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1

Obesity
INDEX
CONTENTS
SR. NO. TITLE PAGE
NO.
1 Introduction
1.1.Pharmacology
1.2.Location
1.3.Body Function
1.4.Classication
1.!.E"#r$ssion
1.%.&$c$#tor
1.'.Physiology
1-14
2 ()$sity
15-17
3 &$lation *ith ()$sity
18-21
4 +ummary
22-26
5 List (, -))r$.iation
27
6 List (, /a)l$s -nd Figur$s
28
7 &$,$r$nc$
29-33
1
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 2st century.
Obesity is a comple! multifactorial disease caused by the interaction of genetic and
environmental factors. "he potential implication of genetic factors in the
development of human obesity is well demonstrated by the description of five
monogenic forms of human obesity. "he genes implicated in these forms of obesity
encode proteins of the leptin a!is and brain#e!pressed targets of leptin involved in
the melanocortin pathway. "hey include leptin, the leptin receptor, proconvertase ,
pro#opiomelanocortin $%O&'(, and the melanocortin#) receptor $&')#*(. +!cept
for &')#*, mutations in these genes cause rare, recessive, syndromic forms of
obesity, associated with multiple endocrine abnormalities.
&')#* is a ,,2#amino acid protein encoded by a single e!on gene localized on
chromosome -.22. &')#* belongs to the family of seven transmembrane / protein0
coupled receptors $/%'*( and signals through activation of adenylate cyclase. &')#*
&')#* belongs to the family of seven transmembrane / protein0coupled receptors
$/%'*( and signals through activation of adenylate cyclase &')#* belongs to the family
of seven transmembrane / protein0coupled receptors $/%'*( and signals through
activation of adenylate cyclase belongs to the family of seven transmembrane / protein0
coupled receptors $/%'*( and signals through activation of adenylate cyclase &')#*
belongs to the family of seven transmembrane / protein0coupled receptors $/%'*( and
signals through activation of adenylate cyclase "he importance of &')#* in body#weight
regulation is clearly demonstrated by the obese phenotype of the homozygous MC4-R0
deficient mice. 1eterozygous 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. "his 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. "he description of a similar case and the report of several MC4-R
1
missense and nonsense mutations in 2 of two cohorts of e!tremely obese children and
adults suggest that such mutations could be a more fre.uent cause of obesity than the
syndromic forms due to the other genes. 3imited 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
&')#* mutations in human obesity.
1
1.1 PHARMACOLOGY
"he melanocortin#) receptor $&')*( as a molecular target for both indications because
it plays an important role in the regulation of appetite and autonomic function $for details
see 4igure (. Our pharmacological approach consisted in the generation and
characterization of functionally active antibodies against e!tracellular se.uences of the
&')*. Our initial studies in rats evealed an obese phenotype after immunization against
the 5#terminal domain of the &')*. "hese e!periments are described in more detail in
our previous biennial report and have been published in 2667. 8n subse.uent e!periments
we attempted to generate monoclonal anti#&')* antibodies since such molecules can be
produced in unlimited amounts. 8mmunization of mice against the 5#terminal domain
resulted in a monoclonal antibody which blocked the activity of the &')*. 8n further in
vitro studies it was characterised as an inverse agonist with non#competitive antagonistic
activity. 9 priority claim has been filed in collaboration with the "echnology "ransfer
:nit of the :niversity of Basel. "he monoclonal antibody is currently being produced in
larger amounts for acute and chronic studies on its blood#brain penetration after
peripheral administration. "hereafter it will be used as a pharmacological tool to e!plore
the therapeutic potential of &')* blockade in various disease models. 9 simple model
for cache!ia#induced anore!ia, i.e. the loss of appetite in association with inflammatory
diseases, has been established and validated in our laboratory. 8t consists of the
continuous monitoring of food intake in rats after the acute administration of
lipopolysaccharide Our immunization studies on the &')* in rats are being
complemented with several series of immunizations against e!tracellular se.uences of the
&',*. "hese e!periments were initiated because presynaptic &',*s appears to
modulate the release of the &')* agonist alpha#melanocyte stimulating hormone $alpha#
&;1( from nerve terminals. 1owever, the precise function of the &',* is not known
1
because of the lack of suitable e!perimental tools. Based on preliminary results with two
antigens from the first and the third e!tracellular loop a long#term immunization study
has been started in rats which are chronically instrumented with telemetry transmitters.
"his 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 &')* resulted in an obese phenotype in rats prompted us to
e!plore whether comparable findings can be obtained in obese patients. We therefore
initiated a clinical study in collaboration with the :niversity 'linic in ;trasbourg, 4rance,
and the communal hospital in Baden#Baden, /ermany. "hese institutions provided more
than 266 plasma samples from patients with a wide range of body mass indices $B&8(.
"he plasma samples were screened in our laboratory with an +38;9 assay using the 5#
terminal peptide se.uence of the &')*. %ositive samples were further assessed by flow
cytometry $49';( and c9&% measurements in 1+<2=, cells which overe!pressed the
human &')*. "he presence of auto#antibodies against the &')* in humans and the
increased prevalence of such autoantibodies in patients with increased B&8 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. ;everal options for further clinical
studies are currently being e!plored and e!perimental studies on possible therapeutic
approaches have been initiated in our group. Our studies on the role of brain derived
neurotrophic factor $B>54( as a downstream mediator of the &')* have been
completed and are subject of a recent publication. 8n this paper we reported for the first
time that &')* stimulation in isolated hypothalami in vitro induced a release of B>54
into the incubation medium. 8n e!periments in vivo we have shown that B>54 and a
&')* agonist have comparable effects on food intake. &oreover, the effects of &')*
stimulation could be prevented by the prior administration of a selective anti#B>54
antibody. 8n an additional series of e!periments in rats with telemetry transmitters we
could demonstrate that B>54 and a &')* 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. "hese effects of &')*
stimulation could also be prevented by the anti#B>54 antibody. "hus B>54 appears to
1
mediate not only the anorectic but also the autonomic effects of &')* stimulation. "his
project was performed in collaboration with %rof. ?ves Barde who also supplied the
monoclonal antibody against B>54. <arl /. 1ofbauer contributed to pharmacology
teaching in the &edical 4aculty and the 4aculty for 5atural ;ciences at the :niversity of
Basel. 1e took on responsibility for the planning and coordination of pharmacology
teaching for medical students in the new Bologna system up to the Bachelor level. 1e
contributed to a newly established course for a &aster of 9dvanced ;tudies in
%harmacology degree at the :niversity of Basel. <arl /. 1ofbauer gave also lectures on
