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Adipositas - Ursachen, Folgeerkrankungen, Therapie 2023; 17(04): 182-190
DOI: 10.1055/a-2185-6864
Review

Genetische Ursachen der Adipositas und ihre therapeutischen Implikationen

Genetic Causes Of Obesity And Its Therapeutic Implications
Luisa Sophie Rajcsanyi
1   Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Deutschland
2   Zentrum für Translationale Neuro- und Verhaltenswissenschaften, Universitätsklinikum Essen, Essen, Deutschland
,
Jasmin Schmidt
1   Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Deutschland
2   Zentrum für Translationale Neuro- und Verhaltenswissenschaften, Universitätsklinikum Essen, Essen, Deutschland
,
Sieglinde Düerkop
1   Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Deutschland
2   Zentrum für Translationale Neuro- und Verhaltenswissenschaften, Universitätsklinikum Essen, Essen, Deutschland
,
Lola Grote
1   Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Deutschland
,
Triinu Peters
1   Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Deutschland
2   Zentrum für Translationale Neuro- und Verhaltenswissenschaften, Universitätsklinikum Essen, Essen, Deutschland
,
Antje Körner
3   Klinik für Kinderheilkunde, Universitätsklinikum Leipzig, Leipzig, Deutschland
,
Pamela Fischer-Posovszky
4   Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Ulm, Ulm, Deutschland
,
Anke Hinney
1   Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Deutschland
2   Zentrum für Translationale Neuro- und Verhaltenswissenschaften, Universitätsklinikum Essen, Essen, Deutschland
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Zusammenfassung

Adipositas ist eine komplexe Störung, die von Umweltfaktoren und genetischen Varianten beeinflusst wird. Basierend auf den genetischen Grundlagen wird zwischen zwei Formen der Adipositas unterschieden. Die monogene (und syndromale) Adipositas ist selten und wird von Mutationen in jeweils einem Gen bedingt. Zur Manifestation einer extremen Adipositas mit Hyperphagie kommt es bereits in den ersten Lebensjahren. Abhängig vom betroffenen Gen können zudem weitere phänotypische Ausprägungen hinzukommen. Die polygene Adipositas dagegen ist weitaus häufiger. Ursächlich für diese Form ist eine Vielzahl von genetischen Varianten, die jeweils einen geringen, aber additiven Effekt auf das Körpergewicht haben. Frühzeitige genetische Diagnostik kann die vorliegende Form der Adipositas identifizieren und die Wahl einer geeigneten Therapieoption, ob Lebensstilintervention, bariatrische Chirurgie oder pharmakologische Behandlung, unterstützen. Wir stellen aktuelle Erkenntnisse der Forschung über die genetischen Ursachen der Adipositas dar. Zudem werden therapeutische und diagnostische Optionen, die teils auf genetischen Befunden basieren, beleuchtet.

Abstract

Obesity is a complex disorder influenced by environmental factors and genetic variants. A classification into two forms of obesity is based on the genetic basis. Monogenic (and syndromal) obesity is rare and caused by mutations in a single gene each. The manifestation of extreme obesity with hyperphagia occurs in the first years of life. Depending on the gene affected, other phenotypic manifestations may occur. Polygenic obesity, on the other hand, is much more common. This form is caused by several genetic variants, each of which has a small but additive effect on the body weight. Early genetic diagnosis can identify the present form of obesity and support the choice of an appropriate therapeutic option, whether lifestyle intervention, bariatric surgery, or pharmacological treatment. We present current research findings on the genetic causes of obesity. In addition, therapeutic and diagnostic options, some of which are based on genetic findings, are highlighted.

