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d=\"M752.64 864H399.36a65.92 65.92 0 0 1-15.36-2.112V768h-39.744c0.448-0.768 0.64-1.664 1.152-2.432L405.12 672h341.76l59.712 93.568a64 64 0 0 1-53.952 98.432z\" fill=\"#006758\" opacity=\".1\"><\/path><path d=\"M836.864 846.144a94.72 94.72 0 0 1-84.16 49.856H399.296A93.568 93.568 0 0 1 384 893.952v-66.112a29.952 29.952 0 0 0 15.296 4.16h353.408a32 32 0 0 0 26.944-49.28L729.6 704H422.4l-40.832 64h-72.32a96 96 0 0 1 9.152-19.648l59.712-93.632 27.008-14.72h341.76l27.008 14.72 59.712 93.568a94.976 94.976 0 0 1 3.264 97.856z\" fill=\"#86d2e9\" data-spm-anchor-id=\"a313x.search_index.0.i30.7a773a81Yn5fO8\" class=\"\"><\/path><path d=\"M672 554.688V288H504.832A285.312 285.312 0 0 1 480 356.032v198.4L425.536 640h300.8z\" fill=\"#515151\" opacity=\".1\" data-spm-anchor-id=\"a313x.search_index.0.i32.7a773a81Yn5fO8\" class=\"selected\"><\/path><path d=\"M704 545.344V320h64V256H510.208A286.336 286.336 0 0 1 448 404.992v140.352L378.176 654.72 405.12 640h58.432l43.456-68.032 4.992-17.28V320h128v234.688l4.992 17.28 43.456 68.032h58.432l26.944 14.72zM320 896H192v128H128v-128H0v-64h128v-128h64v128h128z\" fill=\"#86d2e9\" data-spm-anchor-id=\"a313x.search_index.0.i31.7a773a81Yn5fO8\" class=\"\"><\/path><path d=\"M256 128l-32 32L192 128V0h64zM88.256 43.008l-45.248 45.248 90.496 90.496h44.8v-45.504zM0 192v64h128l32-32L128 192z m43.008 167.744l45.248 45.248 90.496-90.496v-44.8h-45.504zM192 448h64V320l-32-32L192 320z m167.744-43.008l45.248-45.248-90.496-90.496h-44.8v45.504zM448 256V192H320l-32 32 32 32z m-43.008-167.744L359.744 43.008 269.248 133.504v44.8h45.504z\" fill=\"#515151\" data-spm-anchor-id=\"a313x.search_index.0.i33.7a773a81Yn5fO8\" class=\"selected\"><\/path><\/svg>\t\t<\/span>\n\t\t\t\t\t<span class=\"e-n-tab-title-text\">\n\t\t\t\t\u6587\u732e\t\t\t<\/span>\n\t\t<\/button>\n\t\t\t\t\t<\/div>\n\t\t\t<div class=\"e-n-tabs-content\">\n\t\t\t\t<div id=\"e-n-tab-content-161331041\" role=\"tabpanel\" aria-labelledby=\"e-n-tab-title-161331041\" data-tab-index=\"1\" style=\"--n-tabs-title-order: 1;\" class=\"e-active elementor-element elementor-element-7474a255 e-con-full e-flex e-con e-child\" data-id=\"7474a255\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t<div class=\"elementor-element elementor-element-3f461b8f e-flex e-con-boxed e-con e-child\" data-id=\"3f461b8f\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-28cc8a3f elementor-drop-cap-yes elementor-drop-cap-view-default elementor-widget elementor-widget-text-editor\" data-id=\"28cc8a3f\" data-element_type=\"widget\" data-e-type=\"widget\" data-settings=\"{&quot;drop_cap&quot;:&quot;yes&quot;}\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t<p>Setmelanotide (brand name Imcivree\u00ae) is a cyclic octapeptide derivative and the next-generation potent and selective <a href=\"https:\/\/en.wikipedia.org\/wiki\/Melanocortin_4_receptor\"><strong>melanocortin-4 receptor<\/strong><\/a> agonist. The melanocortin-4 receptor is an integral part of the central nervous system <a href=\"https:\/\/en.wikipedia.org\/wiki\/Energy_homeostasis\"><strong>energy homeostasis<\/strong><\/a> regulation network.<\/p><p>Setmelanotide is similar in action to <a href=\"https:\/\/en.wikipedia.org\/wiki\/Endogenous\"><strong>endogenous<\/strong><\/a> human <a href=\"https:\/\/en.wikipedia.org\/wiki\/Melanocortin\"><strong>melanocortins<\/strong><\/a> (such as <a href=\"https:\/\/en.wikipedia.org\/wiki\/Melanocyte-stimulating_hormone\"><strong>\u03b1-melanocyte stimulating hormone, \u03b1-MSH<\/strong><\/a>), but has been developed to be vastly more potent, selective and metabolically stable than the natural <a href=\"https:\/\/en.wikipedia.org\/wiki\/Ligand_(biochemistry)\"><strong>ligand<\/strong><\/a>.