review
Emerging drugs for obesity therapy
Novos fármacos para o tratamento da obesidade
Maria Teresa Zanella1, Fernando Flexa Ribeiro Filho1
Abstract Central obesity have an important impact on the development of risk factors for coronary heart disease, including dislipidemia, glucose intolerance, insulin resistance and hypertension. These factors contri- bute to building cardiovascular (CV) disease as a major cause of death. The approach to obesity therapy should be designed to reduce CV risk and mortality. Diet and lifestyle changes remain the cornerstones 1 Endocrinology Division, of therapy for obesity, but the resultant weight loss is often small and long-term success is uncommon Universidade Federal de São and disappointing. Drug therapy is considered for individuals with a body mass index greater than Paulo (Unifesp), São Paulo, SP, 2 2 Brasil; Clinical Research Center of 30 kg/m or ranging from 25 to 30 kg/m if they have comorbid conditions. Antiobesity agents can be Hypertension and Cardiovascular helpful to some patients in achieving and maintaining meaningful weight loss, but yet our pharmaceu- Metabology, Fundação Oswaldo tical tools are of limited effectiveness considering the magnitude of the problem. At the present, only Ramos, São Paulo, SP, Brasil two drugs, orlistat and sibutramine, are approved for long-term treatment of obesity and promote no more than 5 to 10% of weight loss. Rimonabant, a cannabinoid-1 receptor antagonist, was withdrawn from the market because of concerns about its safety, including risk of suicidal and seizures, although very effective in promoting clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors, rimonabant, a cannabinoid-1 receptor antagonist was withdrawn from the market because it concerns about its safety, including risk of suicidal and seizures. Fortunately, recent fundamental insights into the neuroendocrine mechanisms regulating body weight provide an expanding list of molecular targets for novel, rationally designed antiobesity drugs. In this review, the therapeutic potential of some antiobesity molecules in the development will be analyzed based on an understanding of energy homeostasis. Arq Bras Endocrinol Metab. 2009;53(2):271-280. Keywords Obesity therapy; antiobesity drugs; antiobesity molecules, weight loss
Resumo Obesidade e, particularmente, a obesidade central têm influência importante na predisposição a fa- tores de risco para doença coronariana, incluindo dislipidemia, intolerância à glicose, resistência à insulina e hipertensão. Tais fatores contribuem para tornar as doenças cardiovasculares (DC) causas frequentes de morte. Os métodos de tratamento da obesidade deveriam ser voltados à redução do risco e da mortalidade devido às doenças cardiovasculares. Dietas e mudanças no estilo de vida con- Correspondence to: tinuam sendo fatores-chave no tratamento à obesidade, mas a perda de peso resultante é geralmente Maria Teresa Zanella Departamento de Medicina pequena e o sucesso em longo prazo costuma ser incomum e frustrante. O tratamento com medica- da Universidade Federal de mentos é indicado para indivíduos com índice de massa corpórea superior a 30 kg/m2 ou entre 25 e São Paulo, Hospital do Rim e 2 Hipertensão 30 kg/m , se apresentarem comorbidades. Agentes antiobesidade podem ajudar alguns pacientes a Rua Leandro Dupret, 365 alcançar e manter uma perda de peso significativa, mas, ainda assim, os agentes farmacológicos são 04025-011 – São Paulo, SP, Brasil pouco efetivos considerando-se a magnitude do problema. Atualmente, apenas duas drogas, orlistat [email protected] e sibutramina, são consideradas efetivas para tratamentos em longo prazo, promovendo não mais do Received in Feb/19/2009 que 5% a 10% de perda de peso. Embora seja muito eficaz ao promover perda de peso significativa do Accepted in Mar/09/2009 ponto de vista clínico, redução da circunferência da cintura e melhora no perfil metabólico, o rimona- banto, um antagonista do receptor canabinoide 1, foi retirado do mercado por fatores relacionados à segurança, incluindo a ocorrência de suicídios e convulsões. Felizmente, conhecimentos funda- mentais recentes sobre mecanismos neuroendócrinos que regulam o peso corporal forneceram uma lista considerável de alvos moleculares para novas drogas antiobesidade produzidas racionalmente. Nesta revisão de literatura, a eficácia terapêutica de algumas moléculas antiobesidade será analisada com base no entendimento da homeostase energética. Arq Bras Endocrinol Metab. 2009;53(2):271-280. ABE&M todos os direitos reservados. ABE&M todos os direitos © Descritores Tratamento da obesidade, novas moléculas antiobesidade; drogas antiobesidade; perda de peso Copyright