drug discovery and development at the :niversity of @uerich. <arl 1ofbauer was
involved in several continuing education activities including the co#organization of and
the active contribution to the annual A'ardiovascular %harmacology ;eminarB in 3uzern.
"ogether with several clinical colleagues <arl /. 1ofbauer continued to co#organize a
lecture series at the :niversity of Basel with focus on obesity, metabolism and nutrition
$O&e5(. <arl /. 1ofbauer and members of his group presented their findings at several
national and international scientific meetings including an invited lecture at the Coint
&eeting of the ;wiss and 'anadian %harmacological ;ocieties in Banff, 'anada, in early
2667. 8n addition to original papers and book chapters two reviews from our group
covered the recent developments in the field of anti#obesity drugs.
Figure 1: In the uer !ne" ! s#he$!ti# i""ustr!ti%n %& the stru#ture %& the MC'R is
gi(en.
1
"he activation of the &')* mediates a decrease in food intake and an increase in energy
e!penditure. "hus &')* agonists could be useful drugs for the treatment of obesity.
1owever, the &')* has not only effects on energy balance but also influences
autonomic function. &')* activation results for instance in an increase in blood pressure
and heart rate. 8n order to generate agonists with a selective effect on energy balance it is
essential to identify downstream mechanisms which may mediate the &')* induced
effects separately. B>54 appears to be such a downstream mechanism of the &')* but
it shows no selectivity for the metabolic and autonomic effects. "he subse.uent steps in
the &')* downstream pathway are still unknown.
)*+
1.). LOCATION
"he melanocortin#) receptor $&')*( is e!pressed in the hypothalamus and regulates
energy intake and body weight. In silico screening of the canine chromosome se.uence
and a comparison with the porcine MC4R se.uence by B39;" were performed. "he
nucleotide se.uence of the whole coding region and ,D# and ED#flanking regions of the dog
$2) bp( and red fo! $77 bp( MC4R gene was established and high conservation of the
nucleotide se.uences was revealed $==2(. 4ive sets of %'* primers were designed and a
search for polymorphism was performed by the ;;'% techni.ue in a group of , dogs
representing nineteen breeds and ,E farm red fo!es. ;e.uencing of >59 fragments,
representing the identified ;;'% patterns, revealed three single nucleotide
polymorphisms $including a missense one( in dogs and four silent ;5%s in red fo!es. 9n
average ;5% fre.uency was appro!. F)66 bp in the dog and F,66 bp in the red fo!. We
mapped the MC4R gene by 48;1 to the canine chromosome $'49..( and to the red
fo! chromosome E $GG:Ep.2(.
1.).1. Chr%$%s%$e L%#!ti%n
,
L%#!ti%n* &')* is located on chromosome -.22
P%siti%n* chr-HEI=6EI2#EI-=EI)
Figure sh%-s the "%#!ti%n %& MC'R in #%nte.t %n #hr%$%s%$e 1+.
1
1.).). Pr%tein L%#!ti%n
&')* m*59 has been found in multiple sites in virtually every region of the brain. 8ts
major e!pression sites are thought to be the corte!, thalamus, hypothalamus, brainstem
and spinal cord.
Figure sh%-s the re/i#te/ stru#ture %& the MC'R r%tein. This r%tein !"s% h!s the
syn%ny$ MC'*R
1.).0. Me"!n%#%rtin ' re#et%r, also known as MC'R, is a human gene.
11
it encodes
the MC' protein, a /#protein coupled receptor that binds J#melanocyte stimulating
hormone $J#&;1(. 8n murine models &') receptors have been found to be involved in
feeding behaviour, the regulation of metabolism, se!ual behaviour, and male erectile
function
11*10
8n ==-, it was reported that &')* mutations were associated with inherited
human obesity. "hey were found in heterozygotes, suggesting an autosomal dominant
inheritance pattern. 1owever, based off other research and observations, these mutations
seem to have an incomplete penetrance and some degree of codominance. 8t has a
prevalence of #2.E2 in people with B&8s of greater than ,6, making it the most
commonly known genetic defect predisposing people to obesity.
1'
1.0. 2ODY FUNCTION
>efects in signaling by leptin, a hormone produced primarily by adipose tissue that
informs the brain of the bodyKs energy reserves, result in obesity in mice and humans.
1owever, the majority of obese humans do not have abnormalities in leptin or its receptor
but instead e!hibit leptin resistance that could result from defects in downstream
1
mediators of leptin action. *ecently, two potential downstream mediators, agouti#related
protein $9grp( and its receptor, the melanocortin#) receptor $&c)r(, have been identified.
9grp and &c)r are e!cellent candidates for human disorders of body weight regulation
and represent promising targets for pharmacological intervention in the treatment of these
disorders.
13
"he peptide products of the pro#opiomelanocortin $%O&'( gene have established roles in
the control of physiological processes as diverse as adrenal steroidogenesis, skin
pigmentation, analgesia and inflammation. 8n the last E 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 e!pressing %O&' in
the control of appetite and body weight. Of the five known melanocortin receptors, the
&')* has been most closely linked to body weight regulation. While a#&;1 is active at
this receptor and suppresses appetite after central injection, important roles for other
%O&'#derived products have not been e!cluded. "he development of pharmacological
agonists acting on, or mimicking, the hypothalamic melanocortinergic pathway may
provide e!citing opportunities for the therapy of human obesity.
14
1
1.'. CLA55IFICATION
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1.3. 78PR755ION
1
*egulation of endogenous melanocortin#) receptor e!pression and signaling by gluco
corticoids
)1
9 the melanocortin#) $&')( receptor plays a pivotal role in regulating
food intake and energy e!penditure, and obesity results from mutations that interfere
with the &') receptor pathway. We investigated the effect of gluco corticoids on
endogenous &') receptors e!pressed in /"# cells, an immortalized hypothalamic
neuronal cell line. >e!amethasone $>e!( caused a E# to 6#fold increase in the
c9&% response to the &') receptor agonist, 5>%#alpha &;1. "he stimulatory
effect of >e! reached a ma!imum within 2) h and was blocked by the gluco
corticoid antagonist *:)-I. "his gluco corticoid effect was specific for the &')
receptor and not a result of up#regulation of another component of the c9&%
cascade, because the response to endogenous beta#adrenergic receptor stimulation
was not altered by >e!. >e! also potentiated 5>%#alpha &;1#mediated +*<F2
activation. 9fter 2 h, >e! caused a ,# to E#fold increase in M2E8N5>%#alpha &;1
binding, which was maintained for at least )- h and prevented by *:)-I. >e!
withdrawal caused a rapid return of &') receptor concentration to the basal level.
>e!#mediated increases in &') receptor concentration resulted from a rapid but
transient increase in &') receptor m*59. "his regulation apparently re.uires
genomic regulatory se.uences because >e! did not increase &') receptor
e!pression or signaling in '1O cells e!pressing the &') receptor under the control
of a cytomegalovirus promoter. We conclude that in /"# hypothalamic neurons,
gluco corticoids increase the amplitude of &') receptor signaling. "his regulation
may serve as a control to limit the effects of gluco corticoids on food intake.
+!pression of the human melanocortin#) receptor gene is controlled by several
members of the ;p transcription factor family
))
,the melanocortin#) receptor $&')#
*( plays a key role in the