<\/p><p>It shows very low <a href=\"https:\/\/en.wikipedia.org\/wiki\/EC50\"><strong>EC50<\/strong><\/a> (half-maximal effective concentrations) for both human and rat MC4R\u20130.27 nM and 0.28 nM respectively, thereby reflecting its high receptor activation potency.<\/p><p>Setmelanotide activates intracellular <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cyclic_adenosine_monophosphate\"><strong>cAMP<\/strong><\/a> signaling through stimulation of melanocortin-4 receptors present in different parts of the brain, including the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Hypothalamus\"><strong>hypothalamus<\/strong><\/a>, and therefore regulates appetite, energy expenditure and autonomic nervous activity including modulation of blood pressure control by stimulating preganglionic neurons of the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Sympathetic_nervous_system\"><strong>sympathetic nervous system<\/strong><\/a>.<\/p><p>Due to its superior receptor binding properties, it serves as a valuable tool for studies of MC4R-<a href=\"https:\/\/en.wikipedia.org\/wiki\/Accessory_protein\"><strong>accessory proteins<\/strong><\/a> (e.g., <a href=\"https:\/\/en.wikipedia.org\/wiki\/MRAP2\"><strong>MRAP2<\/strong><\/a>) interaction.<\/p><p>In clinical settings, Setmelanotide has been successfully translated into a therapeutic drug focused on treating rare genetic obesity syndromes derived from defects in the leptin-melanocortin pathway.<\/p><p>It also reverses drug-induced weight gain (e.g., <a href=\"https:\/\/en.wikipedia.org\/wiki\/Risperidone\"><strong>risperidone<\/strong><\/a>), has anti-inflammatory effects in <a href=\"https:\/\/en.wikipedia.org\/wiki\/Astrocyte\"><strong>astrocytes<\/strong><\/a>, and may act synergistically with metabolic interventions such as <a href=\"https:\/\/en.wikipedia.org\/wiki\/Caloric_restriction\"><strong>caloric restriction<\/strong><\/a>\u2014all of which demonstrates its high scientific value and potential applicability in other research fields (such as obesity, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Metabolic_syndrome\"><strong>metabolic syndrome<\/strong><\/a> and <a href=\"https:\/\/en.wikipedia.org\/wiki\/Neuroendocrine_tumor\"><strong>neuroendocrine disorders<\/strong><\/a>).<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div id=\"e-n-tab-content-161331042\" role=\"tabpanel\" aria-labelledby=\"e-n-tab-title-161331042\" data-tab-index=\"2\" style=\"--n-tabs-title-order: 2;\" class=\"elementor-element elementor-element-22600323 e-con-full e-flex e-con e-child\" data-id=\"22600323\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t<div class=\"elementor-element elementor-element-7e303aea e-flex e-con-boxed e-con e-child\" data-id=\"7e303aea\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-4c9e764 elementor-position-inline-start elementor-mobile-position-inline-start elementor-view-default elementor-widget elementor-widget-icon-box\" data-id=\"4c9e764\" 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bridge:Cys2-Cys8)\t\t\t\t\t<\/p>\n\t\t\t\t\n\t\t\t<\/div>\n\t\t\t\n\t\t<\/div>\n\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<div class=\"elementor-element elementor-element-4a1005e0 elementor-widget-divider--view-line elementor-widget elementor-widget-divider\" data-id=\"4a1005e0\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"divider.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<div class=\"elementor-divider\">\n\t\t\t<span class=\"elementor-divider-separator\">\n\t\t\t\t\t\t<\/span>\n\t\t<\/div>\n\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<div class=\"elementor-element elementor-element-4e4b15d8 elementor-position-inline-start elementor-mobile-position-inline-start elementor-view-default elementor-widget elementor-widget-icon-box\" data-id=\"4e4b15d8\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"icon-box.