Arq Bras Endocrinol Metab. 2009;53/2 271 Copyright© ABE&M todos os direitos reservados. fectiveness in the in fectiveness ef- limited of are tools pharmaceutical our yet but loss, weight meaningful maintaining and achieving in tients conditions. Antiobesity agents can be useful to some pa- standing under an on based analyzed be will development the in molecules antiobesity some of potential therapeutic rationally designed In antiobesity this drugs. review, the provide an expanding list of molecular of list expanding an provide 30 kg/m than 30 greater (BMI) index mass body a with dividuals disappointing. Drug therapy has been considered for in- small and long-term success is extremely uncommon and therapy for obesity, but the resultant weight loss is often events andmortality. cardiovascular of risk the reduce to designed be should therapy obesity to many approach the Thus, countries. other and States United the in death of cause major a as disease cardiovascular build to markedly tributing con- been have factors risk these All hypertension. and resistance insulin intolerance, glucose dislipidemia, ing includ- disease, heart coronary for factors risk posing larly central obesity, has an important impact on predis- middle-income and low countries, likeBrazil. in rise now the is on obesity dramatically of prevalence the countries, income 272 and intake energy because activity physical and take in- food in fluctuations large despite time, of periods long for stable remains weight body humans, most In weight Neuroendocrine regul a O INTRODUCTION New drugsforobesity the neuroendocrine mechanisms into insights fundamental recent Fortunately, seizures. and suicidal of risk safety,including its about concerns to due market the from withdrawn was antagonist tor - recep cannabinoid-1 a rimonabant, factors, risk bolic meta- several in improvements and circumference waist in reduction loss, weight meaningful clinically moting and each of these typically promotes 5% to 10% to 5% promotes typically these of each and obesity of treatment the in use long-term for approved At present, only two orlistat drugs, and sibutramine, are f oy eg (1,2). weigh body of Diet and lifestyle changes remain the cornerstones of There is growing evidence that obesity, and particu- wide. Once considered a problem only in high- in only problem a considered Once wide. besity has reached an epidemic world- proportion
of energy homeostasis. 2 , or of 25 to 30 kg/m 30 to 25 of or ,
face of the magnitude of the problem. problem. the of magnitude the of face
- pro in effective very Although tion ofbod
2 regulating regulating body weight if they have comorbid comorbid have they if
targets for novel, targetsnovel, for y
of
loss loss - diture, expen- energy increase and intake food decrease sulin grated by the hypothalamus to determine mealssize. grated bythehypothalamustodetermine inte- primarily are which signals satiety via brain the to ity and content is relayed from the gastrointestinal tract status of body energy stores is communicated to the the central to communicated is stores energy body of status The (CNS). system nervous central and system gestive di- the between communication by achieved is This control 1). (Figure requirements energy current to size weightloss. promote to reduce food intake or increase energy expenditure to networks regulatory catabolic or anabolic target which development, in therapies obesity novel understanding for essential is homeostasis energy regulate that nisms mecha- the understanding Thus, regain. weight favor to synchronically acts and expenditure energy decrease circulating thyroxine and triiodothyronine changes that and tone system nervous leptin, of concentrations ing circulat- in decreases induces reduction weight Body against gain. weight against defends than efficiently more system loss weight homeostatic this diet, who those for Unfortunately, (4). obesity of determinant only the not is behavior that theory the weight supports and body maintain to tends mechanism complex This requirements. energy signaled with line in tered al- is Consequently,intake pathways. food catabolic or anabolic either modify to order in signals satiety adiposity and by brain the to transmitted is reserves ergy en- of status the about information which in system a retarded further weight gain. These observations reflect which expenditure energy in increase an with sociated as- was gain weight Similarly, regain. weight favoring coordinately acts and loss weight further retards which expenditure energy resting and total in decrease a with associated was 20% to 10% of loss Weight (3). excess caloric and restriction caloric during monitored were never-obesewho 23 subjects and obese 18 of study ful of portance this control system was illustrated in im- a care- The homeostasis. energy of mechanism neuroendocrine complex a through matched are expenditure peptides, proportionate decreases in leptin and insulin and an an and insulin and leptin in decreases proportionate thus termed an anabolic hormone. anabolic an termed thus aaoi adiposity catabolic ronal targets, ghrelin targets, ronal mones leptin, mones Acting in the brain, leptin and, in a less a in and, leptin brain, the in Acting Energy homeostasis is maintained by adapting meal meal adapting by maintained is homeostasis Energy
nervous system by the adiposity-associated hor adiposity-associated the by system nervous promoting weight loss, thus being considered considered being thus loss, weight promoting
such as ghrelin (5). Information on meal qual-
insulin and selected gastrointestinal (GI) (GI) gastrointestinal selected and insulin
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exerts the opposite effects and is is and effects opposite the exerts Arq BrasEndocrinol Metab.2009;53/2
Weight loss evokes evokes loss Weight
