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

Peter Kirwan, Richard G. Kay, Bas Brouwers, Vicente Herranz-Pérez, Magdalena Jura, Pierre Larraufie, Julie Jerber, Jason Pembroke, Theresa Bartels, Anne White, Fiona M. Gribble, Frank Reimann, I. Sadaf Farooqi, Stephen O'Rahilly, Florian T. Merkle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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 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 β-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl α-MSH (d-α-MSH) were produced in considerable excess of acetylated α-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 α-MSH and suggest that in humans, d-α-MSH and β-MSH are likely to be the predominant physiological products acting on melanocortin receptors.

Original languageEnglish
Pages (from-to)82-97
Number of pages16
JournalMolecular Metabolism
Volume17
DOIs
Publication statusPublished - Nov 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Keywords

  • Human pluripotent stem cell
  • Leptin
  • MSH
  • Neuropeptide
  • Obesity
  • POMC

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this