hypothalamic control of food intake, lending importance to
the

understanding of the mechanisms that regulate its e!pression.

"o identify factors
controlling the e!pression of the human

$h( &')#* gene, a fragment containing 2E,
bp of the EK#flanking

region of the h&')#* gene was isolated. 9 series of h&')#*
luciferase

constructs were developed and used to transiently transfect

1+<2=, and
/"07 cell lines, both e!pressing endogenous

&')#* m*59, >eletion analysis of
the 2E, bp fragment showed

that the basal promoter activity is mainly restricted to
1
the

7= bp upstream of the transcription start site in both cell

types. &utation of a
putative ;p#binding site located at position

07I bp resulted in a dramatic reduction
of the luciferase

activity in 1+<2=, and /"07 cells by -7 and -62 respectively.
Both in vitro and in vivo studies $gel shift and chromatin immunoprecipitation
analyses( revealed binding of both ;p and ;p, to this site

in 1+<2=, cells,
cotransfection with an ;p e!pression vector

in >rosophila cells that do not e!press
;p, in conjunction

with treatment of 1+<2=, cells with mithramycin 9, a specific
inhibitor of ;p, confirmed the role of ;p. 4or the first time,

we have demonstrated
that the constitutive activity of the h&')#*

promoter is dependent upon ;p
transcription factors.

+!pression of &c#) *eceptor 8n 1ypothalamuic /t# 'ell
3ine9 mutations in the melanocortin#) receptor $&')#*( cause obesity in both mice
and humans, and the receptor is presumed to have an important role in the regulation
of energy homeostasis. "he &')#* is e!pressed in discrete sets of neurons in the
central nervous system, and thus it has been technically difficult to study the
regulation of e!pression and the signaling mechanisms of this receptor. We report
here a neuronal cell line that e!hibits endogenous functional e!pression for the &')#
*. 8nitially, *"#%'* analysis showed the presence of &')#* *59 in the
hypothalamic /"# and /"#7 cells.
)0*)3
8n addition, /"#7 cells e!pressed
melanocortin#, receptor while the /"# subclone specifically e!pressed
predominantly the &')#* *59. 1igh#affinity binding sites were demonstrated in
the /"# and /"#7 cells for 5>%# melanocyte#stimulating hormone $&;1P <i Q
. R 6
#6
and .- R 6
#6
&( and agouti#related protein $9/*%P <i Q .E)- R 6
#=
and
.II,
#=
&(. #&;1#stimulated c9&% production in /"# cells with an +'E6 of 2.2
R 6
#-
&, and c9&% production was inhibited in the presence of 9/*%, an
endogenous antagonist of the &')#*. ;timulation of gonadotropin#releasing
hormone $/n*1( secretion was achieved with n& to S& concentrations of 5>%#
#&;1 while no /n*1 secretion was observed when the /"# cells were treated
with 9/*%. "he data presented here show that /"# cells specifically e!press a
functional &')#* that couples to /n*1 release.
1.4. R7C7PTOR
1
9cetylcholine, 9ngiotensin, 9pelin , Bombesi n, Bradykinin, 'al ci t oni n,
amyl i n, '/*% and adrenomedul l i n, 'alcium#sensing, 'annabinoid,
'hemoki ne, 'hemot act i c pept i de, 'holecystokini, >opami ne, +ndothelin,
/9B9B, /hrelin, /l ut amat e, met abot ropi c, /lutamate, /onadotrophin#
releasing 1ormone $/n*1(, 1i st ami ne, E#1" $E#1ydro!ytryptamine(,
3eukotriene, 3i po!i n, 3ysophosphatidic acid, &el ani n#concent rat i ng
hormone, &elanocortin, &el at oni n, 5europeptide ?, 5eurot ensi n, Opioid
and opioid#like, Ore!in, % 2 ?, %latelet#activating factor $%94(, %rost anoi d,
%rostanoid, %roteinase#activat ed, *ela!in family peptide, ;omat ost at i n,
;phingosine##phosphate, "achyki ni n, "hyrotropin#releasing hormone,
Gasopressi n and o!yt oci n. 9mong these melanocortin receptors are as under.
Me" !n%#%rti n re#et%r
&elanocortin receptors $provisional nomenclature( are activated by members of the
melanocortin family $&;1 0 a, b, and g forms 0 d form is not found in mammals( and
adrenocorticotrophin $9'"1(. +ndogenous antagonists include agouti and agouti#
related protein $9/*%(.
T!b"e n% ). Me"!n%#%rtin Re#et%r
N%$en#"!t
ure
MC1 MC) MC0 MC' MC3
Other
n!$es
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receptor
T T T
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et al., ==-(,
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$Bednarek et
al.,
266(
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&;1
%olymorphisms of the &' receptor have been linked to variations in skin
pigmentation. >efects of the &'2 receptor underlie familial glucocorticoid
deficiency. %olymorphisms of the &') and &'E receptors have been linked to
obesity $'hagnon et al., ==7(.
1.6.PHY5IOLOGY
)4*01
Obesity is caused by a dysregulation in energy homeostasis that