extent, in- extent, - centers responsible forenergy homeostasis. centers responsible both tonically inhibit POMC neurons via NPY Y NPY via neurons POMC inhibit tonically both (GABA); acid gamma-aminobutyric and (AgRP) tein pro- agouti-related release neurons NPY intake. food of suppression to lead (CART), and (a-MSH) mone hor- melanocyte-stimulating of release the via LHA, the in (MCH) hormone melanocortin-concentrating and orexin neuropeptides orexigenic of release the ing inhibit- and PVN, the in (CART) transcript regulated cocaine-and-amphetamine- and (CRH) hormone ing corticotrophin-releas- neuropeptides anorexigenic the lin stimulate POMC the promoting of neurons, release insu- and Leptin (LHA). area hypothalamic lateral and lamic regions such as the paraventricular nucleus (PVN) hypotha- other to ARC the from project that neurons ropeptide Y (NPY) (POMC) and proopiomelanocortin insulin and leptin receptors are located in ARC, on neu- are positively correlated to adiposity (6). Hypothalamic levels circulating its and tissue adipose from secreted especially its arcuate nucleus (ARC). Leptin is primarily balance, energy for centers important most the of one anabolic neuropeptides and neurotransmitters and neuropeptides anabolic Arq Bras EndocrinolMetab.2009;53/2 corresponding induce nals sig- anabolic and catabolic These ghrelin. in increase its tasteandchemicalcontent, andhowmuchthestomachisdistended. hypothalamus. Neuroendocrine signals from the stomach, the gastrointestinal system and the liver are sent to the hindbrain, providing information about the food that is eaten: 1.Figure nrxgnc erppie CH n CR i the in CART and CRH neuropeptides anorexigenic the of release the inhibit neurons NPY/AgRP ceptors. In the central nervous system, the hypothalamus is hypothalamus the system, nervous central the In Signals such as leptin and insulin are secreted in proportion to the size of the fat mass and circulate in the blood. They enter the brain and act at the level of the the of level the at act and brain the blood.enter the They in circulate and mass fat the of size the to proportion in secreted are insulin and leptin as such Signals tissue Adipose
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Pathway Anabolic activation in weight gain. These observations observations These gain. weight in activation
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aoit ad antagonists and agonists ) T NTS New drugsforobesity ting 273
Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 274 intake andbodyweight. food in increases promote centers, reward mesolimbic and nerve, vagus hindbrain, hypothalamus, the on ing act- and, loss weight with increases also Ghrelin initia- tion. meal promote to appears it hunger increasing by and meals, after, than rather before, shortly occurs orexigenic peptide ghrelin, primarily from the stomach, regulat- way,the opposite of the In secretion (5). size meal ing to contribute also which insulin, and leptin hormones, adiposity catabolic long-acting en- by is hanced signals satiation GI afferent to response brain meals, also promotes satiety (14). The sensitivity of the to response in pancreas the from insulin with secreted co- peptide a is which Amylin, size. meal determine to centrally integrated are networks, feeding pothalamic hy- the from those and signals, satiety These brain. the to information convey nerve, vagus the on specific receptors to binding and, (13) feeding during gut in the released are peptide-1) glucagon-like and peptide poly- pancreatic YY3-36, peptide cholecystokinin, (as peptides GI cues, caloric and volumetric to response In tract. (GI) gastrointestinal the from signals satiety communicatedtothe brainthrough nutrient statusare in alterations Short-term pathways. endocrine and ral trollers of energy balance in the brain by means of neu- con- the with communicate vasculature, portal the in elements and Langerhans, of islets pancreatic the gut, The homeostasis. energy of physiology the signaling and sensing key-role a play system gastrointestinal the target sites(12). atmelanocortin release in increase reciprocal a to lead processes These receptors. 5-HT2C on effects 5-HT also directly activates POMC neurons through its input to decreasing GABAergicPOMC cells. inhibitory hyperpolarizes and inhibits NPY/Agrp neurons, thereby 5-HT neurons, receptors, 5-HT1B through NPY respectively.Acting and POMC hypothalamic on located receptors, 5-HT1B and 5-HT2C by mediated are fects inhibition of 5-HT release causes hyperphagia. These ef- agents forobesitytherapyhasbeenalsodiscontinued. velopment of other cannabinoid-1 receptor antagonists the withdrawn of ribonabant the from market. The de- to lead disorders mood-related of incidence increased However, (11). syndrome metabolic with patients in promoting in profile metabolic the effective in improvements and loss weight very be to shown was agent obesity.This of treatment the for antagonist, receptor New drugsforobesity In addition to digesting and assimilating nutrients, assimilating and digesting to addition In Enhanced 5-HT causes release hypophagia, whereas a -MSH and decrease in AgRP in decrease and -MSH namely, suppressor of protein protein tyrosine phosphatase-1B eptin L Central stimulatorsagentsofcatabolicpathways ing energy expenditure. loss, either by a reduction