Schlüsselwörter

Genetik - Varianten - Mutationen - Monogene Adipositas - Polygene Adipositas

Key words

Obesity - genetics - mutation - variants - monogenic obesity - polygenic obesity


Publication History

Article published online:
04 December 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 E. World Health Organization. Regional Office for, WHO European Regional Obesity Report 2022. Copenhagen: World Health Organization; Regional Office for Europe (in en) 2022
    Google Scholar
  • 2 Geserick M, Vogel M, Gausche R. et al. Acceleration of BMI in Early Childhood and Risk of Sustained Obesity. N Engl J Med 2018; 379: 1303-1312 doi: 10.1056/NEJMoa1803527
    CrossrefPubMedGoogle Scholar
  • 3 Twig G, Yaniv G, Levine H. et al. Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood. N Engl J Med 2016; 374: 2430-2440 doi: 10.1056/NEJMoa1503840
    CrossrefPubMedGoogle Scholar
  • 4 Loos RJF, Yeo GSH. The genetics of obesity: from discovery to biology. Nat Rev Genet 2021; 23: 120-133 doi: 10.1038/s41576-021-00414-z
    CrossrefPubMedGoogle Scholar
  • 5 Hinney A, Körner A, Fischer-Posovsky P. The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits. Nat Rev Endocrinol 2022; 18: 623-637 doi: 10.1038/s41574-022-00716-0
    CrossrefPubMedGoogle Scholar
  • 6 Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997; 27: 325-351 doi: 10.1023/a:1025635913927
    CrossrefPubMedGoogle Scholar
  • 7 Stunkard AJ, Sørensen TI, Hanis C. et al. An adoption study of human obesity. N Engl J Med 1986; 314: 193-198 doi: 10.1056/NEJM198601233140401
    CrossrefPubMedGoogle Scholar
  • 8 Hebebrand J, Wulftange H, Goerg T. et al. Epidemic obesity: are genetic factors involved via increased rates of assortative mating?. Int J Obes Relat Metab Disord 2000; 24: 345-353 doi: 10.1038/sj.ijo.0801135
    CrossrefPubMedGoogle Scholar
  • 9 Kleiser C, Schaffrath Rosario A, Mensink Gert BM. et al. Potential determinants of obesity among children and adolescents in Germany: results from the cross-sectional KiGGS Study. BMC Public Health 2009; 9: 46 doi: 10.1186/1471-2458-9-46
    CrossrefPubMedGoogle Scholar
  • 10 Emmer C, Bosnjak M, Mata J. The association between weight stigma and mental health: A meta-analysis. Obes Rev 2020; 21: e12935 doi: 10.1111/obr.12935
    CrossrefPubMedGoogle Scholar
  • 11 Muller TD, Blüher M, Tschöp MH. et al. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022; 21: 201-223 doi: 10.1038/s41573-021-00337-8
    CrossrefPubMedGoogle Scholar
  • 12 von Schnurbein J, Wabitsch M. Monogene Adipositas. Pathophysiologie – Diagnostik – Therapieoptionen 2017; 29: 348-359 doi: 10.1007/s11825-017-0157-z
    PubMedGoogle Scholar
  • 13 Montague CT, Farooqi IS, Whitehead JP. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903-908 doi: 10.1038/43185
    CrossrefPubMedGoogle Scholar
  • 14 Farooqi IS, Keogh JM, Xeo Giles SH. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2023; 348: 1085-1095 doi: 10.1056/NEJMoa022050
    CrossrefPubMedGoogle Scholar
  • 15 Kohlsdorf K, Nunziata A, Funcke JB. et al. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency. Int J Obes (Lond) 2018; 42: 1602-1609 doi: 10.1038/s41366-018-0049-6
    CrossrefPubMedGoogle Scholar
  • 16 Fischer-Posovszky P, von Schnurbein J, Moepps B. et al. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab 2010; 95: 2836-2840 doi: 10.1210/jc.2009-2466
    CrossrefPubMedGoogle Scholar
  • 17 Considine RV, Sinha MK, Heimann ML. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295 doi: 10.1056/NEJM199602013340503
