to codon usage bias, where most silent mutations are expected to be either quickly fixed or removed from the population, which may help explain the unusually low levels of silent polymorphisms in humans. Finally, there is a significant tendency for non-synonymous mutations that impact MC4R function to occur preferentially at sites that are identified by evolutionary analyses as being subject to very strong purifying selection. The information from this study should help inform future epidemiological investigations of MC4R.48

5. LIST OF ABBREVIATION
ACTH: Adrenocorticotropic hormone
AGRP: Agouti related protein
HS014: Cyclic [AcCys11,D-Nal14,Cys18,Asp-NH2(22)]-β-MSH(11-2 2)
HS028: [AcCys11,dichloro-D-phenylalanine14,cys18,Asp-NH2 22]β-MSH(11-22)
α-MSH: α-Melanocyte stimulating hormone
γ-MSH: γ-Melanocyte stimulating hormone
γ2-MSH: γ2-Melanocyte stimulating hormone
Ro 27 3225: N-(1-Oxobutyl)-L-histidyl-L-phenylalanyl-L-arginyl-L-tryptophyl-N2-methyl-glycinamide
Ro 27-4680: N-(1-Oxobutyl)-L-histidyl-3-(2-naphthalenyl)-D-alanyl-L-arginyl-L-tryptophyl-N2-methyl-glycinamide
SHU9119: Ac-Nle4-c[Asp4,D-Nal7,Lys10]-α-MSH(4-10)-NH2
 PCR: polymerase chain reaction; 
SNP: single nucleotide polymorphism; 
SSCP: single strand conformation polymorphism; 
RFLP:  restriction fragment length polymorphism.
BMI: Body mass index;
 SDS: sd score
α-MSH: alpha-melanocyte stimulating hormone;
 MC4R: melanocortin 4 receptor
THIQ: N-([3R]-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-(1R)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1H-1 ,2,4-triazol-1ylmethyl]piperidin-1-yl)-2-oxoethylamine

6. LIST OF TABLES AND FIGURES
1.Figure shows In the upper panel a schematic illustration of the structure of the MC4R is given.
2.Figure shows the location of MC4R in context on chromosome 18.
3.Figure shows the predicted structure of the MC4R protein. This protein also has the synonym MC4-R.
4.Table no 1.  classification of melanocortin receptor
5.Table no 2.  Melanocortin Receptor


7.REFERENCE
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