promotes an increase in
body fat stores. "he neuroendocrine

system regulates energy balance by controlling
appetite, as

well as food intake and utilization. 3eptin, a cytokine#like

peptide produced
by adipose tissue in proportion to adipose

mass, acts on the melanocortin system,
inducing proopio melanocortin

$%O&'(

synthesis in the hypothalamic arcuate nucleus.


"he action of %O&'#derived peptides, #, Z#, and #melanocyte0stimulating

hormone
$&;1(, and adrenocorticotropic hormone $9'"1(, is mediated

by a family of guanosine
triphosphate0binding protein

receptors, one of which, melanocortin receptor ) ;&')*(, is
produced at high concentrations within the central nervous system

and plays an important
role in the control of food intake and

energy balance. "he first compelling evidence that
the POMC

gene is involved in the control of human appetite came from

a report of 2
1
defects in 9'"1 synthesis and in POMC gene translation

in 2 children affected by
hyperphagia and uncontrolled obesity

. 8nvestigation of other POMC mutations confirmed
the link

between this gene and obesity in humans and mice.

8ncreased 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. "hese 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 8taly. Our aims

were to identify mutations in
susceptibility genes in relation

to obesity and to identify subgroups in whom major genes
e!ert

greater phenotypic effects.
01
"his application discloses novel piperazinyl amino acid derivatives as ligands for
melanocortin $&'( receptors. "he e!amples in the filing are built around a key, core
fragment from which there are three points of diversity. 8n 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 &' ligands than others.
0)