    CrossrefPubMedGoogle Scholar
  • 18 Friedman JM. Leptin and the endocrine control of energy balance. Nat Metab 2019; 1: 754-764 doi: 10.1038/s42255-019-0095-y
    CrossrefPubMedGoogle Scholar
  • 19 Vaisse C, Halaas JL, Horvath CM. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Gene 1996; 14: 95-97 doi: 10.1038/ng0996-95
    CrossrefPubMedGoogle Scholar
  • 20 Bertagna X. Proopiomelanocortin-derived peptides. Endocrinol Metab Clin North Am 1994; 23: 467-485. Im Internet: https://www.ncbi.nlm.nih.gov/pubmed/7805649
    PubMed
  • 21 Yeo GSH, Herrera Moro Chao D, Siegert AM. et al. The melanocortin pathway and energy homeostasis: From discovery to obesity therapy. Mol Metab 2021; 48: 101206 doi: 10.1016/j.molmet.2021.101206
    CrossrefPubMedGoogle Scholar
  • 22 Mountjoy KG, Robbins LS, Mortrud MT. et al. The cloning of a family of genes that encode the melanocortin receptors. Science 1992; 257: 1248-1251 doi: 10.1126/science.1325670
    CrossrefPubMedGoogle Scholar
  • 23 Saeed S, Khanam R, Janjua QM. et al. High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor. Cell Rep Med 2023; 4: 101187 doi: 10.1016/j.xcrm.2023.101187
    CrossrefPubMedGoogle Scholar
  • 24 Kaur Y, de Souza RZ, Gibson WT. et al. A systematic review of genetic syndromes with obesity. Obes Rev 2017; 18: 603-634 doi: 10.1111/obr.12531
    CrossrefPubMedGoogle Scholar
  • 25 Rajcsanyi LS, Zheng Y, Fischer-Posovsky P. et al. Prevalence estimates of putatively pathogenic leptin variants in the gnomAD database. PLoS One 2022; 17: e0266642 doi: 10.1371/journal.pone.0266642
    CrossrefPubMedGoogle Scholar
  • 26 Funcke JB, von Schnurbein J, Lennerz B. et al. Monogenic forms of childhood obesity due to mutations in the leptin gene. Mol Cell Pediatr 2014; 1: 3 doi: 10.1186/s40348-014-0003-1
    CrossrefPubMedGoogle Scholar
  • 27 Wabitsch M, Funcke JB, Lennerz B. et al. Biologically inactive leptin and early-onset extreme obesity,”. N Engl J Med 2015; 372: 48-54 doi: 10.1056/NEJMoa1406653
    CrossrefPubMedGoogle Scholar
  • 28 Wabitsch M, Funcke JB, Schnurbein Jvon. et al. Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene. J Clin Endocrinol Metab 2015; 100: 3227-3230 doi: 10.1210/jc.2015-2263
    CrossrefPubMedGoogle Scholar
  • 29 Funcke JB, Moepps B, Roos J. et al. Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity. N Engl J Med 2023; 388: 2253-2261 doi: 10.1056/NEJMoa2204041
    CrossrefPubMedGoogle Scholar
  • 30 Farooqi IS, Jebb SA, Langmack G. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879-884 doi: 10.1056/NEJM199909163411204
    CrossrefPubMedGoogle Scholar
  • 31 Stanik J, Kratzsch J, Landgraf K. et al. Concordance of bioactive vs. total immunoreactive serum leptin levels in children with severe early onset obesity. PLoS One 2017; 12: e0178107 doi: 10.1371/journal.pone.0178107
    CrossrefPubMedGoogle Scholar
  • 32 Wabitsch M, Pridzun L, Ranke M. et al. Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency. Eur J Endocrinol 2017; 176: 315-322 doi: 10.1530/EJE-16-0821
    CrossrefPubMedGoogle Scholar
  • 33 Kleinendorst L, Abawi O, Kamp HJder. et al. Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics. Eur J Endocrinol 2020; 182: 47-56 doi: 10.1530/EJE-19-0678
    CrossrefPubMedGoogle Scholar
  • 34 Chaves C, Kay T, Anselmo J. et al. Early onset obesity due to a mutation in the human leptin receptor gene. Endocrinol Diabetes Metab Case Rep 2022; 2022: 21-0124 doi: 10.1530/EDM-21-0124
    CrossrefPubMedGoogle Scholar