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<div class=\"elementor-icon-box-wrapper\">\n\n\t\t\t\t\t\t<div class=\"elementor-icon-box-icon\">\n\t\t\t\t<span  class=\"elementor-icon\">\n\t\t\t\t<svg xmlns=\"http:\/\/www.w3.org\/2000\/svg\" xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" class=\"icon\" viewbox=\"0 0 1024 1024\" width=\"128\" height=\"128\"><path d=\"M 550.351 736.788 H 293.741 a 26.4086 26.4086 0 0 1 -26.1415 -26.1173 c 0 -14.4421 12.0149 -26.1173 26.1415 -26.1173 H 580.691 a 173.501 173.501 0 0 0 13.0343 -66.2642 v -121.509 c 0 -25.2192 -16.918 -44.0062 -20.0977 -55.9483 c -2.93698 -11.0197 0.436907 -11.0441 21.4084 -11.0441 h 200.709 c 20.6317 0 22.9861 0.0242722 19.9763 11.0441 c -3.20398 11.6266 -19.7337 29.6611 -19.7337 55.2929 v 122.14 c 0 33.9088 8.15559 65.5845 24.9765 92.2358 l 21.5783 32.1369 V 109.609 A 52.3559 52.3559 0 0 0 789.921 57.375 H 163.47 a 52.4288 52.4288 0 0 0 -52.623 52.2346 v 731.722 a 52.3074 52.3074 0 0 0 52.623 52.2346 H 446.95 l 55.6327 -82.5754 l 47.7684 -74.2013 Z M 293.741 214.151 H 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3;\" class=\"elementor-element elementor-element-37bad7de e-con-full e-flex e-con e-child\" data-id=\"37bad7de\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t<div class=\"elementor-element elementor-element-3a623d27 e-flex e-con-boxed e-con e-child\" data-id=\"3a623d27\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-34f8492c elementor-widget elementor-widget-text-editor\" data-id=\"34f8492c\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t<h5>Research Of Setmelanotide<\/h5><h5>1.MC4R Pathway and the MOA of Setmelanotide<\/h5><p>MC4R is a <a href=\"https:\/\/en.wikipedia.org\/wiki\/G_protein-coupled_receptor\"><strong>G protein-coupled receptor (GPCR)<\/strong><\/a> that is mainly expressed in the central nervous system, notably within a few nuclei of the hypothalamus.<\/p><p>These areas represent the core sites for sensing metabolic cues and controlling feeding behavior and energy balance.<\/p><p>In physiological conditions, this MC4R pathway participates in the inhibition of appetite and stimulation of energy expenditure.<\/p><p>This pathway is normally stimulated by \u03b1-melanocyte-stimulating hormone (\u03b1-MSH, a <a href=\"https:\/\/en.wikipedia.org\/wiki\/Pro-opiomelanocortin\"><strong>POMC<\/strong><\/a> derivative) produced by POMC neurons in the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Arcuate_nucleus\"><strong>arcuate nucleus<\/strong><\/a>.<\/p><p>Activation of MC4R by \u03b1-MSH induces a cascade of downstream signals that suppress appetite and meal intake.<\/p><p>But if there are mutations in the POMC gene that prevent \u03b1-MSH synthesis, MC4R will remain \u201cinactive\u201d because it does not receive any activation by its endogenous ligands.<\/p><p>This signaling disruption results in pathological, uncontrolled appetite and subsequent morbid obesity.<\/p><p>Drug discovery for the MC4R pathway was notoriously difficult before Setmelanotide.<\/p><p>Early non-selective MC4R agonists elicited intolerable adverse effects such as skin pigmentation and sexual dysfunction by concomitantly stimulating other <a href=\"https:\/\/en.wikipedia.org\/wiki\/Melanocortin_receptor\"><strong>melanocortin receptors<\/strong><\/a> (i.e., MC1R, MC3R, and MC5R).<\/p><p>The development objective of Setmelanotide was straightforward: to achieve high selectivity for MC4R to optimize its effects in both appetite suppression and increased energy expenditure and minimize side effects related to off-target binding.<\/p><p>The inherent core mechanism of exogenous MC4R agonist Setmelanotide is to act as a substitute for \u03b1-MSH, directly stimulating the MC4R in order to correct pathophysiology upstream and restore this critical signal for energy balance.<\/p><p>The molecular and cellular effects of Setmelanotide ultimately translate into profound systemic physiological responses.