"he natural melanocortin agonists, J#, V#, W#melanocyte#stimulating hormones $&;1s(,
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
aggressiveFdefensive behavior, and mediation of pain. "hese endogenous neuropeptides
are ligands for the five known subtypes of human melanocortin receptors, which are
e!pressed in various tissues, including skin Mhuman melanocortin# receptor $h&'*(N,
adrenal corte! $h&'2*(, and throughout the central nervous system $h&',*, h&')*,
and h&'E*(.
%revious reports from our laboratories had focused on finding potent and selective
agonists and antagonists for the h&',* and h&')*, which have been implicated to play
complementary roles in weight control.
<!(!r!n! et al. and Bednarek et al. have reported that replacing the 9c#5le
)
#9sp
00
part
of the non#selective superagonist &"#88 $9c#5le
)
#cM9sp
E
, >#%he
7
, 3ys
6
NJ#&;1#
512(with a variety of dicarbo!ylic acid linkers yielded several potent and selective
1
h&',* and h&')* agonists and antagonists. +!tending these studies, a series of novel
cyclic J#&;1 analogs possessing a variety of fle!ible aliphatic and constrained aromatic
and heterocyclic dicarbo!ylic acid linkers $cM'O#*#'O#1is#>#%heF>#5al$2D(#9rg#"rp#
3ysN#512( have been designed and synthesized by solid#phase methods to further
investigate the effects of macrocycle size and fle!ibility on melanocortin receptor
selectivity
0'
).O275ITY
Obesity means having too much body fat. 8t is different from being overweight, which
means weighing too much. "he weight may come from muscle, bone, fat andFor body
water. Both terms mean that a personKs weight is greater than whatKs considered healthy
for his or her height.
Obesity occurs over time when you eat more calories than you use. "he balance between
calories#in and calories#out differs for each person. 4actors that might tip the balance
1
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. 8f you are obese, losing even E to 6 percent of your weight can delay or prevent
some of these diseases.
"he +nglish word [Obesity\ derives from the 3atin Obesus meaning [fat\ or [plump\. "he
first +nglish use of the word was made in IE in Noah Bigg\s medical book
Mataeotechnia Medicinae Praxeos.
8n medical studies, obesity is defined as a person having more than 26 per cent of ideal
weight. 8deal weight takes into account height, age, se! and build of a person. 9ccording
to National Health Institte, :;9, the Body &ass 8nde! of a person is the key factor to
define obesity. 9s per 518 standard, a person with ,6 pounds of more fat content in his
or her body is considered obese.
Body &ass 8nde!, or B&8, is a health indicator of the diseases associated with obese men
and women. "hese health factors include Asilent#killersB such asH diabetes, heart disease
and cancer. &any obese individuals do not even realize they have one or more of these
diseases.
By waist measurement and B&8, body fat can be measured. Obesity is defined as a
waistline of ,E inches or higher for woman and for men a waistline of )6 inches or
higher. "he B&8 formula calculates body weight and height. "he formula works by
dividing an individual\s weight $<g( by their height $meters s.uared(. 8t can also be
worked out by multiplying weight in pounds by 76,, and dividing height in inches. 9gain
a division is necessary by height $inches(.
Obesity can also be defined as a B&8 of ,6 pounds over a person considered normal
weight. Weight standards are calculated according to a person\s height. +!cessive obesity
is defined as ! B&8 of )6 or higher. "here is another way of de!ining o"esit#. 8t is
overweight, with a B&8 of 2E to less than ,6. 9 person\s B&8 of about 2E kgFm $s.uared(
corresponds to about 6 per cent over a normal weight.
Body mass inde! $B&8(9 developed by Belgian anthropometrist $dol%he &etelet, is a
widely accepted scale to measure obesity. 8ts formula is division of the weight of an
1
obese in kilograms by his height in s.uare metres. 9nother formula is B&8 Q weight
$lbs.( ] 76, F height $inches(
03
"he following values are commonly acceptedH
9 B&8 less than -.E is underweight
9 B&8 of -.E # 2).= is normal weight
9 B&8 of 2E.6 # 2=.= is overweight
9 B&8 of ,6.6 # ,=.= is obese
9 B&8 of )6.6 or higher is severely $or morbidly( obese
9 B&8 of ,E.6 or higher in the presence of at least one other significant co
morbidity is also classified by some bodies as morbid obesity.
"o interpret B&8, physicians take into account race, ethnicity, lean mass, age, se! and
other similar factors. 9lthough there is no dispute to accept B&8 to measure obesity, but
it is not accurate in judging body fact of a very muscular person, for e!ample an athlete
or the lost mass of an old person. 8t is also not correct in measuring waist circumference
as it does not take into account differing ratios of adipose to lean tissues. B&8 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 e!tra fat that is stored in tissues as a
result of e!cessive consumption of caloric food, which is not compatible with the routine
manual labor undertaken. ;imply put, what a person takes in they must put out. "his
involves the physical act of eating in comparison with the level of physical movement.
Obesity has become a growing epidemic that pla.ues 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. &any of these health issues are called Asilent#killersB 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. 'hildren and teenagers are becoming
obese at alarming rates. 8t is said that if this trend continues our children\s generation will
not live as long as their parents. "his 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.
1
0.R7LATION =ITH O275ITY
7!r"y Onset Obesity ;MC'R>
4re.uently :sed 9bbreviationsH J#&;1H alpha#melanocyte stimulating hormoneP &')*H
melanocortin ) receptor. Obesity is associated with major causes of morbidity and
mortality. 8t affects appro!imately E62 of the adult and 2E2 of the pediatric population
in the :nited ;tates, making it one of the country\s $and the industrialized world\s( major
current health problems. 8n appro!imately 62 of affected children $2.E2 of the pediatric
1
population(, obesity can be considered severe. 8n appro!imately E2 of severely obese
children, the condition has been linked to autosomal dominant mutations in the gene for
the melanocortin ) receptor $&')*(
04
+arly diagnosis of &')*#related obesity is important, as this type of obesity is unlikely
to resolve without aggressive treatment. <nowing that a child with &')*#related obesity
may not e!perience 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. 8n addition, a diagnosis of &')*#related obesity may relieve feelings of guilt and