  • 35 Voigtmann F, Wolf P, Landgraf K. et al. Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity. Metabolism 2021; 116: 154438 doi: 10.1016/j.metabol.2020.154438
    CrossrefPubMedGoogle Scholar
  • 36 Nunziata A, Funcke JB, Borck G. et al. Functional and Phenotypic Characteristics of Human Leptin Receptor Mutations. J Endocr Soc 2019; 3: 27-41 doi: 10.1210/js.2018-00123
    CrossrefPubMedGoogle Scholar
  • 37 Clement K, Vaisse C, Lahlou N. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398-401 doi: 10.1038/32911
    CrossrefPubMedGoogle Scholar
  • 38 Perge K, Pons L, Protsenko N. et al. A Novel Leptin Receptor LEPR Variant in a Toddler With Early-Onset Fatal Obesity. Pediatrics 2023; 152: e2022059569 doi: 10.1542/peds.2022-059569
    CrossrefPubMedGoogle Scholar
  • 39 Graves LE, Khouri JM, Kristidis P. et al. Proopiomelanocortin deficiency diagnosed in infancy in two boys and a review of the known cases. J Paediatr Child Health 2021; 57: 484-490 doi: 10.1111/jpc.15407
    CrossrefPubMedGoogle Scholar
  • 40 Krude H, Biebermann H, Luck W. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 155-157 doi: 10.1038/509
    CrossrefPubMedGoogle Scholar
  • 41 Le Collen L, Delemer B, Poitou C. et al. Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use. Genet Med 2023; 25: 100857 doi: 10.1016/j.gim.2023.100857
    CrossrefPubMedGoogle Scholar
  • 42 Kuhnen P, Clément K, Wiegand S. et al. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med 2016; 375: 240-246 doi: 10.1056/NEJMoa1512693
    CrossrefPubMedGoogle Scholar
  • 43 Kuhnen P, Handke D, Waterland RA. et al. Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity. Cell Metab 2016; 24: 502-509 doi: 10.1016/j.cmet.2016.08.001
    CrossrefPubMedGoogle Scholar
  • 44 Lechner L, Opitz R, Silver MJ. et al. Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment. Sci Transl Med 2023; 15: eadg1659 doi: 10.1126/scitranslmed.adg1659
    CrossrefPubMedGoogle Scholar
  • 45 Stutzmann F, Tan K, Vatin V. et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 2008; 57: 2511-2518 doi: 10.2337/db08-0153
    CrossrefPubMedGoogle Scholar
  • 46 Vaisse C, Clement K, Guy-Grand B. et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20: 113-114 doi: 10.1038/2407
    CrossrefPubMedGoogle Scholar
  • 47 Yeo GS, Farooqi IS, Aminian S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20: 111-112 doi: 10.1038/2404
    CrossrefPubMedGoogle Scholar
  • 48 Dempfle A, Hinney A, Heinzel-Gutenbrunner M. et al. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J Med Genet 2004; 41: 795-800 doi: 10.1136/jmg.2004.018614
    CrossrefPubMedGoogle Scholar
  • 49 Kaisinger LR, Kentistou KA, Stankovic S. et al. Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity. Cell Genom 2023; 3: 100362 doi: 10.1016/j.xgen.2023.100362
    CrossrefPubMedGoogle Scholar
  • 50 Wade KH, Lam BYH, Melvin A. et al. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort. Nat Med 2021; 27: 1088-1096 doi: 10.1038/s41591-021-01349-y
    CrossrefPubMedGoogle Scholar
  • 51 Geller F, Reichwald K, Dempfle A. et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet 2004; 74: 572-581 doi: 10.1086/382490
    CrossrefPubMedGoogle Scholar
  • 52 Lotta LA, Mokrosinski J, Mendes de Oliveira E. et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 2019; 177: 597-607e9 doi: 10.1016/j.cell.2019.03.044
    CrossrefPubMedGoogle Scholar
  • 53 Rojo D, McCarthy C, Raingo J. et al. Mouse models for V103I and I251L gain of function variants of the human MC4R display decreased adiposity but are not protected against a hypercaloric diet. Mol Metab 2020; 42: 101077 doi: 10.1016/j.molmet.2020.101077