in food intake, or by increas- weight in results that development in agents cological priority. a be should drugs effective and safe of development the state, pandemic treat- ments and the public-health implications of the obesity weight-loss successful of lack the Considering EXPERIMENT tion of either of these autoinhibitory intracellular proteins gy homeostasis. Leptin receptor activation engages two diators of leptin resistance in brain areas critical to ener diet-induced obesity have identified some potential me- with animals in studies Experimental investigation. tive hypothalamic leptin and insulin resistance are under ac- of lowleptinlevels. effects neuroendocrine counter-regulatory the reduce weight loss agent to an adjunctive therapy to a primary as developed be could leptin Thus, (15). energy expenditure in decrease the to associated gain weight the preventing by loss weight significant after weight ing study suggested that leptin therapy may prevent regain- small One not. or sustained be can effect the whether overcome with high doses of leptin, but it is not known (16). These results suggest that leptin resistance can be 0.03 the in mg/kg group and to -7.1 kg in kg the 0.30 mg/kg group -1.4 to group placebo the in kg -1.3 dose-dependent decrease in body weight, ranging from kcal less than requirement each day), there was a weakly nant human leptin for 24 weeks (and advised to eat 500 en and men given placebo or doses varying of recombi- duced with weight loss. In a study with 47 obese wom- re- be can which levels, leptin circulating elevated have and leptin-resistant are patients obese that discovered an effective antiobesity therapy. However, shortly it was provide would leptin that hoped was it identified, first When (15). loss weight causes and intake food creases de- leptin of doses physiological of administration the deficiency,leptin with humans few in and mice In sue. Leptin is a peptide produced primarily in adipose tis- The intracellular signaling mechanisms involved in in involved mechanisms signaling intracellular The Mechanisms ofinsulinandleptinresistance AL DRUGS
that terminate receptor signaling –
cytokine signaling-3 (SOCS3) and Arq BrasEndocrinol Metab.2009;53/2 There are several pharma- several are There
(PTP1B) – and inhibi-
factors could theo- - uain n L4 are TLR4 in mutation sistance (23). mice Furthermore, with a loss-of-function tracellular pathwaysinflammatory that induce insulinre- ment of diet-induced obesity and ly in body-weight regulatory body-weight in ly sity deserves caution since SOCS3 since caution deserves sity ever, the inhibition of SOCS3 as a strategy to treat obe- inln. y nacn eeg epniue n sup- and expenditure energy enhancing By signaling. is related to the Arq Bras EndocrinolMetab.2009;53/2 the intermediary is key POMC first pathway, leptin-melanocortin the In Melanocortin-4 receptoragonists shown that SOCS3 been has It (17,18). sensitivity leptin increase retically translating However, (21). hypothalamus in action insulin and tin diet. These were effects associated with increases in lep- high-fat after adiposity and weight body in reductions intake, food in decreases in results ventricle, third the surrounding areas hypothalamic rat in oligonucleotide, antisense an of infusion by induced expression, PTP1B of blockade selective that shown been has In it addition, (20). diet high-fat a fed when obesity to and resistant leptin and insulin to hypersensitive are mice out just leptin signaling, and homozygous global homozygous and signaling, leptin just the treatment ofobesityandinsulinresistance. the treatment for strategy important an as future, the in emerge, may activation its to response inflammatory the with or even TLR4 with interference selective a Thus, (25). tin resistance to the anorexigenic hormones insulin and lep- induces an response inflammatory which determines the network, signaling intracellular the triggering and, mus hypothala- the in acids fatty saturated for target lecular mo- predominant a as acts of obesity,TLR4 diet-induced models animal in that shown was it recently More ugss an suggests mice die mice activation of TLR4 signaling leads to up regulation talk (22) and has been recognized as a mediator in the cross- munity. TLR4 can be activated by saturated fatty saturated by activated be can munity.TLR4 im- and inflammation in role important an play which receptors Toll-like of subclass a is (TLR4) 4 receptor The Toll-like response. inflammatory abnormal of state functionsofthisenzyme. ing inotherimportant be a viable It is well known that obesity is associated with a a with associated is obesity that known well is It
between inflammatory and metabolic signals. The signals. metabolic and inflammatory between in utero utero in
antiobesity drug antiobesity target, drug since PTP1B knock- these promising findings into clinical utility utility clinical into findings promising these
tooia rl i lpi rssac. How- resistance. leptin in role etiological
difficulty of inhibiting PTP1B selective- (19). Also, potentially,Also, might (19). PTB1B
activity is increased in obesity, which
downstream of leptin-receptor leptin-receptor of downstream rtce aant h develop- the against protected
circuits without interfer without circuits
insulin resistance (24).
