Project B02 – Signaling dynamics of MC4R: development of advanced treatment strategies
The melanocortin 4 receptor (MC4R) is a key regulation of body weight. In the first funding period we could demonstrate that signaling dynamics towards Gq/11 activation is the driving factor for the hyperphagia-reducing effect of the peptidic unselective MC4R ligand setmelanotide in specific groups of patients. In close cooperation with A01 (Scheerer), A07 (Meiler), B01 (Beck-Sickinger) and Z03 we aim to identify new MC4R selective and Gq/11 pathway specific ligands. In addition a human hypothalamic cell system that resemble neurons of the nucleus paraventricularis will be established by differentiation from induced pluripotent stem cells. This new human cell model will allow us to investigate MC4R signaling dynamics under physiological conditions and to test newly identify MC4R ligands.
Melanocortin 4 receptor signaling revisited: from ligand/receptor interphase to signaling modulation
The melanocortin 4 receptor (MC4R) is a key G protein-coupled receptor (GPCR) in hypothalamic weight regulation. This project aims to achieve a comprehensive picture of MC4R signaling dynamics in the presence of various ligands. Research questions of this project are: (i) What are the determinants in the dynamic interplay between MC4R and different ligands (cooperation with A01 (Scheerer)); and which pathways are activated and how are they evolutionary conserved (cooperation with C04 (Prömel/Schöneberg)? (ii) Which MC4R pathways are required for satiety-induction (induced pluripotent stem cell (iPSC) approach) and which MC4R pathways have to be partially blocked to reduce side effects (cooperation with C03 (Annibale/Lohse))?
Contact
Nina Reininghaus (PhD Student)
Charité - University Medicine Berlin
Institute for Experimental Pediatric Endocrinology
Biomedical Research Center Forum 4, R. 1.0550
Augustenburger Platz 1, D-13353 Berlin
Frederike Höpfner (PhD Student, associated)
Charité - University Medicine Berlin
Institute for Experimental Pediatric Endocrinology
Biomedical Research Center Forum 4, R. 1.0550
Augustenburger Platz 1, D-13353 Berlin
Resources
- Characterization of (fluorophor-labeled) ligands at human iPSCs differentiated into hypothalamic neurons
Publications
Höpfner F, Paisdzior S, Reininghaus N, Sohail I, Scheerer P, Annibale P, Biebermann H, Kühnen P. Evaluation of Pharmacological Rescue of Melanocortin-4 Receptor Nonsense Mutations by Aminoglycoside. Life (Basel). 2022; 12:1793.
Kühnen P, Biebermann H, Wiegand S.Pharmacotherapy in Childhood Obesity. Horm Res Paediatr. 2022; 95:177-192.
Kühnen P, Clément K. Long-Term MC4R Agonist Treatment in POMC-Deficient Patients. N Engl J Med. 2022; 387:852-854.
Reininghaus N, Paisdzior S, Höpfner F, Jyrch S, Cetindag C, Scheerer P, Kühnen P, Biebermann H. A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation. Biomolecules. 2022 Aug 15;12(8):1119. doi: 10.3390/biom12081119. PMID: 36009013.
Graffunder AS, Paisdzior S, Opitz R, Renko K, Kühnen P, Biebermann H. Design and Characterization of a Fluorescent Reporter Enabling Live-cell Monitoring of MCT8 Expression. Exp Clin Endocrinol Diabetes. 2021 Aug 5. doi: 10.1055/a-1522-8535.
Heyder NA, Kleinau G, Speck D, Schmidt A, Paisdzior S, Szczepek M, Bauer B, Koch A, Gallandi M, Kwiatkowski D, Bürger J, Mielke T, Beck-Sickinger A, Hildebrand P, Spahn CMT, Hilger D, Schacherl M, Biebermann H, Hilal T, Kühnen P, Kobilka BK, Scheerer P. Structures of active melanocortin-4 receptor−Gs-protein complexes with NDP-α-MSH and setmelanotide. Cell Res. 2021; 31:1176-1189.
Heyder N, Kleinau G, Szczepek M, Kwiatkowski D, Speck D, Soletto L, Cerdá-Reverter JM, Krude H, Kühnen P, Biebermann H, Scheerer P. Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective. Front Endocrinol (Lausanne). 2019 Jul 31;10:515. doi: 10.3389/fendo.2019.00515. eCollection 2019. PMID: 31417496
Kühnen P, Wiegand S, Biebermann H. Pharmacological treatment strategies for patients with monogenic obesity. J Pediatr Endocrinol Metab. 2020; /j/jpem.ahead-of-print/jpem-2020-0129/jpem-2020-0129.xml. Epub ahead of print.
Paisdzior S, Dimitriou IM, Schöpe PC, Annibale P, Scheerer P, Krude H, Lohse MJ, Biebermann H, Kühnen P. Differential Signaling Profiles of MC4R Mutations with Three Different Ligands. Int J Mol Sci. 2020 Feb 12;21(4). pii: E1224. doi: 10.3390/ijms21041224. PMID: 32059383
Heyder N, Kleinau G, Szczepek M, Kwiatkowski D, Speck D, Soletto L, Cerdá-Reverter JM, Krude H, Kühnen P, Biebermann H, Scheerer P. Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective. Front Endocrinol (Lausanne). 2019; 10:515.
Kühnen P, Krude H, Biebermann H. Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment. Trends Mol Med. 2019; 25:136-48.
Clément K, Biebermann H, Farooqi IS, Van der Ploeg L, Wolters B, Poitou C, Puder L, Fiedorek F, Gottesdiener K, Kleinau G, Heyder N, Scheerer P, Blume-Peytavi U, Jahnke I, Sharma S, Mokrosinski J, Wiegand S, Müller A, Weiß K, Mai K, Spranger J, Grüters A, Blankenstein O, Krude H, Kühnen P. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24:551-5.
Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 2016; 375:240-6.
Kühnen P, Handke D, Waterland RA, Hennig BJ, Silver M, Fulford AJ, Dominguez-Salas P, Moore SE, Prentice AM, Spranger J, Hinney A, Hebebrand J, Heppner FL, Walzer L, Grötzinger C, Gromoll J, Wiegand S, Grüters A, Krude H. Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity. Cell metabolism. 2016; 24:502-9.
Hildebrand L, Rossbach B, Kühnen P, Gossen M, Kurtz A, Reinke P, Seemann P, Stachelscheid H. Generation of integration free induced pluripotent stem cells from fibrodysplasia ossificans progressiva (FOP) patients from urine samples. Stem Cell Res. 2016; 16:54-8.
Piechowski CL, Rediger A, Lagemann C, Mühlhaus J, Müller A, Pratzka J, Tarnow P, Grüters A, Krude H, Kleinau G, Biebermann H. Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2. J Mol Endocrinol. 2013; 51:109-18
Biebermann H, Kühnen P, Kleinau G, Krude H. The neuroendocrine circuitry controlled by POMC, MSH, and AGRP. Handb Exp Pharmacol. 2012; 209:47-75.
Biebermann H, Castañeda TR, van Landeghem F, von Deimling A, Escher F, Brabant G, Hebebrand J, Hinney A, Tschöp MH, Grüters A, Krude H. A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab. 2006; 3:141-6.
Biebermann H, Krude H, Elsner A, Chubanov V, Gudermann T, Grüters A. Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization. Diabetes. 2003; 52:2984-8.
Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998; 19:155-7.
