Quantitative mass spectrometry for human melanocortin peptides in vitro and in vivo suggests prominent roles for b-MSH and desacetyl a-MSH in energy homeostasis
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Other documents of the author: Kirwan, Peter; Kay, Richard G.; Brouwers, Bas; Herranz-Pérez, Vicente; Jura, Magdalena; Larraufie, Pierre; Jerber, Julie; Pembroke, Jason; Bartels, Theresa; White, Anne; Gribble, Fiona M.; Reimann, Frank; Farooqi, I. Sadaf; O’Rahilly, Stephen; Merkle, Florian
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Title
Quantitative mass spectrometry for human melanocortin peptides in vitro and in vivo suggests prominent roles for b-MSH and desacetyl a-MSH in energy homeostasisAuthor (s)
Date
2018Publisher
ElsevierISSN
2212-8778Bibliographic citation
KIRWAN, Peter, et al. Quantitative mass spectrometry for human melanocortin peptides in vitro and in vivo suggests prominent roles for β-MSH and desacetyl α-MSH in energy homeostasis. Molecular metabolism, 2018, vol. 17, p. 82-97.Type
info:eu-repo/semantics/articlePublisher version
https://www.sciencedirect.com/science/article/pii/S2212877818305325#!Version
info:eu-repo/semantics/publishedVersionSubject
Abstract
Objective: The lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both
humans and rodents that is treatable with synthetic melanocortins. However, there ... [+]
Objective: The lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both
humans and rodents that is treatable with synthetic melanocortins. However, there are significant differences in POMC processing between
humans and rodents, and little is known about the relative physiological importance of POMC products in the human brain. The aim of this study
was to determine which POMC-derived peptides are present in the human brain, to establish their relative concentrations, and to test if their
production is dynamically regulated.
Methods: We analysed both fresh post-mortem human hypothalamic tissue and hypothalamic neurons derived from human pluripotent stem
cells (hPSCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine the sequence and quantify the production of
hypothalamic neuropeptides, including those derived from POMC.
Results: In both in vitro and in vivo hypothalamic cells, LC-MS/MS revealed the sequence of hundreds of neuropeptides as a resource for the
field. Although the existence of b-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl a-MSH
(d-a-MSH) were produced in considerable excess of acetylated a-MSH. In hPSC-derived hypothalamic neurons, these POMC derivatives were
appropriately trafficked, secreted, and their production was significantly (P < 0.0001) increased in response to the hormone leptin.
Conclusions: Our findings challenge the assumed pre-eminence of a-MSH and suggest that in humans, d-a-MSH and b-MSH are likely to be
the predominant physiological products acting on melanocortin receptors. [-]
Is part of
Molecular Metabolism, Volume 17, November 2018.Investigation project
SBF001\1016 ; MR/P501967/1 ; MR/M009041/1 ; 4050281695 ; MC UU 12012/3 ; MC UU 12012/5 ; 106262/Z/14/Z ; 106263/Z/14/Z ; PSAG/097 ; PROMETEOII/2014/075 ; OTAR0039 ; RD16/0011/0026Rights
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