regulates more than than more regulates
knockout knockout
of in- acids acids - oe ovrae1 produces, convertase-1 mone prohor by POMC of Cleavage weight. body of tion - regula hypothalamic the in role primary a play POMC from derived peptides melanocortin appetite, pressing and dexfenfluramine and of serotonin-induced satiety, probably acting through through acting probably satiety, serotonin-induced of mediators as recognized specifically been have receptors 5-HT2C and 5-HT1B Serotonin processes. behavioral cs through acts theoppositeeffect. activationproduces 5-HT receptor decreasing whereas consumption, food reduces ceptors, - re 5-HT the the of activation in direct the reuptake or cleft, and synaptic release its affecting by 5-HT of availability the Increasing neurotransmission. tonergic sero- and dopaminergic noradrenergic, influencing by effects their mediate and adrenaline), and noradrenalin dopamine, neurotransmitters the of structure skeletal 5-HT system are typically derived the from targeting medications Anorectic (5-HT)]. tor subtypes to modulate to subtypes tor lncly o treat to clinically Three of the pharmacological agents that have been used Subtype-selective serotonin-receptoragonists h neurotransmitter the the processing ofthebodyfatsignal(27). the processing receptors or of at the subsequent melanocortin steps in level the at alterations from derive may peptides MSH ACTH/ to sensitivity decreased a subjects, overweight in that is hypothesis The systems. regulatory weight ic hypothalam- on administration melanocortin of effects the to susceptible not are subjects overweight humans, normal-weight with contrasting that, conclude authors The placebo. of effects the to compared as leptin and insulin of levels plasma and fat, body weight, body in reduction significant any induce not did (4-10) ACTH tions (26). However, in individuals, overweight MSH/ concentra- plasma insulin and leptin in decreases cant signifi- by accompanied fat, body and weight body of core fragment of POMC resulted in a distinct reduction (4-10) MSH/ACTH the of administration intranasal tion downstream their specificroles in energy homeostasis and their posi- of because therapies antiobesity for targets possible as tors (Mc3r, c4r). M These receptors were recognized a -MSH, which activates melanocortin-3 and melanocortin-3 activates which -MSH, Serotonin is a monoaminergic neurotransmitter that that neurotransmitter monoaminergic a is Serotonin
n suy n omlwih aut, h 6-week the adults, normal-weight in study a In
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(d-FEN) – all increase signaling by by signaling increase all – (d-FEN)
serotonin [5-hydroxytryptamine [5-hydroxytryptamine serotonin
numerous sensory, motor, and and motor,sensory, numerous
among other peptides, peptides, other among b -phenethylamine (the
resistance. New drugsforobesity
- recep -4 275 -
Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. mechanism of action has to be proven yet. yet. mechanism ofactionhastobeproven drug potential this However, compound. this of action anorexigenic the to contribute mCPP,can theoretically, of action anti-inflammatory cerebral this (27), resistance pathways involved in the hypothalamic leptin and insulin inflammatory intracellular of regulation up the in cated impli- is acids fatty saturated by TLR4 of activation the that Considering (29). kinase protein mitogen-activated p38 of phosphorylation and B factor-kappa nuclear the 1beta and TNF-alpha, and inhibits both the activation of the expression of cytokines,pro-inflammatory such as attenuates IL- mCPP that cultures astrocyte and microglia (LPS)-stimulated lipopolysaccharide in shown been has it action, serotoninergic its to addition In intake. loric ca- reduced in resulting humans, obese and lean both in appetite modify to showed have (mCPP) nylpiperazine - chlorophe agonist receptor 5-HT2C the and fluoxetine 276 increases food intake been shown that chronic NPY administration powerfully has It leptin. and insulin hormones anorexigenic the by inhibited neuropeptide anabolic hypothalamic a is NPY Neuropeptide Y(NP) pa Central Ihibtorsgetsofanabolc activate hypothalamic POMC input hibitory to POMC cells. Serotoninergic agents also inhibits NPY/ and hyperpolarizes 5-HT receptors, 5-HT1B through Acting system. melanocortin hypothalamic the New drugsforobesity ment. Lorcaserin (APD356) is a selective 5-HT receptors receptors which subsequently reducing development isthe5-HT Board (EDSMB), and so the trial continues (31). Also in Monitoring Safety Data Echocardiographic dependent in- an by developed criteria trial-stopping the meet not did (“BLOOM”) trials IIIclinical Phase three of first the of participants the of echocardiograms the vation, obser of months 12 After drugs. serotonergic drawn with- previously as way same the in damage valve heart cause not does Lorcaserin (30). group placebo the for kg 0.3 with compared respectively,daily, mg 20 or 15 10, of administration 12-week a following kg 3.6 and compound demonstrated average weight loss of 1.8, 2.6 the final phase III of clinical undergoing trials. Phase IIb data for currently this is which obesity, for agonist tor thw eea 5-HT Several ern, hs eraig AAri in- GABAergic decreasing thus neurons, Agrp a
food intake (28). Sibutramine, dexfenfluramine, ys 2C eetr gnss r i develop- in are agonists receptor
and body weight. NPY, however, is 2C agonistWAY-163909 (32).