failure related to the child\s weight problems in both patient and parents.
/enetic testing provides the only method for definitive diagnosis of &')*#linked
obesity. /enetic testing can also identify carriers of obesity#associated mutations in
&')*, who may be at an increased risk for developing obesity.
M%n%geni# C!uses %& 7!r"y Onset Obesity
;everal different monogenic causes of childhood obesity have been identified. 8n every
case, the mutated gene product plays a role in a comple! signaling pathway believed to
be involved in controlling eating behavior. Within this pathway, binding of J#melanocyte
stimulating hormone $J#&;1( to &')* appears to form a central link.9ffected %rotein
5ormal %hysiological 4unction 3eptin
06
%rotein hormone produced by adipocytesP serves
as one of inputs into signaling pathway believed to be involved in control of eating
behavior 3eptin receptor in hypothalamus. Binding of leptin to leptin receptor stimulates
synthesis of pro#opiomelanocortin. %ro#opiomelano#cortin $%O&'(. %recursor protein for
several peptide hormones, including J#melanocyte stimulating hormone $J#&;1(
%rohormone convertase# 'atalyzes post#translational cleavage of %O&' into J#&;1
&elanocortin ) receptor $&')*( J &;1 receptor e!pressed in the hypothalamusP
binding of J#&;1 to &')* activates anore!igenic signals &')* is e!pressed in the
hypothalamus. ;timulation of &')* by J#&;1 binding triggers the activation of
anore!igenic signals, which, through a series of further steps, are believed to reduce food
intake by creating the perception of satiety. 8n cell culture studies, many of the obesity#
linked &')* mutations have been shown to render the receptor protein dys# or non#
functional. "hus, mutations in &')* appear to prevent the activation of anore!igenic
1
signals in response to J#&;1 binding, so that individuals with obesity#linked mutations
in &')* may not e!perience the feeling of satiety.
3eptin is a protein hormone produced in adipose tissue. 8ts secretion is correlated to
energy intakeH While insulin and cortisol increase leptin secretion, catecholamines
decrease leptin secretion. 9 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 a!es, allowing the body to conserve energy. 8t
is not yet clear, what role short#term leptin fluctuations play in the normal physiology of
weight regulation.
C"ini#!" Present!ti%n %& 7!r"y Onset Obesity
+arly onset obesity first occurs in children
0+
under ten years of age, and is characterized
by hyperphagia and a body mass inde! $B&8( appro!imately four standard deviations
higher than age appropriate. 8n children as in adults, severe obesity leads to insulin
resistance and, conse.uently, hyperinsulinemia. 9ppro!imately ,62 of hyperinsulinemic
individuals eventually develop pancreatic V#cell failure and type 2 diabetes. 9s severely
obese children reach adulthood, other common complications of obesity begin to
manifest themselves, including the metabolic syndrome with its attendant atherosclerotic
cardiovascular disease, type 2 diabetes, nephropathy, retinopathy, and neuropathy. 8n
addition, obese individuals are prone to developing hepatic steatosis, obstructive sleep
apnea, orthopedic complications, and acanthosis nigricans.
8n contrast to several other known monogenic causes of obesity, defects in &')* lead to
non#syndromic obesity. ;ymptoms linked to &')*related early onset obesity include
binge eating behavior, severe hyperinsulinemia, an increase in bone minerals, a higher
linear growth velocity, and an earlier than normal onset of puberty.
Di!gn%sis %& MC'R*Re"!te/ Obesity
;ymptoms accompanying &')*#related early onset obesity are also seen with other
types of obesity and may become apparent only over e!tended periods of time. "hus,
these symptoms do not permit the differential diagnosis of &')*#related early onset
obesity. 8n contrast, genetic testing allows a diagnosis of &')*#related early onset
obesity at any age.
0,
1
Tre!t$ent %& MC'R*Re"!te/ Obesity
"raditionally, childhood obesity has been managed by dietary approaches combined with
efforts to increase physical activity. 1owever, dietary management in general is often
ineffective, and more and more older children and young adults are undergoing bariatric
surgeries. "hese procedures are highly effective in promoting weight loss in the short
term, but have their own attendant complications.
;everal drugs for targeted therapy of &')*#related obesity are presently undergoing
clinical development. "he therapeutic concept is based on the finding that most patients
with &')*#related obesity are heterozygous for the mutation in the &')* gene. ;tudies
in cell culture have indicated that the functionality of a normal &')* protein is not
affected by presence of a mutated receptor protein in the same cell. "herefore, increased
stimulation of the remaining healthy &')* protein with specific drugs may be able to
compensate for the loss of function in the mutated receptor.
Geneti#s %& MC'R*Re"!te/ Obesity
&')*#related early onset obesity is inherited in an autosomal dominant manner. While
individuals with mutations in only one of the two &')* gene copies $heterozygotes( can
e!press the obesity phenotype, patients with mutations in both copies of the &')* gene
$homozygotes( demonstrate more severe obesity. 8n heterozygotes, e!pression of the
obesity phenotype appears to be due to haploinsufficiency, i.e., insufficient amounts of
intact &')* protein are e!pressed from the remaining normal gene copy. %enetrance of
the mutation varies within and between families, i.e., not all heterozygous individuals
carrying an obesityassociated &')* mutation are obese. Within families, female carriers
of obesity#linked &')* mutations are often more severely affected than males with the
same mutation.
'1
Geneti# Testing &%r MC'R*Re"!te/ Obesity
"he +arly Onset Obesity $&')*( +valuation detects mutations in the gene coding for
&')*, which represent the most common monogenic cause of early onset obesity known
to date.
>59 for se.uencing is obtained from leukocytes present in a small blood sample. "he
coding se.uences of &')* are amplified in a highly specific manner through a
1
polymerase chain reaction $%'*(, and all %'* products are fully se.uenced. ;e.uencing
results are interpreted, and a detailed result report is sent to the patient\s physician.
'1
'. 5UMMARY
M!su?!:i H et !". 9 variety of metabolicFmolecular changes in obese adipose tissue
considerably contribute to the pathophysiology of life style#related diseases. 4at cell#
derived hormone leptin controls appetite and energy homeostasis, thereby enhancing