    CrossrefPubMedGoogle Scholar
  • 54 Frayling TM, Timpson NJ, Weedon MN. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889-894 doi: 10.1126/science.1141634
    CrossrefPubMedGoogle Scholar
  • 55 Locke AE, Kahali B, Berndt SI. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197-206 doi: 10.1038/nature14177
    CrossrefPubMedGoogle Scholar
  • 56 Yengo L, Sidorenki J, Kemper KE. et al. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum Mol Genet 2018; 27: 3641-3649 doi: 10.1093/hmg/ddy271
    CrossrefPubMedGoogle Scholar
  • 57 Hinney A, Nguyen TT, Scherag A. et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2007; 2: e1361 doi: 10.1371/journal.pone.0001361
    CrossrefPubMedGoogle Scholar
  • 58 Smemo S, Tena JJ, Kim KH. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 2014; 507: 371-375 doi: 10.1038/nature13138
    CrossrefPubMedGoogle Scholar
  • 59 Claussnitzer M, Dankel SN, Kim KH. et al. FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med 2015; 373: 895-907 doi: 10.1056/NEJMoa1502214
    CrossrefPubMedGoogle Scholar
  • 60 Zhang Z, Chen N, Yin N. et al. The rs1421085 variant within FTO promotes brown fat thermogenesis. Nat Metab 2023; 5: 1337-1351 doi: 10.1038/s42255-023-00847-2
    CrossrefPubMedGoogle Scholar
  • 61 Hirtz R, Zheng Y, Rajcsanyi LS. et al. [Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation]. Z Kinder Jugendpsychiatr Psychother 2021; 50: 175-185 doi: 10.1024/1422-4917/a000829. Ebenen der genetischen Analyse komplexer Phanotypen am Beispiel der Anorexia nervosa und der Varianz des Korpergewichts.
    PubMedGoogle Scholar
  • 62 Khera AV, Chaffin M, Wade KH. et al. Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood,”. Cell 2019; 177: 587-596e9 doi: 10.1016/j.cell.2019.03.028
    CrossrefPubMedGoogle Scholar
  • 63 Huls A, Wright MN, Bogl LH. et al. Polygenic risk for obesity and its interaction with lifestyle and sociodemographic factors in European children and adolescents. Int J Obes (Lond) 2021; 45: 1321-1330 doi: 10.1038/s41366-021-00795-5
    CrossrefPubMedGoogle Scholar
  • 64 Finn EB, Whang C, Houlin Hong P. et al. Strategies to improve the implementation of intensive lifestyle interventions for obesity. Front Public Health 2023; 11: 1202545 doi: 10.3389/fpubh.2023.1202545
    CrossrefPubMedGoogle Scholar
  • 65 Machado AM, Sernizon Guimarães N, Bortolosso Bocardi V. et al. Understanding weight regain after a nutritional weight loss intervention: Systematic review and meta-analysis. Clin Nutr ESPEN 2022; 49: 138-153 doi: 10.1016/j.clnesp.2022.03.020
    CrossrefPubMedGoogle Scholar
  • 66 Reinehr T, Hebebrand J, Friedel S. et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring) 2009; 17: 382-389 doi: 10.1038/oby.2008.422
    CrossrefPubMedGoogle Scholar
  • 67 Trier C, Hollensted C, Schnurr TM. et al. Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations. Int J Obes (Lond) 2021; 45: 66-76 doi: 10.1038/s41366-020-00673-6
    CrossrefPubMedGoogle Scholar
  • 68 Jastreboff AM, Kaplan LM, Frìas JP. et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med 2023; 389: 514-526 doi: 10.1056/NEJMoa2301972
    CrossrefPubMedGoogle Scholar
  • 69 Frìas JP, Davies MJ, Rosenstock J. et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med 2021; 385: 503-515 doi: 10.1056/NEJMoa2107519
    CrossrefPubMedGoogle Scholar
  • 70 Jastreboff AM, Aronne LJ, Stefanski A. Tirzepatide Once Weekly for the Treatment of Obesity. Reply. N Engl J Med 2022; 387: 1434-1435 doi: 10.1056/NEJMc2211120
