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Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

Peter Kirwan, Richard Kay, Bas Brouwers, Vicente Herranz-Perez, Magdalena Jura, Pierre Larraufie, Jason Pembroke, Theresa Bartels, Anne White, Fiona Gribble, Frank Reimann, I. Sadaf Farooqi, Stephen O’Rahilly, Florian T. Merkle
doi: https://doi.org/10.1101/257121
Peter Kirwan
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UKThe Anne McLaren Laboratory, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK
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Richard Kay
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
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Bas Brouwers
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UKThe Anne McLaren Laboratory, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK
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Vicente Herranz-Perez
Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, 46980 Valencia, SpainPredepartamental Unit of Medicine, Faculty of Health Sciences, Universitat Jaume I, 12071 Castelló de la Plana, Spain
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Magdalena Jura
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UKThe Anne McLaren Laboratory, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK
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Pierre Larraufie
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
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Jason Pembroke
LGC Ltd. Newmarket Road, Fordham, Cambridgeshire, CB7 5WW
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Theresa Bartels
The Anne McLaren Laboratory, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK
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Anne White
Faculty of Life Sciences, and Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, University of Manchester, Manchester, UK
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Fiona Gribble
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
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Frank Reimann
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
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I. Sadaf Farooqi
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
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Stephen O’Rahilly
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
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Florian T. Merkle
Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UKThe Anne McLaren Laboratory, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK
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  • For correspondence: fm436@medschl.cam.ac.uk
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ABSTRACT

Human obesity can result from the aberrant production or processing of proopiomelanocortin (POMC) in hypothalamic neurons, but it is unclear which human POMC-derived peptides are most relevant to body weight regulation. To address this question, we analysed both hypothalamic neurons derived from human pluripotent stem cells (hPSCs) and primary human hypothalamic tissue using quantitative liquid chromatography tandem mass spectroscopy (LC-MS/MS). In both in vitro- and in vivo-derived samples, we found that POMC was processed into β-melanocyte stimulating hormone (β-MSH), whose existence in the human brain has been controversial. β-MSH and desacetyl α-MSH (d-α-MSH) were produced at roughly equimolar concentrations and in vast excess to acetylated α-MSH (5-to 200-fold), suggesting that the importance of both d-α-MSH and β-MSH to human obesity has been underestimated. Since body weight is sensitive to changes in MSH concentration, we asked whether hPSC-derived hypothalamic neurons could provide mechanistic insights into the processing and secretion of MSH peptides. We found that cultured human hypothalamic neurons appropriately trafficked POMC and its derivatives, and robustly (P<0.0001) secreted them when depolarised. Furthermore, the adipocyte-derived hormone leptin significantly (P<0.01) promoted their production of both d-α-MSH and β-MSH. These results establish hPSC-derived hypothalamic neurons as a model system for studying human-specific aspects of POMC processing that might be therapeutically harnessed to treat obesity.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 31, 2018.
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Human POMC processing in vitro and in vivo revealed by quantitative peptidomics
Peter Kirwan, Richard Kay, Bas Brouwers, Vicente Herranz-Perez, Magdalena Jura, Pierre Larraufie, Jason Pembroke, Theresa Bartels, Anne White, Fiona Gribble, Frank Reimann, I. Sadaf Farooqi, Stephen O’Rahilly, Florian T. Merkle
bioRxiv 257121; doi: https://doi.org/10.1101/257121
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Human POMC processing in vitro and in vivo revealed by quantitative peptidomics
Peter Kirwan, Richard Kay, Bas Brouwers, Vicente Herranz-Perez, Magdalena Jura, Pierre Larraufie, Jason Pembroke, Theresa Bartels, Anne White, Fiona Gribble, Frank Reimann, I. Sadaf Farooqi, Stephen O’Rahilly, Florian T. Merkle
bioRxiv 257121; doi: https://doi.org/10.1101/257121

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