whole body insulin sensitivity. 1owever, clinical application of leptin for the treatment of
1
obesityFmetabolic syndrome has been hampered by the fact that leptin does not fully e!ert
its beneficial metabolic impact on prevalent forms of obesity. 8n an attempt to elucidate
underlying mechanism of leptin resistance in obesity, we found that the activity of
skeletal muscle 9&%#activated protein kinase $9&%<( tightly parallels hypothalamic
leptin sensitivity and metabolic phenotype in transgenic mice overe!pressing leptin.
9ctually, intracerebroventricular administration of melanocortin agonist &"#88 robustly
overcomes high fat diet#induced leptin resistance and ameliorates fuel dyshomeostasis
and hyperphagia in mice, with a concomitant recovery of 9&%< activity in skeletal
muscle, thereby highlighting the system as a therapeutic target for leptin resistance. 8n
this conte!t, type ) melanocortin receptor is a promising drug target for the treatment of
obesityFmetabolic syndrome.
')
H%&b!uer <G et !". OBC+'"8G+H 9ctive immunization in rats may serve several
purposesH the production of a disease#like phenotype, the generation of pharmacologic
tools, and the development of clinically useful therapies. We selected the melanocortin#)
receptor $&')*( as a target because its blockade could provide a treatment for anore!ia
and cache!ia. &+"1O>;H We used a se.uence of the 5#terminal $5"( domain of the
&')* as an antigen. *ats immunized against the 5" peptide produced specific &')*
antibodies $9bs( that were purified and characterized in vitro and in vivo. *+;:3";H "he
9bs acted as inverse agonists and reduced under basal conditions the production of cyclic
adenosine monophosphate in 1+<#2=, cells e!pressing the human &')*. *ats
immunized against the 5" peptide developed a phenotype consistent with hypothalamic
&')* 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. 8n separate e!periments an increase in food
intake was observed after injection of purified &')* 9bs into the third ventricle. When
lipopolysaccharide was administered in 5"#immunized rats the reduction of food intake
was partly prevented in this model of cytokine#induced anore!ia. 'O5'3:;8O5H Our
results show that active immunization of rats against the &')* resulted in the generation
of specific 9bs that stimulated food intake by acting as inverse agonists of the
hypothalamic &')*. %harmacologically active monoclonal &')* 9bs could be the
1
starting point for the development of novel treatments for patients with anore!ia or
cache!ia.
'0
Ti!n 8 et !". 9 study that was designed to identify plausible replacements for highly
basic guanidine moiety contained in potent &')* agonists, as e!emplified by , led to
the discovery of initial nonguanidine lead E. %ropyl analog 2, was subse.uently found to
be e.uipotent to E, whereas analogs bearing smaller and branched alkyl groups at the ,
position of the o!opiperazine template demonstrated reduced binding affinity and agonist
potency for &')*. 9cylation of the 512 group of the )4#>#%he residue of ,#propyl
analog 2, significantly increased the binding affinity and the functional activity for
&')*. 9nalogs with neutral and weakly basic capping groups of the >#%he residue
e!hibited e!cellent &')* selectivity against &'* whereas those with an amino acid
had moderate &')*F&'* selectivity. We have also demonstrated that compound ,E
showed promising oral bioavailability and a moderate oral half life and induced
significant weight loss in a 2-#day rat obesity model.
''
<!-!h!r! Y et !". *59 editing that converts adenosine to inosine replaces the gene#
encoded 8le, 9sn, and 8le $858( of serotonin ME#hydro!ytryptamine $E#1"(N receptor 2'
$E#1"$2'(*( with Gal, /ly, and Gal $G/G(. :p to 2) different E#1"$2'(* isoforms are
detected in different brain regions $Burns et al., ==7P 4itzgerald et al., ===P Wang et al.,
2666(. "o elucidate the physiological significance of E#1"$2'(* m*59 editing, we
derived mutant mouse lines harboring a knock#in 858 or G/G allele, resulting in sole
e!pression of one of two e!tremely different editing isoforms E#1"$2'(*#858 $editing
blocked( or #G/G $fully edited(. 9lthough 858 mice grew normally, G/G mice had a
severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive
activation of the sympathetic nervous system and increased energy e!penditure.
4urthermore, serotonergic neurotransmission was oversensitized in G/G mice, most
likely because of the increased cell surface e!pression of G/G receptors. &elanocortin )
receptor $&')*( regulates energy homeostasis $Balthasar et al., 266EP 1eisler et al.,
266IP 3am et al., 266-(, and &c)r$#F#( mice are obese because of hyperphagia and
reduced energy e!penditure $1uszar et al., ==7(. 1owever, the elevated energy
e!penditure of G/G mice could not be rescued in the &c)r$#F#( background, indicating
the presence of a distinct signaling pathway mediated via E#1"$2'(*#G/G that
1
dominates the &')*#dependent pathway in control of energy e!penditure. Our results
highlight the importance of regulated E#1"$2'(* m*59 editing, because dysregulation
could result in the pathological conse.uences such as growth retardation seen in G/G
mice.
'3
P!r: T@ et !". 8t has been demonstrated that human melanocortin#) receptor $h&')*(
plays an important role in the control of energy homeostasis, and heterozygous mutations
in the h&')* gene are the most fre.uent genetic cause of severe human obesity. 8n order
to obtain additional insight into the structure and function, we cloned, e!pressed, and
purified the second transmembrane domain of the wild#type h&')* $wt#"&2( and
>=65 mutant h&')* $m#"&2(. "o facilitate structural studies of these h&')* by solid#
state 5&*, efficient methods for the production of milligram .uantities of isotopically
labeled protein are necessary. 1owever, large#scale production of most transmembrane
proteins has been limited by e!perimental adversities due to insufficient yields and low
solubility of protein. 5evertheless, through the optimization of the e!pression and
purification approach, we could obtain uniformly or selectively labeled fusion proteins in
yields as high as 266#2E6 mg per liter &= minimal medium. "hese proteins were
overe!pressed in inclusion bodies as a fusion protein with ketosteroid isomerase $<;8( in
+scherichia coli, and the fusion protein was purified using immobilized metal affinity
chromatography under denaturing conditions. wt#Fm#"&2 peptides were released from
the fusion by cyanogen bromide cleavage at the &et residue and separated from the
carrier <;8 by size e!clusion chromatography. 8nitial structural data obtained by solution