    PubMedGoogle Scholar
  • 71 Farooqi IS, Matarese G, Lord GM. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002; 110: 1093-1103 doi: 10.1172/JCI15693
    CrossrefPubMedGoogle Scholar
  • 72 von Schnurbein J, Remy M, Brandt S. et al. Positive effect of leptin substitution on mood and behaviour in patients with congenital leptin deficiency. Pediatr Obes 2023; 18: e13057 doi: 10.1111/ijpo.13057
    CrossrefPubMedGoogle Scholar
  • 73 Heymsfield SB, Greenberg AS, Fujioka K. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999; 282: 1568-1575 doi: 10.1001/jama.282.16.1568
    CrossrefPubMedGoogle Scholar
  • 74 Hukshorn CJ, Saris WH, Westerterp-Plantenga MS. et al. Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. J Clin Endocrinol Metab 2000; 85: 4003-4009 doi: 10.1210/jcem.85.11.6955
    CrossrefPubMedGoogle Scholar
  • 75 Hirtz R, Hinney A. Genetic and epigenetic findings in anorexia nervosa. Medizinische Genetik 2020; 32: 25-29 doi: 10.1515/medgen-2020-2005
    CrossrefPubMedGoogle Scholar
  • 76 Milos G, Antel J, Kaufmann LK. et al. Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects. Transl Psychiatry 2020; 10: 303 doi: 10.1038/s41398-020-00977-1
    CrossrefPubMedGoogle Scholar
  • 77 Gradl-Dietsch G, Milos G, Wabitsch M. et al. Rapid Emergence of Appetite and Hunger Resulting in Weight Gain and Improvement of Eating Disorder Symptomatology during and after Short-Term Off-Label Metreleptin Treatment of a Patient with Anorexia Nervosa. Obes Facts 2023; 16: 99-107 doi: 10.1159/000527386
    CrossrefPubMedGoogle Scholar
  • 78 Antel J, Tan S, Grabler M. et al. Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism. Eur Child Adolesc Psychiatry 2022; 31: 1573-1579 doi: 10.1007/s00787-021-01778-7
    CrossrefPubMedGoogle Scholar
  • 79 Hebebrand J, Hinney A, Antel J. Could leptin substitution therapy potentially terminate entrapment in anorexia nervosa?. Nat Rev Endocrinol 2023; 19: 435-436 doi: 10.1038/s41574-023-00863-y
    CrossrefPubMedGoogle Scholar
  • 80 Muller TD, Bluher M. [Obesity treatment: will pharmacotherapies replace metabolic surgery in the future?]. Inn Med (Heidelb) 2023; 64: 629-635 doi: 10.1007/s00108-023-01530-0. Adipositastherapie - werden Pharmakotherapien die Alternative zur metabolischen Chirurgie sein?
    CrossrefPubMedGoogle Scholar
  • 81 Clement K, van den Akker E, Argente J. et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol 2020; 8: 960-970 doi: 10.1016/S2213-8587(20)30364-8
    CrossrefPubMedGoogle Scholar
  • 82 Pi-Sunyer X, Astrup A, Fujioka K. et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med 2015; 373: 11-22 doi: 10.1056/NEJMoa1411892
    CrossrefPubMedGoogle Scholar
  • 83 Wilding JPH, Batterham RL, Calanna S. et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021; 384: 989-1002 doi: 10.1056/NEJMoa2032183
    CrossrefPubMedGoogle Scholar
  • 84 Davies M, Faerch L, Jeppesen OK. et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021; 397: 971-984 doi: 10.1016/S0140-6736(21)00213-0
    CrossrefPubMedGoogle Scholar
  • 85 Iepsen EW, Zhang J, Thomsen HS. et al. Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist. Cell Metab 2018; 28: 23-32e3 doi: 10.1016l/j.cmet.2018.05.008
    CrossrefPubMedGoogle Scholar
  • 86 Iepsen EW, Have CT, Veedfald S. et al. GLP-1 Receptor Agonist Treatment in Morbid Obesity and Type 2 Diabetes Due to Pathogenic Homozygous Melanocortin-4 Receptor Mutation: A Case Report. Cell Rep Med 2020; 1: 100006 doi: 10.1016/j.xcrm.2020.100006
    CrossrefPubMedGoogle Scholar