<\/p><p>By stimulating MC4R neurons at important sites throughout the brain like the hypothalamus PVN, Setmelanotide is able to:<\/p><p>Obesity and Rare Genetic Obesity Syndromes Studies: Setmelanotide is an essential tool in studying the function of the MC4R pathway.<\/p><p>More notably, it has been shown to be effective in treating rare genetic forms of obesity due to deficiency in POMC, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Leptin_receptor\"><strong>LEPR<\/strong><\/a> or <a href=\"https:\/\/en.wikipedia.org\/wiki\/Proprotein_convertase_1\"><strong>PCSK1<\/strong><\/a> and reverse serious early onset obesity from mutations in the MC4R pathway.<\/p><p>Setmelanotide acts to restore the function of energy balance regulation by activating the MC4R pathway, leading to substantial weight loss, decreased hunger, and improvement in metabolic parameters.<\/p><h5>2.Regulation of Inflammation Function<\/h5><p>Studies of Setmelanotide in astrocytes have shown that it serves a special anti-inflammatory function.<\/p><p>In pro-inflammatory <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cytokine\"><strong>cytokine<\/strong><\/a> (TNF-\u03b1\/IFN-\u03b3)\u2013activated astrocytes, Setmelanotide can dramatically suppress the activation of NF-\u03baB signaling pathway and decrease the secretion of pro-inflammatory <a href=\"https:\/\/en.wikipedia.org\/wiki\/Chemokine\"><strong>chemokines<\/strong><\/a> (such as <a href=\"https:\/\/en.wikipedia.org\/wiki\/CCL2\"><strong>CCL2<\/strong><\/a> and <strong>CXCL10<\/strong>).<\/p><p>Apart from inhibition of inflammation, Setmelanotide also induces astrocytes to secrete cytokines <a href=\"https:\/\/en.wikipedia.org\/wiki\/Interleukin_6\"><strong>IL-6<\/strong><\/a> and <a href=\"https:\/\/en.wikipedia.org\/wiki\/Interleukin_11\"><strong>IL-11<\/strong><\/a> that can promote <a href=\"https:\/\/en.wikipedia.org\/wiki\/Macrophage_polarization\"><strong>macrophage polarization<\/strong><\/a> into an anti-inflammatory phenotype (M2 type).<\/p><h5>3.Energy Expenditure Enhancement<\/h5><p>In addition to directly reducing food intake (consumption), Setmelanotide also elevates resting energy expenditure (REE).<\/p><p>It\u2019s like flipping on the body\u2019s metabolic switch, enabling it to burn calories even at rest as if exercising.<\/p><p>Setmelanotide produced a large increase in <a href=\"https:\/\/en.wikipedia.org\/wiki\/Basal_metabolic_rate\"><strong>basal metabolic rate (BMR)<\/strong><\/a> and active energy expenditure (AEA) , leading to rapid weight reduction in obese mouse models (e.g., <a href=\"https:\/\/en.wikipedia.org\/wiki\/MAGEL2\"><strong>the Magel2-null syndrome model<\/strong><\/a>).<\/p><p><a href=\"https:\/\/en.wikipedia.org\/wiki\/Respiratory_quotient\"><strong>The respiratory quotient (RER)<\/strong><\/a> decreases in animals after treatment, which indicates that the body switches from carbohydrate to fat oxidation, necessary for depleting liver and stored fat.<\/p><p><a href=\"https:\/\/en.wikipedia.org\/wiki\/Resting_energy_expenditure\"><strong>Resting energy expenditure (REE)<\/strong><\/a> was increased by 6.4% with Setmelanotide in a Phase III study on healthy obese subjects, during a relatively short treatment duration of 72 hours (111 kcal\/24 h).<\/p><p>This means the patient\u2019s body is burning extra calories, without any changes to diet.<\/p><h5>4.Improved Metabolic Health<\/h5><p>Setmelanotide not only induced weight loss but it also demonstrated reversal of obesity related metabolic diseases, including hepatic steatosis and <a href=\"https:\/\/en.wikipedia.org\/wiki\/Insulin_resistance\"><strong>insulin resistance<\/strong><\/a>.<\/p><p>Setmelanotide treatment not only reduced weight, but also reduced liver fat content, and hepatic damage.