activates Mc3R and Mc4r,
neurons through 5-HT2C 5-HT2C through neurons 2C - recep - This phagia on administration of selective Y selective of administration on phagia the ARC and preclinical data have shown marked hyper to target them for obesity without difficulty a imposes It Y6). and Y5, Y4, Y2, (Y1, types pic functions that act through at least fivereceptors sub- - pleiotro with neuropeptide, central abundant most the ucin byn feig sc a locomotor as such feeding, beyond functions mediated are MCH of effects feeding The area. hypothalamic eral lat- the of neurons in expressed is and resistance leptin one of the isoforms as receptor Y5 the identified studies Some effects. side The NPY Y NPY The loss. weight promote to targeted be could that NPY of an dicinal blockade of MCH signaling has been explored as Melanin-concentrating hormone(MCH) tite and decreases food intake apparently by activating by apparently intake food decreases and tite appe- suppresses (PYY) YY peptide hormone gut The Peptide YY (PYY) 1). (NTS) inthebrainstem(Figure which nerve, projects thevagal to the nucleus as of the tract such solitary neurons of activity the influence to CNS the of outside function postrema. also may peptides area These the and hypothalamus the of (ARC) nucleus arcuate the including intake, food of ulation direct access to regions of the brain involved in the reg- have peptides gastrointestinal circulating the of Many Food Int Gastrointestinal PeptidesTha asaneffective proven be to yet has antagonism MCHR1 effects. side unde- sirable eliciting without homeostasis energy modulate ropeptide neu- hypothalamic orexigenic leptin-inhibited Another 0577 were abandoned because of lack of efficacy (33). abandonedbecauseoflackefficacy(33). 0577 were MK- of trials two phase, 1-year a in However 3.6 kg. of (1,600 S-2367 administered patients, obese with trial clinical a ever,in and MK-0577, are NPY Y NPY are MK-0577, and S-2367 system, NPY the targeting Compounds nists. is not easy to design anti-MCH agents that selectively that agents anti-MCH design to easy not is it learning; and processing sensory aggression, anxiety,
antiobesity modality. However, MCH regulates many
peptide acts downstream of at least some levels of of levels some least at of downstream acts peptide
by, the MCH1 receptor (MCHR1) (34). Me- (34). (MCHR1) receptor by,MCH1 the is melanin-concentrating hormone (MCH). (MCH). hormone melanin-concentrating is ake 5 receptor is located on POMC neurons in in neurons POMC on located is receptor mg, 12 weeks) promoted a weight loss loss weight a promoted weeks) 12 mg,
responsible responsible for the orexigenic effects
treatment forobesity.treatment 5 Arq BrasEndocrinol Metab.2009;53/2 receptor antagonists. How- antagonists. receptor
eliciting unacceptable t Regula 5 receptor ago- receptor
activity, te -
hours (37). As with PYY with As (37). hours 24 following the over intake food in - pro decrease a longed causes and hours, two just after appetite ishes dimin- rapidly infusion PP individuals, normal-weight a biphasic manner, in proportion to calories ingested. In neurons neurons in the hypothalamus, nous PYY nous intrave- short-term that adults, lean and obese of trial a in shown, been has It neurons. POMC anorexigenic norgd long-term encouraged (TM30338) of both PYY both of (TM30338) analogue synthetic A postrema. area the in located tors agonist of both the Y Arq Bras EndocrinolMetab.2009;53/2 lizard the from lated iso- receptor GLP-1 the of agonist occurring naturally a is Amylin/Lilly), (Byetta; exenatide (39) Exendin-4 Glucagon-like peptide-1(GL P-1) PYY Like take. in- food by regulated primarily are concentrations PP PYY.Plasma as family peptide same the to belongs gut distal and pancreas the of cells endocrine duodenal the in expressed primarily is that peptide 36-amino-acid A Pancreatic polypeptide(PP) autoinhibitory level, uptoatleastninehoursafterdosing(38). significant statistically a at intake, food inhibited jects subcutaneous dosing of TM30338 in obese human sub- pment. Recently, data reported indicate that once-a-day longer biological activity than GLP-1. This protease-re- anorectic effects through the anorectic highly effects expressed Y PP is thought to mediate its obese subjects. Circulating to nauseaandvomiting. due out dropped patients of 60% because group, PYY respectively) kg, (36). Weight loss 3.7 could not be assessed in the 600 mcg and (2.8 groups PYY mcg 200 and weight exercise, loss was similar in the placebo and a day before meals) or placebo, in conjunction with diet assigned to intranasal randomly PYY (200 or were 600 mcg three who times patients obese 133 of trial week 12- a in However, loss. weight promote could metics cacy of exogenous PYY effi- anorectic the that observation the Also, (35). loss weight for therapy useful a be might PYY that gesting sug- 30% loric in intake both by groups, approximately chronic administration of PYY of administration chronic 3-36 administration decreased appetite and ca- and appetite decreased administration
