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.
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Kirwan, P., Kay, R., Brouwers, B., Herranz-Pérez, V., Jura, M., Larraufie, P., Jerber, J., et al. (2018). 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, 17 82-97. https://doi.org/10.1016/j.molmet.2018.08.006
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 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 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 beta-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl alpha-MSH (d-alpha-MSH) were produced in considerable excess of acetylated alpha-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 beta-MSH and suggest that in humans, d-alpha-MSH and beta-MSH are likely to be the predominant physiological products acting on melanocortin receptors.
Hypothalamus, Neurons, Pluripotent Stem Cells, Humans, Leptin, Pro-Opiomelanocortin, alpha-MSH, beta-MSH, Neuropeptides, Receptors, Melanocortin, Chromatography, Liquid, Homeostasis, Female, Male, Mass Spectrometry, Tandem Mass Spectrometry, Melanocortins
Wellcome Trust (100574/Z/12/Z)
WELLCOME TRUST (105602/Z/14/Z)
Academy of Medical Sciences (Springboard)
MEDICAL RESEARCH COUNCIL (MR/M009041/1)
MEDICAL RESEARCH COUNCIL (G0900554)
MEDICAL RESEARCH COUNCIL (MR/M024873/1)
External DOI: https://doi.org/10.1016/j.molmet.2018.08.006
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285059
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/