<\/p><p>This is not just an effect of weight loss but it\u2019s a direct enhancement in liver function.<\/p><p>Concomitantly, patients\u2019 fasting insulin levels markedly decreased with amelioration of insulin resistance, reflecting an improved state of glucose metabolism.<\/p><p>When fat mass declined, serum levels of <a href=\"https:\/\/en.wikipedia.org\/wiki\/Leptin\"><strong>leptin<\/strong><\/a> also fell.<\/p><p>This is generally believed to be an indicator of better metabolic health &#8211; since leptin levels that are too high often indicate obesity and insulin resistance.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div id=\"e-n-tab-content-161331044\" role=\"tabpanel\" aria-labelledby=\"e-n-tab-title-161331044\" data-tab-index=\"4\" style=\"--n-tabs-title-order: 4;\" class=\"elementor-element elementor-element-49a5cd78 e-flex e-con-boxed e-con e-child\" data-id=\"49a5cd78\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div 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aria-labelledby=\"e-n-tab-title-161331045\" data-tab-index=\"5\" style=\"--n-tabs-title-order: 5;\" class=\"elementor-element elementor-element-4c09dbb8 e-flex e-con-boxed e-con e-child\" data-id=\"4c09dbb8\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t<div class=\"elementor-element elementor-element-396a4f1e e-con-full e-flex e-con e-child\" data-id=\"396a4f1e\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t<div class=\"elementor-element elementor-element-1b2e1a18 elementor-widget elementor-widget-text-editor\" data-id=\"1b2e1a18\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t<p><strong><a href=\"http:\/\/10.1007\/s40265-021-01470-9\"><u>(1) Markham, A. Setmelanotide: First Approval. <\/u><em><u>Drugs <\/u><\/em><u>2021<\/u><u>, <\/u><em><u>81<\/u><\/em><u>\u00a0(3), 397-403. DOI: 10.1007\/s40265-021-01470-9.<\/u><\/a><\/strong><\/p><p><strong><a href=\"https:\/\/www.uspharmacist.com\/article\/treating-genetic-obesity-with-the-novel-agent-setmelanotide\"><u>(2) Prit Gor, M. I., Shuhad Mashadani, Ashley Stefanski. Treating genetic obesity with the novel agent setmelanotide. In <\/u><em><u>US Pharm<\/u><\/em><u>, 2024; Vol. 49, pp 17-26.<\/u><\/a><\/strong><\/p><p><strong><a href=\"https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC8603737\/pdf\/pr69_s245.pdf\"><u>(3) Hainer, V.; Aldhoon Hainerov\u00c1, I.; Kune\u0160Ov\u00c1, M.; Taxov\u00c1 Braunerov\u00c1, R.; Zamrazilov\u00c1, H.; Bendlov\u00c1, B. Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R). Physiological Research 2020, S245-S254. DOI: 10.33549\/physiolres.9345<\/u><\/a><\/strong><\/p><p><strong><a href=\"https:\/\/www.sochob.cl\/web1\/wp-content\/uploads\/2019\/12\/Future-Pharmacotherapy-for-Obesity-New-Anti-obesity-Drugs-on-the-Horizon..pdf\"><u>(4) Srivastava, G.; Apovian, C. Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon. <\/u><em><u>Current Obesity Reports <\/u><\/em><u>2018<\/u><u>, <\/u><em><u>7<\/u><\/em><u>\u00a0(2), 147-161. DOI: 10.1007\/s13679-018-0300-4.<\/u><\/a><\/strong><\/p><p><strong><a href=\"https:\/\/edm.bioscientifica.com\/view\/journals\/edm\/2020\/1\/EDM19-0139.xml\"><u>(5) Akinci, B.; Meral, R.; Rus, D.; Hench, R.; Neidert, A. H.; DiPaola, F.; Westerhoff, M.; Taylor, S. I.; Oral, E. A. The complicated clinical course in a case of atypical lipodystrophy after development of neutralizing antibody to metreleptin: treatment <\/u><\/a><\/strong><\/p><p><strong><a href=\"https:\/\/digitalcommons.library.tmc.edu\/cgi\/viewcontent.cgi?article=4487&amp;context=baylor_docs\"><u>(6) Zhao, S.; Li, N.; Xiong, W.; Li, G.; He, S.; Zhang, Z.; Zhu, Q.; Jiang, N.; Ikejiofor, C.; Zhu, Y.; et al. Leptin Reduction as a Required Component for Weight Loss. <\/u><em><u>\u7cd6\u5c3f\u75c5 <\/u><\/em><u>2024<\/u><u>, <\/u><em><u>73<\/u><\/em><u>\u00a0(2), 197-210. 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