(3–36) eetr o oeiei NPY/Agrp orexigenic on receptors PP is released postprandially, in released but is PP 2 and Y 3-36 eoem suspectum Heloderma
tde t dtrie whether determine to studies (3–36) (3–36) is
4 fully intact in obese people, receptors, is under develo , levels of PP are lower in in lower are PP of levels , and PP, which acts as an an as acts PP,which and
and thereby derepressing 3-36
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Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 278 hor growth human of Levels (44). mass fat-cell reduce of fatty can circulation free acids increase and ultimately it lipase, lipoprotein of inhibitor an As properties. genic (hGH) has Human hormone lipolytic/antilipo- growth Lipid metabolismmodulators fororlistat. withthatreported fects) compared ef- side gastrointestinal severe fewer (90% profile effect over placebo in three months) but with a loss favorable side- weight kg 3 showed trial clinical IIb (Phase listat or- to efficacy comparable has ATL-962 that indicate available data is Clinical Alizyme). obesity (Cetilistat; ATL-962 of treatment the for development in clinical currently inhibitor lipase other only The calories. nance) when used in conjunction with mainte- a diet of weight reduced and loss weight (including obesity of or tetra-hydrolipstatin, is indicated for the management Roche), (Xenia; Krista fat. dietary of absorption temic sys- decrease to tract gastrointestinal the of lumen the Lipase inhibitors inhibit gastric and pancreatic lipases in Lipase inhibitors mechanisms Agents actingthroughperipherl forobesity.tial treatment support results continued evaluation of These pramlintide as a group. poten- placebo the in 2% loss to compared weight greater or 5% achieved pramlintide with treated subjects of 31% approximately cm; 1.1 ± 3.6 of circumference body waist in and 0.5% ± in 3.7% of weight reductions placebo-corrected experienced treatment pramlintide of week 16 completing Subjects (29%). groups pramlintide-treated and (25%) placebo to similar were rates withdrawal the and tolerated, well itant lifestyle (43). intervention The drug was generally times a day before meals for 16 week, without concom- three injection subcutaneous via placebo or mg) 240 = dose pramlintide escalation (nonforced < or ministered self-ad- subjects obese 204 study, placebo-controlled double-blind, randomized, a In patients. obese betic subjects. hypoglycemia innormal provoke not do pramlintide of doses supraphysiologic New drugsforobesity duces abdominal fat both in men and postmenopausal postmenopausal and men in both fat abdominal duces age. It has been - increasing shown that hGH therapy re mone are typically suppressed in the obese state and with The effects of pramlintide were assessed in non dia- non in assessed were pramlintide of effects The - with and the anticonvulsant agent topiramate, is being is topiramate, agent anticonvulsant the and with amphetamine-derived the phentermine releaser, catecholamine a and of compound doses low containing ofbodyweight. control toachieveeffective be necessary tion therapies targeting several points in the network may diabetes), combina- diseases (e.g., hypertension, chronic the loss of an orexigen mechanism. Therefore, as in other limited in its in limited theoretically is signals anabolic of antagonism cological safety profiles. safety profiles. good with the compounds selective proved developing in was difficulty it as success, limited with but targets, therapeutic potential as investigated been have agonists hormone receptor (48). efficacyandsafety profiles cause ofpoordrug be- discontinued been have agents receptor adrenergic with trials 2 phase several However, thermogenesis. increase and lipolysis cause agonists receptor adrenergic creasing energy expenditure have also