5&* measurements of wt#Fm#"&2 is also presented. "he successful application to the
production of the second transmembrane domain of human &')* indicates that the
method can be applied to other transmembrane proteins as well and also enable its
structural and functional studies using solid#state 5&* spectroscopy.
'4
Gut! A et !". "he offspring of high fat $14( diet#fed rats display increased body weight
during adulthood. 1owever, 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 14 diet prior to and during pregnancy on leptin and insulin signaling and
the e!pression of ore!igenic and anore!igenic peptides in term fetal hypothalami. "he
consumption of a 14 diet prior to and during pregnancy resulted in obesity in 14 female
1
ratsP additionally, 14 female rats e!hibited hyperinsulinemia and hyperleptinemia which
were e!aggerated in late gestation compared with control female rats that were fed a
standard rodent laboratory chow $3'(. "erm fetuses of 14 female rats $414( also had
significantly higher serum leptin and insulin levels compared with control fetuses $43'(
while there was no difference in average fetal weight between the two groups. 414
hypothalami showed elevated levels of m*59 and proteins for leptin long receptor and
insulin receptor beta subunit. 1owever, the protein levels of ;"9"#, and insulin receptor
substrate#2, the downstream signaling components of leptin and insulin signaling
respectively, were decreased. 9lso, 414 hypothalami had increased m*59 levels of
neuropeptide ? and agouti#related polypeptide indicating that ore!igenic neuropeptides in
14 progeny are already upregulated by term fetal stage. 9dditionally, the m*59 levels
of pro#opiatemelanocortin and melanocortin receptor#) were also increased in the 14
fetal hypothalami. "hese findings indicate potential programming effects of an altered
intrauterine environment induced by 14 diet consumption on appetite#regulating
neuropeptides and leptin and insulin signaling in the late fetal period.
'6
Hughes DA et !". "he melanocortin ) receptor $&')*( is routinely investigated for the
role it plays in human obesity, as mutations in &')* are the most common dominantly
inherited form of the disease. 9s little is known about the evolutionary history of this
locus, we investigated patterns of variation at &')* in a worldwide sample of ,6E
humans from E populations, and in - central chimpanzees. "here is a significant paucity
of diversity at &')* in humans, but not in chimpanzees. "he 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. "he &')* coding region was rese.uenced in 2 primate species and
se.uences from an additional 2= vertebrates were included in molecular evolutionary
analyses. &')* is highly conserved throughout vertebrate evolution, and has apparently
been subject to high levels of continuous purifying selection that increased appro!imately
threefold during primate evolution. 4urthermore, the strong selection e!tends to codon
usage bias, where most silent mutations are e!pected to be either .uickly fi!ed or
removed from the population, which may help e!plain the unusually low levels of silent
polymorphisms in humans. 4inally, there is a significant tendency for non#synonymous
1
mutations that impact &')* function to occur preferentially at sites that are identified by
evolutionary analyses as being subject to very strong purifying selection. "he information
from this study should help inform future epidemiological investigations of &')*.
'+
3. LI5T OF A22R7AIATION
ACTHH 9drenocorticotropic hormone
AGRPH 9gouti related protein
H511'H 'yclic M9c'ys,>#5al),'ys-,9sp#512$22(N#V#&;1$#2 2(
H51)+H M9c'ys,dichloro#>#phenylalanine),cys-,9sp#512 22NV#&;1$#22(
J*M5HH J#&elanocyte stimulating hormone
1
W*M5HH W#&elanocyte stimulating hormone
W)*M5HH W2#&elanocyte stimulating hormone
R% )6 0))3H 5#$#O!obutyl(#3#histidyl#3#phenylalanyl#3#arginyl#3#tryptophyl#52#
methyl#glycinamide
R% )6*'4+1H 5#$#O!obutyl(#3#histidyl#,#$2#naphthalenyl(#>#alanyl#3#arginyl#3#
tryptophyl#52#methyl#glycinamide
5HU,11,H 9c#5le)#cM9sp),>#5al7,3ys6N#J#&;1$)#6(#512
PCR: polymerase chain reactionP
5NP: single nucleotide polymorphismP
55CP: single strand conformation polymorphismP
RFLPH restriction fragment length polymorphism.
2MI: Body mass inde!P
5D5: sd score
-MSH: alpha#melanocyte stimulating hormoneP
MC4R: melanocortin ) receptor
THIB: 5#$M,*N#,2,,,)#tetrahydroiso.uinolinium#,#ylcarbonyl(#$*(##$)#
chlorobenzyl(#2#$)#cyclohe!yl#)#M1# ,2,)#triazol#ylmethylNpiperidin##yl(#2#
o!oethylamine
4. LI5T OF TA2L75 AND FIGUR75
. 4igure shows 8n the upper panel a schematic illustration of the structure of the
&')* is given.
2. 4igure shows the location of &')* in conte!t on chromosome -.
,. 4igure shows the predicted structure of the &')* protein. "his protein also has
the synonym &')#*.
1
). "able no . classification of melanocortin receptor
E. "able no 2. &elanocortin *eceptor
6.R7F7R7NC7
'. www.jci.org^articles^view
(. 1ofbauer, <. /., 9nker, ;. >., 8nui, 9.,5icholson, C. *., +ds. $266I(
Phar)acothera%# o! Cachexia, '*' %ress, "aylor _ 4rancis /roup, Boca *aton,
43, :;9, 266I.
1
*. 5icholson, C. *., <ohler, /., ;chaerer, 4., ;enn, '., Weyermann, %. _ 1ofbauer,
<. /. $266I(. %eripheral administration of a melanocortin )#receptor inverse
agonist prevents loss of lean body mass in tumorbearing mice. +. Phar)acol ,x%
"her ,7, 77#777.
4. 5ordheim, :., 5icholson, C. *., >okladny, <., >unant, %. _ 1ofbauer, <. /.
$266I(. 'ardiovascular responses to melanocortin ) # receptor stimulation in
conscious unrestrained normotensive rats. Pe%tides 27, ),-#)),.
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Clin ,ndocrinol .ia" ), )7E#)-).
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<. /. $2667(. 9ntibodies against the melanocortin#) receptor act as inverse
agonists in vitro and in vivo. + Ph#siol Regl Integr Co)% Ph#siol 2=2, *2E#
*2E-.
0. 5icholson, C. *., %eter, C. '., 3ecourt, 9. '., Barde, ?. 9. _ 1ofbauer, <. /.
$2667(.
1. receptor activation stimulates hypothalamic B>54 release to regulate food intake,
body.
2. temperature and cardiovascular function. +. Neroendocrinolog# =, =7)#=-2.
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*oetzler, chromosomal location of the MC4R $melanocortin#) receptor( gene in
the dog and red fo!, >epartment of /enetics and 9nimal Breeding, 266IP2H627.
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httpHFFwww.ncbi.nlm.nih.govFsitesFentreza
>bQgene_'mdQ;how>etailGiew_"erm"o;earchQ)I6.
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in obesity in mice`. --H ,#).
1
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