been explored. thanplacebooverthecourseof12 weeks. more 1 mg AOD9604 once a day led to weight loss of 2.0 kg of a Phase IIb clinical trial showed that administration of tion) described as a lipid-metabolism modulator. Results cycliza- to (due peptide available orally an as AOD9604, Pharmaceuticals Metabolic by development under oy egt s eedd y eudn regulatory redundant by defended is weight Body Combina of the molecule. The fragment hGH fragment The molecule. the of region amino-terminal the with associated effects diabeto- genic the without (47) fat new of synthesis the its inhib- and fats, stored of breakdown the enhances by - there and tissues, and cells isolated both in lipid into incorporation glucose reduces which hepatocytes, and adipocytes in carboxylase A co-enzyme acetyl of activity because changes in that only that intervention an from resulting loss weight that so tems tive increase tive omn (eius 7-9) hGH 177-191). (residues intact the hormone of terminus carboxyl the as identified been has molecule hGH the of domain lipolytic The effects. side unwanted other and diabetogenic its of because ful success- been not have treatment obesity long-term for hGH of However,applications (45,46). clinical women nx (I02) a hraetcl combination pharmaceutical a (VI-0521), Qnexa Thyroid Thyroid hormone increases thermogenesis via thyroid Compounds that aim body at weight reducing by in-
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sys- b b 3- 3- Arq Bras EndocrinolMetab.2009;53/2 a cure, but an indutor of a pharmacologic that effect occurs sity. Like many for drugs chronic disease, medication is not obe- underlie that mechanisms peripheral and central plex com- the regarding unknown remains much homeostasis, Despite the incredible gains in our understanding of energy CONCLUSIOS a inbodyweight(53). synergistic decrease cause to studies, preclinical in shown, been has tin Finally,lep- and sibutramine with therapy combination weight loss than treatment with zonisamide alone more (52). in resulted bupropion and zonisamide of ment treat- combination trial, preliminary open-label, term, a-MSH and CART and increase 5-HT levels. In of a release short- the enhance both anticonvulsant; an amide, justment ofthecomponentsmightdiminishit. ad- dosage that thought is it withdrawals, to led (40%) nausea Although (51). respectively (placebo), 0.9% and alone) (naltrexone 2.2% alone), (bupropion 3.8% with comparison in 40, to 30 from ranging BMI a with jects sub- in weeks 24 after loss weight non-plateaued 6.6% a demonstrated weeks) 24 q.d., mg 50 naltrexone b.i.d., neurons. Phase II data for Contrave (bupropion 150 a blocking by intake food reducing with associated is that system (POMC) pro-opiomelanocortin the stimulate gistically syner to reported been have naltrexone and Bupropion dependency.alcohol and narcotic treat to used tagonist weight loss (50), and naltrexone, an opioid-receptor an- dose-related demonstrated has that inhibitor reuptake noradrenalin- and dopamine a bupropion, medications 500 caloriesperday. by intake caloric reduce to asked were and separately), ingredients active the of placebo/one (or Qnexa of es Subjects with an average BMI of 38 daily received dos- alone. administered agents comparator topiramate and body phentermine of total sum the than more greater was or loss weight 10% achieving patients of tion propor- the and weeks, 24 after kg 9.2 of loss weight Qnexa demonstrated a placebo-adjusted non-plateaued tyric acid) and glutamate systems (49). Phase II data for sodium channels and action on the GABA (g-amino bu- voltage-dependent of blockade involving CNS, the on effects multifactorial has which and agent antimigraine anti-epileptic/ an as approved is that fructose stituted developed for obesity. Topiramate is a sulphamate-sub- xai i a obnto o bpoin n zonis- and bupropion of combination a is Excalia acting centrally the of combination a Contrave, -endorphin-mediated inhibition of POMC POMC of inhibition b-endorphin-mediated mg mg - therapy while more efficacious drugs are notavailable. are efficaciousdrugs therapy whilemore bination of agents may in result better outcomes in obesity com- a with treatment forward, Moving taken. is it while REFERENCES was reported. Disclosure: No potential conflict of interestrelevant to this article 18. 7. 1 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1.
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